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Sample records for cardiomyopathy mutations affect

  1. The Mutations Associated with Dilated Cardiomyopathy

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    Ruti Parvari

    2012-01-01

    Full Text Available Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM. The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes.

  2. Inherited cardiomyopathies caused by troponin mutations

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    Qun-Wei Lu; Xiao-Yan Wu; Sachio Morimoto

    2013-01-01

    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.

  3. MT-CYB mutations in hypertrophic cardiomyopathy

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    Hagen, Christian M; Aidt, Frederik H; Havndrup, Ole

    2013-01-01

    Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT-CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT-CYB mutations might play an important...... and m.15482T>C; p.S246P were identified. Modeling showed that the p.C93Y mutation leads to disruption of the tertiary structure of Cytb by helix displacement, interfering with protein-heme interaction. The p.S246P mutation induces a diproline structure, which alters local secondary structure and induces...... of HCM patients. We propose that further patients with HCM should be examined for mutations in MT-CYB in order to clarify the role of these variants....

  4. How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance

    NARCIS (Netherlands)

    Germans, T.; Russel, I.K.; Gotte, M.J.W.; Spreeuwenberg, M.D.; Doevendans, P.A.; Pinto, Y.M.; van der Geest, R.J.; van der Velden, J.; Wilde, A.A.M.; van Rossum, A.C.

    2010-01-01

    ABSTRACT: BACKGROUND: Clinical data on myocardial function in HCM mutation carriers (carriers) is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormali

  5. How do hypertrophic cardiomyopathy mutations affect myocardial function in carriers with normal wall thickness? Assessment with cardiovascular magnetic resonance

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    Pinto Yigal M

    2010-03-01

    Full Text Available Abstract Background Clinical data on myocardial function in HCM mutation carriers (carriers is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormalities using cardiovascular magnetic resonance (CMR, and to investigate if sensitive functional assessment could be employed to identify carriers. Results 28 carriers and 28 controls were studied. Global left atrial (LA and left ventricular (LV dimensions, segmental peak systolic circumferential strain (SCS and peak diastolic circumferential strain rate (DCSR, as well as the presence of late Gadolinium enhancement (LGE were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. lv mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio was larger in carriers than in controls (1.3 ± 0.2 versus 1.1 ± 0.1, p 1.2 and a peak DCSR -1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio 105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR. Conclusions HCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.

  6. Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy

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    van Spaendonck-Zwarts, Karin Y.; Posafalvi, Anna; van den Berg, Maarten P.; Hilfiker-Kleiner, Denise; Bollen, Ilse A. E.; Sliwa, Karen; Alders, Marielle; AlMomani, Rowida; van Langen, Irene M.; van der Meer, Peter; Sinke, Richard J.; van der Velden, Jolanda; Van Veldhuisen, Dirk J.; van Tintelen, J. Peter; Jongbloed, Jan D. H.

    2014-01-01

    Aim Peripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM. Methods and results We collected 18 families with PPCM and DCM cases from various countries. We studied th

  7. Subtle abnormalities in contractile function are an early manifestation of sarcomere mutations in dilated cardiomyopathy

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    Lakdawala, Neal K; Thune, Jens J; Colan, Steven D;

    2012-01-01

    Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere ...

  8. A novel mitochondrial tRNA gene mutation in a chinese family with dilated cardiomyopathy and sensorineural deafness

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    Xianghong Wu; Xiumei Xie; Guotian Ma; Guoju Sun; Xiaobin Chen

    2006-01-01

    Objective: To determine whether a mutation of mitochondrial DNA induces familial dilated cardiomyopathy in Chinese families with cardiomyopathy, and analyzed the correlation between the genotype and phenotype. Methods: Affected members in three Chinese families of the familial dilated cardiomyopathy underwent clinical evaluation and DNA analysis. Polymerase chain reaction and direct DNA sequencing were used to screen for mitochondrial DNA mutation. The type of mtDNA vairations and clinical situation were analysed on the patients with mitochondrial DNA mutation. Results: The mitochondrial A3434G mutation was identified in one of the three families,the 3434 th nucleotide A was replaced by G, which led to change of amino acid. No mutations were identified in the clinically unaffected members of the family and all members of the other two families.Conclusion: This study indicates that the mitochondrial A3434G mutation maybe related with familial dilated cardiomyopathy and deafness.

  9. Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation

    NARCIS (Netherlands)

    T.L. Lynch (Thomas L.); M. Sivaguru (Mayandi); M. Velayutham (Murugesan); A.J. Cardounel (Arturo J.); M. Michels (Michelle); D. Barefield (David); S. Govindan (Suresh); C.D. Remedios (Cristobal Dos); J. van der Velden (Jolanda); S. Sadayappan (Sakthivel)

    2015-01-01

    textabstractCardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopa

  10. Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation

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    Thomas L. Lynch

    2015-01-01

    Full Text Available Cardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C. However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopathies has not been elucidated. To determine whether oxidative stress markers were elevated in MYBPC3-mutated cardiomyopathies, a previously characterized 3-month-old mouse model of dilated cardiomyopathy (DCM expressing a homozygous MYBPC3 mutation (cMyBP-C(t/t was used, compared to wild-type (WT mice. Echocardiography confirmed decreased percentage of fractional shortening in DCM versus WT hearts. Histopathological analysis indicated a significant increase in myocardial disarray and fibrosis while the second harmonic generation imaging revealed disorganized sarcomeric structure and myocyte damage in DCM hearts when compared to WT hearts. Intriguingly, DCM mouse heart homogenates had decreased glutathione (GSH/GSSG ratio and increased protein carbonyl and lipid malondialdehyde content compared to WT heart homogenates, consistent with elevated oxidative stress. Importantly, a similar result was observed in human cardiomyopathy heart homogenate samples. These results were further supported by reduced signals for mitochondrial semiquinone radicals and Fe-S clusters in DCM mouse hearts measured using electron paramagnetic resonance spectroscopy. In conclusion, we demonstrate elevated oxidative stress in MYPBC3-mutated DCM mice, which may exacerbate the development of heart failure.

  11. A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy

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    Biagi Diogo G

    2012-01-01

    Full Text Available Abstract Background Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy. Results We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (FKBP12 and FKBP12.6. No missense variant was found. Five no-coding variations were found but not related to the disease. Conclusions These data corroborate other studies suggesting that mutations in FKBP12 and FKBP12.6 genes are not commonly related to cardiac diseases.

  12. Nesprin-1 mutations in human and murine cardiomyopathy

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    Puckelwartz, Megan J.; Kessler, Eric J.; Kim, Gene; DeWitt, Megan M.; Zhang, Yuan; Earley, Judy U.; Depreux, Frederic F.S.; Holaska, James; Mewborn, Stephanie K.; Pytel, Peter; McNally, Elizabeth M.

    2009-01-01

    Mutations in LMNA, the gene encoding the nuclear membrane proteins, lamins A and C, produce cardiac and muscle disease. In the heart, these autosomal dominant LMNA mutations lead to cardiomyopathy frequently associated with cardiac conduction system disease. Herein, we describe a patient with the R374H missense variant in nesprin-1α, a protein that binds lamin A/C. This individual developed dilated cardiomyopathy requiring cardiac transplantation. Fibroblasts from this individual had increased expression of nesprin-1α and lamins A and C, indicating changes in the nuclear membrane complex. We characterized mice lacking the carboxy-terminus of nesprin-1 since this model expresses nesprin-1 without its carboxy-terminal KASH domain. These Δ/Δ KASH mice have a normally assembled but dysfunctional nuclear membrane complex and provide a model for nesprin-1 mutations. We found that Δ/Δ KASH mice develop cardiomyopathy with associated cardiac conduction system disease. Older mutant animals were found to have elongated P wave duration, elevated atrial and ventricular effective refractory periods indicating conduction defects in the myocardium, and reduced fractional shortening. Cardiomyocyte nuclei were found to be elongated with reduced heterochromatin in the Δ/Δ KASH hearts. These findings mirror what has been described from lamin A/C gene mutations and reinforce the importance of an intact nuclear membrane complex for a normally functioning heart. PMID:19944109

  13. Cardiac troponin T mutations in Chinese patients with hypertrophic cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    吴恒芳; 杨笛; 万文辉; 卞智萍; 徐晋丹; 马文珠; 张寄南

    2004-01-01

    @@ Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by unexplained ventricular hypertrophy and myofibrillar disarray, with a prevalence of about 0.2% in general population. HCM is associated with gene abnormalities. Nearly 200 mutations have been described in ten genes in patients with HCM.1 Cardiac troponin T (cTnT) is an essential component of the troponin complex and plays a central role in the calcium regulation of contractions in cardiac myocytes

  14. A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity

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    Paal Skytt Andersen

    2012-01-01

    Full Text Available Hypertrophic cardiomyopathy (HCM is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm, a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm. Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset.

  15. Lamin A/C mutation affecting primarily the right side of the heart

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    Laura Ollila

    2013-04-01

    Full Text Available LMNA mutations are amongst the most important causes of familial dilated cardiomyopathy. The most important cause of arrhythmogenic right ventricular cardiomyopathy (ARVC is desmosomal pathology. The aim of the study was to elucidate the role of LMNA mutations among Finnish cardiomyopathy patients. We screened 135 unrelated cardiomyopathy patients for LMNA mutations. Because of unusual phenotype, two patients were screened for the known Finnish ARVC-related mutations of desmosomal genes, and their Plakophilin-2b gene was sequenced. Myocardial samples from two patients were examined by immunohistochemical plakoglobin staining and in one case by electron microscopy. We found a new LMNA mutation Phe237Ser in a family of five affected members with a cardiomyopathy affecting primarily the right side of the heart. The phenotype resembles ARVC but does not fulfill the Task Force Criteria. The main clinical manifestations of the mutation were severe tricuspid insufficiency, right ventricular enlargement and failure. Three of the affected patients died of the heart disease, and the two living patients received heart transplants at ages 44 and 47. Electron microscopy showed nuclear blebbing compatible with laminopathy. Immunohisto - chemical analysis did not suggest desmosomal pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes a phenotype different from traditional cardiolaminopathy. Our findings suggest that cardiomyopathy affecting primarily the right side of the heart is not always caused by desmosomal pathology. Our observations highlight the challenges in classifying cardiomyopathies, as there often is significant overlap between the traditional categories.

  16. Hypertrophic Cardiomyopathy: How do Mutations Lead to Disease?

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    Marsiglia, Júlia Daher Carneiro, E-mail: julia.marsiglia@usp.br; Pereira, Alexandre Costa [Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-03-15

    Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease's genotype correlates with phenotype.

  17. Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.

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    Caleshu, Colleen; Sakhuja, Rahul; Nussbaum, Robert L; Schiller, Nelson B; Ursell, Philip C; Eng, Celeste; De Marco, Teresa; McGlothlin, Dana; Burchard, Esteban González; Rame, J Eduardo

    2011-09-01

    Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

  18. Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins.

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    Bang, Marie-Louise

    2017-01-01

    The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc.

  19. The Nonlinear Structure of the Desmoplakin Plakin Domain and the Effects of Cardiomyopathy-Linked Mutations

    NARCIS (Netherlands)

    C. Al-Jassar; T. Knowles; M. Jeeves; K. Kami; E. Behr; H. Bikker; M. Overduin; M. Chidgey

    2011-01-01

    Desmoplakin is a cytoplasmic desmosomal protein that plays a vital role in normal intercellular adhesion. Mutations in desmoplakin can result in devastating skin blistering diseases and arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder associated with ventricular arrhythmias,

  20. Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.

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    Reinstein, Eyal; Orvin, Katia; Tayeb-Fligelman, Einav; Stiebel-Kalish, Hadas; Tzur, Shay; Pimienta, Allen L; Bazak, Lily; Bengal, Tuvia; Cohen, Lior; Gaton, Dan D; Bormans, Concetta; Landau, Meytal; Kornowski, Ran; Shohat, Mordechai; Behar, Doron M

    2015-04-01

    We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.

  1. Early onset cardiomyopathy associated with the mitochondrial tRNALeu((UUR)) 3271T>C MELAS mutation.

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    Brisca, Giacomo; Fiorillo, Chiara; Nesti, Claudia; Trucco, Federica; Derchi, Maria; Andaloro, Antonio; Assereto, Stefania; Morcaldi, Guido; Pedemonte, Marina; Minetti, Carlo; Santorelli, Filippo M; Bruno, Claudio

    2015-03-13

    Mitochondrial disorders are a heterogeneous group of diseases sharing a defect of the oxidative phosphorylation system. Point mutations in the mitochondrial DNA are a common cause of mitochondrial disorders and frequently affect the sequences encoding mitochondrial transfer RNAs. The m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) is traditionally reported in patients with clinical features of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and in mitochondrial diabetes. Here we describe the clinical, pathological, and molecular features of an Italian child and his asymptomatic mother, carrying the m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) gene, in association with an unusual clinical phenotype dominated by hypertrophic cardiomyopathy and provide review literature of cases with this mutation. To the best of our knowledge, there are no reports describing the association of this mutation with cardiomyopathy, and our cases suggest that the m.3271T>C mutation has to be taken into account in the diagnostic approach of maternally inherited cardiomyopathies.

  2. Recurrent and founder mutations in the Netherlands : mutation p.K217del in troponin T2, causing dilated cardiomyopathy

    NARCIS (Netherlands)

    Otten, E.; Deprez, R. H. Lekanne Dit; Weiss, M. M.; van Slegtenhorst, M.; Joosten, M.; van der Smagt, J. J.; Kerstjens-Frederikse, W. S.; Roofthooft, M. T. R.; Balk, A. H. M. M.; van den Berg, M. P.; van Tintelen, J. P.; Ruiter, J.S.; de Jonge, N.

    2010-01-01

    Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lanain A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall pheno

  3. Tafazzin gene mutations are uncommon causes of dilated cardiomyopathy in adults

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    Matthew Taylor

    2011-07-01

    Full Text Available Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and dilated cardiomyopathy in boys due to tafazzin (TAZ mutations. Pure dilated cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in dilated cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with dilated cardiomyopathy (209 male and 83 female probands for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu. The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with dilated cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in dilated cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.

  4. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

    NARCIS (Netherlands)

    Bhonsale, Aditya; Groeneweg, Judith A.; James, Cynthia A.; Dooijes, Dennis; Tichnell, Crystal; Jongbloed, Jan D. H.; Murray, Brittney; Riele, Anneline S. J. M. te; van den Berg, Maarten P.; Bikker, Hennie; Atsma, Douwe E.; de Groot, Natasja M.; Houweling, Arjan C.; van der Heijden, Jeroen F.; Russell, Stuart D.; Doevendans, Pieter A.; van Veen, Toon A.; Tandri, Harikrishna; Wilde, Arthur A.; Judge, Daniel P.; van Tintelen, J. Peter; Calkins, Hugh; Hauer, Richard N.

    2015-01-01

    AIMS: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers. METHODS AND RESULTS: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in

  5. Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy

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    Lakdawala, Neal K; Thune, Jens Jakob; Maron, Barry J

    2011-01-01

    In hypertrophic cardiomyopathy (HC), electrocardiographic (ECG) changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when left ventricular (LV) wall thickness is still normal. However, the ECG features of mutation carriers have not been fully ch...

  6. Electrocardiographic features of sarcomere mutation carriers with and without clinically overt hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Lakdawala, Neal K; Thune, Jens Jakob; Maron, Barry J;

    2011-01-01

    In hypertrophic cardiomyopathy (HC), electrocardiographic (ECG) changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when left ventricular (LV) wall thickness is still normal. However, the ECG features of mutation carriers have not been fully...

  7. Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis

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    Rasmussen, Torsten B; Nissen, Peter H; Palmfeldt, Johan;

    2014-01-01

    BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The disease is most often caused by mutations in the desmosomal gene for plakophilin-2 (PKP2), which is expressed in both myocardial...... individuals. It was evident that PKP2 mutations introducing a premature termination codon in the reading frame were associated with PKP2 transcript and protein levels reduced to ≈50%, whereas a missense variant did not seem to affect the amount of PKP2 protein. CONCLUSIONS: The results of this study showed...

  8. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.

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    Klauke, Baerbel; Kossmann, Sabine; Gaertner, Anna; Brand, Kristina; Stork, Ines; Brodehl, Andreas; Dieding, Mareike; Walhorn, Volker; Anselmetti, Dario; Gerdes, Désirée; Bohms, Birte; Schulz, Uwe; Zu Knyphausen, Edzard; Vorgerd, Matthias; Gummert, Jan; Milting, Hendrik

    2010-12-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we found disease-associated sequence variants. In addition, we screened for desmin mutations and found a novel desmin-mutation p.N116S in a patient with ARVC and terminal heart failure, which is located in segment 1A of the desmin rod domain. The mutation leads to the aggresome formation in cardiac and skeletal muscle without signs of an overt clinical myopathy. Cardiac aggresomes appear to be prominent, especially in the right ventricle of the heart. Viscosimetry and atomic force microscopy of the desmin wild-type and N116S mutant isolated from recombinant Escherichia coli revealed severe impairment of the filament formation, which was supported by transfections in SW13 cells. Thus, the gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients.

  9. Mutation analysis of the phospholamban gene in 315 South Africans with dilated, hypertrophic, peripartum and arrhythmogenic right ventricular cardiomyopathies.

    Science.gov (United States)

    Fish, Maryam; Shaboodien, Gasnat; Kraus, Sarah; Sliwa, Karen; Seidman, Christine E; Burke, Michael A; Crotti, Lia; Schwartz, Peter J; Mayosi, Bongani M

    2016-02-26

    Cardiomyopathy is an important cause of heart failure in Sub-Saharan Africa, accounting for up to 30% of adult heart failure hospitalisations. This high prevalence poses a challenge in societies without access to resources and interventions essential for disease management. Over 80 genes have been implicated as a cause of cardiomyopathy. Mutations in the phospholamban (PLN) gene are associated with dilated cardiomyopathy (DCM) and severe heart failure. In Africa, the prevalence of PLN mutations in cardiomyopathy patients is unknown. Our aim was to screen 315 patients with arrhythmogenic right ventricular cardiomyopathy (n = 111), DCM (n = 95), hypertrophic cardiomyopathy (n = 40) and peripartum cardiomyopathy (n = 69) for disease-causing PLN mutations by high resolution melt analysis and DNA sequencing. We detected the previously reported PLN c.25C > T (p.R9C) mutation in a South African family with severe autosomal dominant DCM. Haplotype analysis revealed that this mutation occurred against a different haplotype background to that of the original North American family and was therefore unlikely to have been inherited from a common ancestor. No other mutations in PLN were detected (mutation prevalence = 0.2%). We conclude that PLN is a rare cause of cardiomyopathy in African patients. The PLN p.R9C mutation is not well-tolerated, emphasising the importance of this gene in cardiac function.

  10. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene

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    Lehrke Stephanie

    2008-10-01

    Full Text Available Abstract Background Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM and may also lead to dilated cardiomyopathy (DCM. MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations. Methods 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded. Results In 16 HCM (18.4% and two DCM (2.8% index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2% had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1% suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families. Conclusion MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.

  11. A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.

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    Houman Ashrafian

    2010-06-01

    Full Text Available Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM. However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.

  12. Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy

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    Rajkumar Revathi

    2012-03-01

    Full Text Available Abstract Background The Ser358Leu mutation in TMEM43, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC. The pathogenetic mechanisms of this mutation are poorly understood. Methods To determine the frequency of TMEM43 mutations as a cause of ARVC, we screened 11 ARVC families for mutations in TMEM43 and five desmosomal genes previously implicated in the disease. Functional studies were performed in COS-7 cells transfected with wildtype, mutant, and 1:2 wildtype:mutant TMEM43 to determine the effect of the Ser358Leu mutation on the stability and cellular localization of TMEM43 and other nuclear envelope and desmosomal proteins, assessed by solubility assays and immunofluorescence imaging. mRNA expression was assessed of genes potentially affected by dysfunction of the nuclear lamina. Results Three novel mutations in previously documented desmosomal genes, but no mutations in TMEM43, were identified. COS-7 cells transfected with mutant TMEM43 exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant TMEM43 did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies. Conclusions Mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of TMEM43 mutations in ARVC remains uncertain.

  13. The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Daniel Vega; Andersen, Paal Skytt; Hedley, Paula

    2009-01-01

    We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently...... by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found...

  14. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy

    DEFF Research Database (Denmark)

    Christensen, A H; Andersen, C B; Tybjærg-Hansen, A;

    2011-01-01

    Christensen AH, Andersen CB, Tybjærg-Hansen A, Haunso S, Svendsen JH. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. A single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right...... with anti-TMEM43, anti-plakoglobin, anti-plakophilin-2, anti-connexin-43, and anti-emerin antibodies was performed on myocardium from TMEM43-positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T...

  15. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Zou, Yubao; Wang, Jizheng; Liu, Xuan; Wang, Yilu; Chen, Yi; Sun, Kai; Gao, Shuo; Zhang, Channa; Wang, Zhimin; Zhang, Yin; Feng, Xinxing; Song, Ying; Wu, Yajie; Zhang, Hongju; Jia, Lei; Wang, Hu; Wang, Dong; Yan, Chaowu; Lu, Minjie; Zhou, Xianliang; Song, Lei; Hui, Rutai

    2013-06-01

    Genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM) has been challenging because of the genetic and clinical heterogeneity. To determine the mutation profile of Chinese patients with HCM and to correlate genotypes with phenotypes, we performed a systematic mutation screening of the eight most commonly mutated genes encoding sarcomere proteins in 200 unrelated Chinese adult patients using direct DNA sequencing. A total of 98 mutations were identified in 102 mutation carriers. The frequency of mutations in MYH7, MYBPC3, TNNT2 and TNNI3 was 26.0, 18.0, 4.0 and 3.5 % respectively. Among the 200 genotyped HCM patients, 83 harbored a single mutation, and 19 (9.5 %) harbored multiple mutations. The number of mutations was positively correlated with the maximum wall thickness. We found that neither particular gene nor specific mutation was correlated to clinical phenotype. In summary, the frequency of multiple mutations was greater in Chinese HCM patients than in the Caucasian population. Multiple mutations in sarcomere protein may be a risk factor for left ventricular wall thickness.

  16. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

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    Damien Galant

    2016-04-01

    Full Text Available ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD, Progeria or Mandibulo-Acral Dysplasia (MAD. We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

  17. A mutation in the {beta}-myosin rod associated with hypertrophic cardiomyopathy has an unexpected molecular phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Armel, Thomas Z. [Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309 (United States); Leinwand, Leslie A., E-mail: leslie.leinwand@colorado.edu [Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309 (United States)

    2010-01-01

    Hypertrophic cardiomyopathy (HCM) is a common, autosomal dominant disorder primarily characterized by left ventricular hypertrophy and is the leading cause of sudden cardiac death in youth. HCM is caused by mutations in several sarcomeric proteins, with mutations in MYH7, encoding {beta}-MyHC, being the most common. While many mutations in the globular head region of the protein have been reported and studied, analysis of HCM-causing mutations in the {beta}-MyHC rod domain has not yet been reported. To address this question, we performed an array of biochemical and biophysical assays to determine how the HCM-causing E1356K mutation affects the structure, stability, and function of the {beta}-MyHC rod. Surprisingly, the E1356K mutation appears to thermodynamically destabilize the protein, rather than alter the charge profile know to be essential for muscle filament assembly. This thermodynamic instability appears to be responsible for the decreased ability of the protein to form filaments and may be responsible for the HCM phenotype seen in patients.

  18. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy

    DEFF Research Database (Denmark)

    Arndt, Anne-Karin; Schafer, Sebastian; Drenckhahn, Jorg-Detlef

    2013-01-01

    Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction...... cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription...... of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM....

  19. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

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    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  20. Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Ho, Carolyn Y; Carlsen, Christian; Thune, Jens Jakob;

    2009-01-01

    preclinical (G+/LVH-), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (-) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (epsilon(sys)) and longitudinal systolic strain rate were not significantly......BACKGROUND: Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy...... (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear. METHODS AND RESULTS: Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68...

  1. Targeting Mitogen-Activated Protein Kinase Signaling in Mouse Models of Cardiomyopathy Caused by Lamin A/C Gene Mutations.

    Science.gov (United States)

    Muchir, Antoine; Worman, Howard J

    2016-01-01

    The most frequently occurring mutations in the gene encoding nuclear lamin A and nuclear lamin C cause striated muscle diseases virtually always involving the heart. In this review, we describe the approaches and methods used to discover that cardiomyopathy-causing lamin A/C gene mutations increase MAP kinase signaling in the heart and that this plays a role in disease pathogenesis. We review different mouse models of cardiomyopathy caused by lamin A/C gene mutations and how transcriptomic analysis of one model identified increased cardiac activity of the ERK1/2, JNK, and p38α MAP kinases. We describe methods used to measure the activity of these MAP kinases in mouse hearts and then discuss preclinical treatment protocols using pharmacological inhibitors to demonstrate their role in pathogenesis. Several of these kinase inhibitors are in clinical development and could potentially be used to treat human subjects with cardiomyopathy caused by lamin A/C gene mutations.

  2. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy

    NARCIS (Netherlands)

    Karakikes, Ioannis; Stillitano, Francesca; Nonnenmacher, Mathieu; Tzimas, Christos; Sanoudou, Despina; Termglinchan, Vittavat; Kong, Chi-Wing; Rushing, Stephanie; Hansen, Jens; Ceholski, Delaine; Kolokathis, Fotis; Kremastinos, Dimitrios; Katoulis, Alexandros; Ren, Lihuan; Cohen, Ninette; Gho, Johannes M. I. H.; Tsiapras, Dimitrios; Vink, Aryan; Wu, Joseph C.; Asselbergs, Folkert W.; Li, Ronald A.; Hulot, Jean-Sebastien; Kranias, Evangelia G.; Hajjar, Roger J.

    2015-01-01

    A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias. Here we generate i

  3. Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy

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    Peuhkurinen Keijo

    2011-06-01

    Full Text Available Abstract Background The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM with cardiovascular magnetic resonance (CMR. We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. Methods Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV myocardium were visually estimated. Results Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. Conclusions Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.

  4. Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation

    Science.gov (United States)

    Hwang, Ji-won; Jang, Mi-Ae; Jang, Shin Yi; Seo, Soo Hyun; Seong, Moon-Woo; Park, Sung Sup; Ki, Chang-Seok

    2017-01-01

    Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies.

  5. Co segregation of the m.1555A>G mutation in the MT-RNR1 gene and mutations in MT-ATP6 gene in a family with dilated mitochondrial cardiomyopathy and hearing loss: A whole mitochondrial genome screening.

    Science.gov (United States)

    Alila-Fersi, Olfa; Chamkha, Imen; Majdoub, Imen; Gargouri, Lamia; Mkaouar-Rebai, Emna; Tabebi, Mouna; Tlili, Abdelaziz; Keskes, Leila; Mahfoudh, Abdelmajid; Fakhfakh, Faiza

    2017-02-26

    Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to dysfunction of the mitochondrial respiratory chain, which is responsible for the generation of most cellular energy. Because cardiac muscles are one of the high energy demanding tissues, mitochondrial cardiomyopathies is one of the most frequent mitochondria disorders. Mitochondrial cardiomyopathy has been associated with several point mutations of mtDNA in both genes encoded mitochondrial proteins and mitochondrial tRNA and rRNA. We reported here the first description of mutations in MT-ATP6 gene in two patients with clinical features of dilated mitochondrial cardiomyopathy. The mutational analysis of the whole mitochondrial DNA revealed the presence of m.1555A>G mutation in MT-RNR1 gene associated to the m.8527A>G (p.M>V) and the m.8392C>T (p.136P>S) variations in the mitochondrial MT-ATP6 gene in patient1 and his family members with variable phenotype including hearing impairment. The second patient with isolated mitochondrial cardiomyopathy presented the m.8605C>T (p.27P>S) mutation in the MT-ATP6 gene. The three mutations p.M1V, p.P27S and p.P136S detected in MT-ATP6 affected well conserved residues of the mitochondrial protein ATPase 6. In addition, the substitution of proline residue at position 27 and 136 effect hydrophobicity and structure flexibility conformation of the protein.

  6. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

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    Dirk J Lefeber

    2011-12-01

    Full Text Available Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years with a predominant presentation of dilated cardiomyopathy (DCM. Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG. Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

  7. A Scandinavian case of skin fragility, alopecia and cardiomyopathy caused by DSP mutations.

    Science.gov (United States)

    Vahlquist, A; Virtanen, M; Hellström-Pigg, M; Dragomir, A; Ryberg, K; Wilson, N J; Östman--Smith, I; Lu, L; McGrath, J A; Smith, F J D

    2014-01-01

    Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.

  8. Evaluation of the flanking nucleotide sequences of sarcomeric hypertrophic cardiomyopathy substitution mutations.

    Science.gov (United States)

    Meurs, Kathryn M; Mealey, Katrina L

    2008-07-03

    Hypertrophic cardiomyopathy (HCM) is a familial myocardial disease with a prevalence of 1 in 500. More than 400 causative mutations have been identified in 13 sarcomeric and myofilament related genes, 350 of these are substitution mutations within eight sarcomeric genes. Within a population, examples of recurring identical disease causing mutations that appear to have arisen independently have been noted as well as those that appear to have been inherited from a common ancestor. The large number of novel HCM mutations could suggest a mechanism of increased mutability within the sarcomeric genes. The objective of this study was to evaluate the most commonly reported HCM genes, beta myosin heavy chain (MYH7), myosin binding protein C, troponin I, troponin T, cardiac regulatory myosin light chain, cardiac essential myosin light chain, alpha tropomyosin and cardiac alpha-actin for sequence patterns surrounding the substitution mutations that may suggest a mechanism of increased mutability. The mutations as well as the 10 flanking nucleotides were evaluated for frequency of di-, tri- and tetranucleotides containing the mutation as well as for the presence of certain tri- and tetranculeotide motifs. The most common substitutions were guanine (G) to adenine (A) and cytosine (C) to thymidine (T). The CG dinucleotide had a significantly higher relative mutability than any other dinucleotide (pmutation was calculated; none were at a statistically higher frequency than the others. The large number of G to A and C to T mutations as well as the relative mutability of CG may suggest that deamination of methylated CpG is an important mechanism for mutation development in at least some of these cardiac genes.

  9. Combination of Whole Genome Sequencing, Linkage and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy with Features of Left Ventricular Non-Compaction

    Science.gov (United States)

    Hooper, Charlotte; Ormondroyd, Liz; Pagnamenta, Alistair; Lise, Stefano; Salatino, Silvia; Knight, Samantha JL; Taylor, Jenny C.; Thomson, Kate L.; Arnold, Linda; Chatziefthimiou, Spyros D.; Konarev, Petr V.; Wilmanns, Matthias; Ehler, Elisabeth; Ghisleni, Andrea; Gautel, Mathias; Blair, Edward; Watkins, Hugh; Gehmlich, Katja

    2016-01-01

    Background High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease amongst the eight surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterised in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small angle X-ray scattering and circular dichroism spectroscopy suggest partial unfolding and domain destabilisation in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Conclusions Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left-ventricular non-compaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left un-interpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. PMID:27625337

  10. How mutation affects evolutionary games on graphs.

    Science.gov (United States)

    Allen, Benjamin; Traulsen, Arne; Tarnita, Corina E; Nowak, Martin A

    2012-04-21

    Evolutionary dynamics are affected by population structure, mutation rates and update rules. Spatial or network structure facilitates the clustering of strategies, which represents a mechanism for the evolution of cooperation. Mutation dilutes this effect. Here we analyze how mutation influences evolutionary clustering on graphs. We introduce new mathematical methods to evolutionary game theory, specifically the analysis of coalescing random walks via generating functions. These techniques allow us to derive exact identity-by-descent (IBD) probabilities, which characterize spatial assortment on lattices and Cayley trees. From these IBD probabilities we obtain exact conditions for the evolution of cooperation and other game strategies, showing the dual effects of graph topology and mutation rate. High mutation rates diminish the clustering of cooperators, hindering their evolutionary success. Our model can represent either genetic evolution with mutation, or social imitation processes with random strategy exploration.

  11. Sporadic myopathy, myoclonus, leukoencephalopathy, neurosensory deafness, hypertrophic cardiomyopathy and insulin resistance associated with the mitochondrial 8306 T>C MTTK mutation.

    Science.gov (United States)

    Cardaioli, Elena; Malfatti, Edoardo; Battisti, Carla; Da Pozzo, Paola; Rubegni, Anna; Gallus, Gian Nicola; Malandrini, Alessandro; Federico, Antonio

    2012-10-15

    We report a new T8306C transition in the D-stem of the MTTK gene of a 67-year-old man who manifested severe adult onset myopathy, myoclonus, leukoencephalopathy, neurosensory hypoacusis, hypertrophic cardiomyopathy and insulin resistance. No other family member was affected, suggesting that our patient was a sporadic case. The T8306C mutation was heteroplasmic in several tissues of the proband, while it was absent from his asymptomatic siblings. Single fibre analysis confirmed the segregation of higher mutational load in cytochrome c oxidase-deficient fibres. The mutation T8306C is predicted to disrupt a highly conserved base pair and was not found in more than 120 controls. This finding broadens the phenotypic and molecular spectrum of mitochondrial tRNA(Lys) associated disorders.

  12. An Indian family with an Emery-Dreifuss myopathy and familial dilated cardiomyopathy due to a novel LMNA mutation

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    Khushal B Jadhav

    2012-01-01

    Full Text Available Emery-Dreifuss myopathy can be associated with a cardiomyopathy and cardiac dysrhythmias. The inheritance pattern of Emery-Dreifuss muscular dystrophy (EDMD is X linked, whereas EDMD2 is autosomal dominant. EDMD2 is caused by lamin A/C gene (LMNA mutations that produce alterations in the lamin proteins that are integral to nuclear and cell integrity. A 53-year-old man was brought to us with a right internal carotid artery dissection. Detailed work-up of the patient and family members revealed some unusual features, and genetic sequencing of the LMNA gene was undertaken. A novel mutation was identified in two of the samples sent for analysis. We present the first Indian family of EDMD2 with familial dilated cardiomyopathy and cardiac dysrhythmias in whom LMNA gene sequencing was performed. A novel mutation was identified and additional unusual clinical features were described.

  13. An in silico analysis of troponin I mutations in hypertrophic cardiomyopathy of Indian origin.

    Directory of Open Access Journals (Sweden)

    Gayatri Ramachandran

    Full Text Available Hypertrophic Cardiomyopathy (HCM is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD. Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T, is an important gene for sarcomeric function. Four mutations (1 novel were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382. The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.

  14. The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Mezghani, Najla [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Mnif, Mouna [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Mkaouar-Rebai, Emna, E-mail: emna_mkaouar@mail2world.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Kallel, Nozha [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Salem, Ikhlass Haj [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Charfi, Nadia; Abid, Mohamed [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

    2011-07-29

    Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

  15. Myocardial structural alteration and systolic dysfunction in preclinical hypertrophic cardiomyopathy mutation carriers.

    Directory of Open Access Journals (Sweden)

    Kai Hang Yiu

    Full Text Available BACKGROUND: To evaluate the presence of myocardial structural alterations and subtle myocardial dysfunction during familial screening in asymptomatic mutation carriers without hypertrophic cardiomyopathy (HCM phenotype. METHODS AND FINDINGS: Sixteen HCM families with pathogenic mutation were studied and 46 patients with phenotype expression (Mut+/Phen+ and 47 patients without phenotype expression (Mut+/Phen- were observed. Twenty-five control subjects, matched with the Mut+/Phen- group, were recruited for comparison. Echocardiography was performed to evaluate conventional parameters, myocardial structural alteration by calibrated integrated backscatter (cIBS and global and segmental longitudinal strain by speckle tracking analysis. All 3 groups had similar left ventricular dimensions and ejection fraction. Basal anteroseptal cIBS was the highest in Mut+/Phen+ patients (-14.0±4.6 dB, p-19.0 dB basal anteroseptal cIBS or >-18.0% basal anteroseptal longitudinal strain had a sensitivity of 98% and a specificity of 72% in differentiating Mut+/Phen- group from controls. CONCLUSION: The use of cIBS and segmental longitudinal strain can differentiate HCM Mut+/Phen- patients from controls with important clinical implications for the family screening and follow-up of these patients.

  16. R25G mutation in exon 1 of LMNA gene is associated with dilated cardiomyopathy and limb-girdle muscular dystrophy 1B

    Institute of Scientific and Technical Information of China (English)

    YUAN Wo-liang; HUANG Wei-jun; HUANG Chun-yan; WANG Jing-feng; XIE Shuang-lun; NIE Ru-qiong; LIU Ying-mei; LIU Pin-ming; ZHOU Shu-xian; CHEN Su-qin

    2009-01-01

    Background Mutations of the LMNA gene encoding lamin A and C are associated with dilated cardiomyopathy (DCM), conduction system defects and skeletal muscle dystrophy. Here we report a family with a mutation of the LMNA gene to identify the relationship between genotype and phenotype.Methods All 30 members of the family underwent clinical and genetic evaluation. A mutation analysis of the LMNA gene was performed. All of the 12 exons of LMNA gene were extended with polymerase chain reaction (PCR) and the PCR products were screened for gene mutation by direct sequencing.Results Ten members of the family had limb-girdle muscular dystrophy (LGMD) and 6 are still alive. Two patients suffered from DCM. Cardiac arrhythmias included atrioventricular block and atrial fibrillation; sudden death occurred in 2 patients. The pattern of inheritance was autosomal dominant. Mutation c.73C>G (R25G) in exon 1 encoding the globular domains was confirmed in all of the affected members, resulting in the conversion of arginine (Arg) to glycine (Gly). Conclusions The mutation R25G in exon 1 of LMNA gene we reported here in a Chinese family had a phenotype of malignant arrhythmia and mild LGMD, suggesting that patients with familial DCM, conduction system defects and skeletal muscle dystrophy should be screened by genetic testing for the LMNA gene.

  17. Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness

    Directory of Open Access Journals (Sweden)

    Marcus Tim J

    2011-01-01

    Full Text Available Abstract Background Increased left ventricular (LV torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM, and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness. Methods Seventeen carriers with an LV wall thickness Results LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively. Conclusions Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.

  18. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika

    2012-11-15

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  19. A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic: a case report

    Directory of Open Access Journals (Sweden)

    Zagal Ahmad

    2010-04-01

    Full Text Available Abstract Congenital disorders of glycosylation (CDG are an expanding group of inherited metabolic diseases with multisystem involvement. ALG6-CDG (CDGIc is an endoplasmatic reticulum defect in N-glycan assembly. It is usually milder than PMM2-CDG (CDG-Ia and so is its natural course. It is characterized by psychomotor retardation, seizures, ataxia, and hypotonia. In contrast to PMM2-CDG (CDGIa, there is no cerebellar hypoplasia. Cardiomyopathy has been reported in a few CDG types and in a number of patients with unexplained CDG. We report an 11 year old Saudi boy with severe psychomotor retardation, seizures, strabismus, inverted nipples, dilated cardiomyopathy, and a type 1 pattern of serum transferrin isoelectrofocusing. Phosphomannomutase and phosphomannose isomerase activities were normal in fibroblasts. Full gene sequencing of the ALG6 gene revealed a novel mutation namely c.482A>G (p.Y161C and heterozygosity in the parents. This report highlights the importance to consider CDG in the differential diagnosis of unexplained cardiomyopathy.

  20. Haplotype sharing test maps genes for familial cardiomyopathies

    NARCIS (Netherlands)

    van der Zwaag, P. A.; van Tintelen, J. P.; Gerbens, F.; Jongbloed, J. D. H.; Boven, L. G.; van der Smagt, J. J.; van der Roest, W. P.; van Langen, I. M.; Bikker, H.; Hauer, R. N. W.; van den Berg, M. P.; Hofstra, R. M. W.; te Meerman, Gerhardus

    2011-01-01

    Identifying a mutation in a heterogeneous disease such as inherited cardiomyopathy is a challenge because classical methods, like linkage analysis, can often not be applied as there are too few meioses between affected individuals. However, if affected individuals share the same causal mutation, the

  1. Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Mireia Alcalde

    Full Text Available BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC. METHODS AND RESULTS: Thirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2. Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology. CONCLUSIONS: Familial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides.

  2. Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM.

    Science.gov (United States)

    Selvi Rani, Deepa; Nallari, Pratibha; Dhandapany, Perundurai S; Rani, Jhansi; Meraj, Khunza; Ganesan, Mala; Narasimhan, Calambur; Thangaraj, Kumarasamy

    2015-05-01

    Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases-patient #1, aged 44, and patient #2, aged 65-and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. Interestingly, two novel thick filaments, D896N (homozygous) and I524K (heterozygous) mutations, in the MYH7 gene were identified exclusively in patient #1 and his family members. Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM).

  3. Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene, OCTN2.

    Science.gov (United States)

    Xiaofei, E; Wada, Yasuhiko; Dakeishi, Miwako; Hirasawa, Fujiko; Murata, Katsuyuki; Masuda, Hirotake; Sugiyama, Toshihiro; Nikaido, Hiroko; Koizumi, Akio

    2002-07-01

    The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.

  4. Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children.

    Science.gov (United States)

    Mayr, Johannes A; Zimmermann, Franz A; Horváth, Rita; Schneider, Hans-Christian; Schoser, Benedikt; Holinski-Feder, Elke; Czermin, Birgit; Freisinger, Peter; Sperl, Wolfgang

    2011-11-01

    In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia. One child died in infancy, two survived a clinically severe neonatal period. At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development. In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased. This protein is expressed in two tissue-specific isoforms generated by mutually exclusive alternative splicing of the SLC25A3 gene transcript. We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele.

  5. A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy.

    Science.gov (United States)

    Lopez-Ayala, J M; Ortiz-Genga, M; Gomez-Milanes, I; Lopez-Cuenca, D; Ruiz-Espejo, F; Sanchez-Munoz, J J; Oliva-Sandoval, M J; Monserrat, L; Gimeno, J R

    2015-08-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.

  6. Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy mutation carriers: The patients' perspective

    NARCIS (Netherlands)

    Christiaans, Imke; Van Langen, Irene M.; Birnie, Erwin; Bonsel, Gouke J.; Wilde, Arthur A. M.; Smets, Ellen M. A.

    2009-01-01

    Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with sudden cardiac death. Predictive genetic counseling and testing are performed using adapted Huntington guidelines, that is, psychosocial care and time for reflection are not obligatory and the test result can be d

  7. Obtaining insurance after DNA diagnostics : A survey among hypertrophic cardiomyopathy mutation carriers

    NARCIS (Netherlands)

    Christiaans, Imke; Kok, Tjitske M.; Van Langen, Irene M.; Birnie, Erwin; Bonsel, Gouke J.; Wilde, Arthur A. M.; Smets, Ellen M. A.

    2010-01-01

    Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with increased mortality. Disclosure of DNA test results may have social implications such as low access to insurance. In the Netherlands, insurance companies are restricted in the use of genetic information of their c

  8. Mitochondrial 12S Ribosomal RNA A1555G Mutation Associated with Cardiomyopathy and Hearing Loss following High-Dose Chemotherapy and Repeated Aminoglycoside Exposure

    DEFF Research Database (Denmark)

    Skou, Anne-Sofie; Tranebjærg, Lisbeth; Jensen, Tim;

    2014-01-01

    A 19-month-old girl with the A1555G mitochondrial mutation in the 12S ribosomal RNA gene and acute myelogenous leukemia developed dilated cardiomyopathy and bilateral sensorineural hearing loss before undergoing allogeneic stem cell transplantation. She had received gentamicin during episodes of ...

  9. Genotype-phenotype correlation between the cardiac myosin binding protein C mutation A31P and hypertrophic cardiomyopathy in a cohort of Maine Coon cats

    DEFF Research Database (Denmark)

    Granström, S; Godiksen, M T N; Christiansen, M;

    2015-01-01

    OBJECTIVES: A missense mutation (A31P) in the cardiac myosin binding protein C gene has been associated with hypertrophic cardiomyopathy (HCM) in Maine Coon cats. The aim of this study was to investigate the effect of A31P on development of HCM, myocardial diastolic dysfunction detected by color ...

  10. Peripartum cardiomyopathy presenting with syncope due to Torsades de pointes: a case of long QT syndrome with a novel KCNH2 mutation.

    Science.gov (United States)

    Nishimoto, Orie; Matsuda, Morihiro; Nakamoto, Kei; Nishiyama, Hirohiko; Kuraoka, Kazuya; Taniyama, Kiyomi; Tamura, Ritsu; Shimizu, Wataru; Kawamoto, Toshiharu

    2012-01-01

    Peripartum cardiomyopathy (PPCM) is a cardiomyopathy of unknown cause that occurs in the peripartum period. We report a case of PPCM presenting with syncope 1 month after an uncomplicated delivery. Electrocardiography showed Torsades de pointes (TdP) and QT interval prolongation. Echocardiography showed left ventricular systolic dysfunction and endomyocardial biopsy showed myocyte degeneration and fibrosis. Administration of magnesium sulfate and temporary pacing eliminated recurrent TdP. Genetic analyses revealed that recurrent TdP occurred via electrolyte disturbance and cardiac failure due to PPCM on the basis of a novel mutation in KCNH2, a gene responsible for inherited type 2 long QT syndrome.

  11. Interaction between Hsp60 and Bax in normal human myocardium and in myocardium affected by dilated cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Tykhonkova I. O.

    2009-04-01

    Full Text Available The main functional compartments of molecular chaperone Hsp60 are mitochondria and cytoplasm. Up to 30 % of Hsp60 are located in cytoplasm of cardiomyocytes. The interaction between molecular chaperone Hsp60 and proapoptotic Bax protein in the cytoplasmic fraction from normal human heart tissue has been revealed by co-immunoprecipitation in contrast to myocardium affected by dilated cardiomyopathy, where this interaction has not been observed

  12. Mutations affecting gyrase in Haemophilus influenzae

    Energy Technology Data Exchange (ETDEWEB)

    Setlow, J.K.; Cabrera-Juarez, E.; Albritton, W.L.; Spikes, D.; Mutschler, A.

    1985-11-01

    Mutants separately resistant to novobiocin, coumermycin, nalidixic acid, and oxolinic acid contained gyrase activity as measured in vitro that was resistant to the antibiotics, indicating that the mutations represented structural alterations of the enzyme. One Novr mutant contained an altered B subunit of the enzyme, as judged by the ability of a plasmid, pNov1, containing the mutation to complement a temperature-sensitive gyrase B mutation in Escherichia coli and to cause novobiocin resistance in that strain. Three other Novr mutations did not confer antibiotic resistance to the gyrase but appeared to increase the amount of active enzyme in the cell. One of these, novB1, could only act in cis, whereas a new mutation, novC, could act in trans. An RNA polymerase mutation partially substituted for the novB1 mutation, suggesting that novB1 may be a mutation in a promoter region for the B subunit gene. Growth responses of strains containing various combinations of mutations on plasmids or on the chromosome indicated that low-level resistance to novobiocin or coumermycin may have resulted from multiple copies of wild-type genes coding for the gyrase B subunit, whereas high-level resistance required a structural change in the gyrase B gene and was also dependent on alteration in a regulatory region. When there was mismatch at the novB locus, with the novB1 mutation either on a plasmid or the chromosome, and the corresponding wild-type gene present in trans, chromosome to plasmid recombination during transformation was much higher than when the genes matched, probably because plasmid to chromosome recombination, eliminating the plasmid, was inhibited by the mismatch.

  13. Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members

    DEFF Research Database (Denmark)

    Saberniak, Jørg; Hasselberg, Nina E; Borgquist, Rasmus;

    2014-01-01

    patients and 45 mutation-positive family members. Athletes were defined as subjects with ≥4 h vigorous exercise/week [≥1440 metabolic equivalents (METs × minutes/week)] during a minimum of 6 years. Athlete definition was fulfilled in 37/110 (34%) subjects. We assessed right ventricular (RV) and left......AIMS: Exercise increases risk of ventricular arrhythmia in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed to investigate the impact of exercise on myocardial function in ARVC subjects. METHODS AND RESULTS: We included 110 subjects (age 42 ± 17 years), 65 ARVC...... family members (47 ± 3% vs. 52 ± 6%, P 

  14. One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region

    DEFF Research Database (Denmark)

    Hougs, Lotte; Havndrup, Ole; Bundgaard, Henning

    2005-01-01

    -causing mutations were identified in the rod region in four probands using capillary electrophoresis single-strand conformation polymorphism as a screening method. All mutations were novel: N1327K, R1712W, and E1753K. Two of the probands had already been shown to carry other FHC-associated mutations. In conclusion...

  15. Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

    Science.gov (United States)

    Fleming, Jennifer R.; Anderson, Brian R.; Williams, Rhys; Franke, Barbara; Bullard, Belinda; Granzier, Henk

    2016-01-01

    Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected. PMID:27683155

  16. Knock-in Mice Harboring a Ca2+ Desensitizing Mutation in Cardiac Troponin C Develop Early Onset Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Bradley K McConnell

    2015-08-01

    Full Text Available The physiological consequences of aberrant Ca2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was twelve weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction and fractional shortening, were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM. In conclusion, our results suggest that decreasing Ca2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

  17. Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

    Energy Technology Data Exchange (ETDEWEB)

    Sipola, Petri [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); University of Eastern Finland, Institute of Clinical Medicine, Faculty of Health Sciences, Kuopio (Finland); Magga, Jarkko; Peuhkurinen, Keijo [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Husso, Minna [Kuopio University Hospital, Department of Clinical Radiology, Kuopio (Finland); Jaeaeskelaeinen, Pertti; Kuusisto, Johanna [Kuopio University Hospital, Department of Medicine, Kuopio (Finland); Kuopio University Hospital, Heart Center, P.O. Box 1777, Kuopio (Finland)

    2011-07-15

    To evaluate the value of cardiac magnetic resonance imaging (CMRI)-assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the {alpha}-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness {>=}17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis. (orig.)

  18. Dilated Cardiomyopathy Mutation (R134W) in Mouse Cardiac Troponin T Induces Greater Contractile Deficits against α-Myosin Heavy Chain than against β-Myosin Heavy Chain

    OpenAIRE

    Gollapudi, Sampath K.; Murali Chandra

    2016-01-01

    Many studies have demonstrated that depressed myofilament Ca2+ sensitivity is common to dilated cardiomyopathy (DCM) in humans. However, it remains unclear whether a single determinant — such as myofilament Ca2+ sensitivity — is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms...

  19. Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study

    Science.gov (United States)

    Mattos, Beatriz Piva e; Scolari, Fernando Luís; Torres, Marco Antonio Rodrigues; Simon, Laura; de Freitas, Valéria Centeno; Giugliani, Roberto; Matte, Úrsula

    2016-01-01

    Background: Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. Objective: To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations. Methods: Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families. Results: Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals. Conclusions: In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation. PMID:27737317

  20. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms

    DEFF Research Database (Denmark)

    Rasmussen, T B; Hansen, Jakob; Nissen, P H;

    2013-01-01

    identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans....

  1. Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.

    Science.gov (United States)

    Baertling, Fabian; A M van den Brand, Mariel; Hertecant, Jozef L; Al-Shamsi, Aisha; P van den Heuvel, Lambert; Distelmaier, Felix; Mayatepek, Ertan; Smeitink, Jan A; Nijtmans, Leo G J; Rodenburg, Richard J T

    2015-01-01

    COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.

  2. A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy

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    Mohammad A. Alqahtani

    2015-01-01

    Full Text Available Congenital adrenal hyperplasia (CAH due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260∗, resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260∗ was reported in a patient with papillary thyroid cancer (COSMIC database. In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

  3. Peripartum cardiomyopathy: a review.

    Science.gov (United States)

    Bhattacharyya, Anirban; Basra, Sukhdeep Singh; Sen, Priyanka; Kar, Biswajit

    2012-01-01

    Peripartum cardiomyopathy is idiopathic heart failure occurring in the absence of any determinable heart disease during the last month of pregnancy or the first 5 months postpartum. The incidence varies worldwide but is high in developing nations; the cause of the disease might be a combination of environmental and genetic factors. Diagnostic echocardiographic criteria include left ventricular ejection fraction 2.7 cm/m(2). Electrocardiography, magnetic resonance imaging, endomyocardial biopsy, and cardiac catheterization aid in the diagnosis and management of peripartum cardiomyopathy. Cardiac protein assays can also be useful, as suggested by reports of high levels of NT-proBNP, cardiac troponin, tumor necrosis factor-α, interleukin-6, interferon-γ, and C-reactive protein in peripartum cardiomyopathy. The prevalence of mutations associated with familial dilated-cardiomyopathy genes in patients with peripartum cardiomyopathy suggests an overlap in the clinical spectrum of these 2 diseases.Treatment for peripartum cardiomyopathy includes conventional pharmacologic heart-failure therapies-principally diuretics, angiotensin-converting enzyme inhibitors, vasodilators, digoxin, β-blockers, anticoagulants, and peripartum cardiomyopathy-targeted therapies. Therapeutic decisions are influenced by drug-safety profiles during pregnancy and lactation. Mechanical support and transplantation might be necessary in severe cases. Targeted therapies (such as intravenous immunoglobulin, pentoxifylline, and bromocriptine) have shown promise in small trials but require further evaluation. Fortunately, despite a mortality rate of up to 10% and a high risk of relapse in subsequent pregnancies, many patients with peripartum cardiomyopathy recover within 3 to 6 months of disease onset.

  4. Cardiomyopathy-related mutation (A30V) in mouse cardiac troponin T divergently alters the magnitude of stretch activation in α- and β-myosin heavy chain fibers.

    Science.gov (United States)

    Mickelson, Alexis V; Gollapudi, Sampath K; Chandra, Murali

    2017-01-01

    The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation A28V in cardiac troponin T (TnT). The A28V mutation is located within the NH2 terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the functional effect of the NH2 terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms. Recombinant wild-type mouse TnT (TnTWT) and the mouse equivalent of the human A28V mutation (TnTA30V) were reconstituted into detergent-skinned cardiac muscle fibers extracted from normal (α-MHC) and transgenic (β-MHC) mice. Dynamic and steady-state contractile parameters were measured in reconstituted muscle fibers. Step-like length perturbation experiments demonstrated that TnTA30V decreased the magnitude of the muscle length-mediated recruitment of new force-bearing cross bridges (ER) by 30% in α-MHC fibers. In sharp contrast, TnTA30V increased ER by 55% in β-MHC fibers. Inferences drawn from other dynamic contractile parameters suggest that directional changes in ER in TnTA30V + α-MHC and TnTA30V + β-MHC fibers result from a divergent impact on cross bridge-regulatory unit (troponin-tropomyosin complex) cooperativity. TnTA30V-mediated effects on Ca(2+)-activated maximal tension and instantaneous muscle fiber stiffness (ED) were also divergently affected by α- and β-MHC. Our study demonstrates that TnTA30V + α-MHC and TnTA30V + β-MHC fibers show contrasting contractile phenotypes; however, only the observations from β-MHC fibers are consistent with the clinical data for A28V in humans.

  5. MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    Distelmaier, F.; Haack, T.B.; Catarino, C.B.; Gallenmuller, C.; Rodenburg, R.J.T.; Strom, T.M.; Baertling, F.; Meitinger, T.; Mayatepek, E.; Prokisch, H.; Klopstock, T.

    2015-01-01

    Defects in mitochondrial translation may lead to combined respiratory chain deficiency and typically cause childhood-onset multisystem disease. Only recently, a homozygous missense mutation (c.467T > G, p.Leu156Arg) in MRPL44, encoding a protein of the large subunit of the mitochondrial ribosome,

  6. A Systematic Review of Phenotypic Features Associated With Cardiac Troponin I Mutations in Hereditary Cardiomyopathies

    DEFF Research Database (Denmark)

    Mogensen, Jens; Hey, Thomas; Lambrecht, Sascha

    2015-01-01

    , before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype). METHODS: We reviewed the literature...

  7. A Mitochondrial DNA A8701G Mutation Associated with Maternally Inherited Hypertension and Dilated Cardiomyopathy in a Chinese Pedigree of a Consanguineous Marriage

    Institute of Scientific and Technical Information of China (English)

    Ye Zhu; Xiang Gu; Chao Xu

    2016-01-01

    Background: Cardiovascular diseases, including dilated cardiomyopathy (DCM) and hypertension, are the leading cause of death worldwide.The role of mitochondrial DNA (mtDNA) in the pathogenesis of these diseases has not been completely clarified.In this study, we evaluate whether A8701G mutation is associated with maternally inherited hypertension and DCM in a Chinese pedigree of a consanguineous marriage.Methods: Fourteen subjects in a three-generation Han Chinese family with hypertension and DCM, in which consanguineous marriage was present in the parental generation, were interviewed.We divided all the family members into case (7 maternal members) and control group (7 nonmaternal members) for comparison.Clinical evaluations and sequence analysis ofmtDNA were obtained from all participants.Frequency differences between maternal and nonmaternal members were tested to locate the disease-associated mutations.Results: The majority of the family members presented with a maternal inheritance of hypertension and DCM.Sequence analysis of mtDNA in this pedigree identified eight mtDNA mutations.Among the mutations identified, there was only one significant mutation: A8701G (P =0.005), which is a homoplasmic mitochondrial missense mutation in all the matrilineal relatives.There was no clear evidence for any synergistic effects between A8701G and other mutations.Conclusions: A8701G mutation may act as an inherited risk factor for the matrilineal transmission of hypertension and DCM in conj unction with genetic disorders caused by consanguineous marriage.

  8. Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

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    Muchir, Antoine, E-mail: a.muchir@institut-myologie.org [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Wu, Wei [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Sera, Fusako; Homma, Shunichi [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Worman, Howard J., E-mail: hjw14@columbia.edu [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY (United States)

    2014-10-03

    Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left

  9. Large-scale mapping of mutations affecting zebrafish development

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    Neuhauss Stephan C

    2007-01-01

    Full Text Available Abstract Background Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. Results We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. Conclusion By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations.

  10. Clinical significance of genetic mutation in hypertrophic cardiomyopathy%肥厚型心肌病基因突变的临床意义

    Institute of Scientific and Technical Information of China (English)

    张咏梅; 董林波

    2011-01-01

    Hypertrophic cardiomyopathy (HCM) is a primary cardiac disorder characterized by the thickening of myocardi -al, especially thickening of the left ventricular wall, fiber hypertrophy and arrangement of myocardial, and it is one of the most common cause of sudden death in the young and athletes. This disease is usually inherited as a Mendelian autosomal dominant trait. There are cardiac sarcomere gene mutations, mitochondrial DNA mutations and modifying gene mutations, more than 900 types of mutations, related to the progress and clinical phenotype of HCM. This review has focused on the correlations between HCM genetic mutation and progression and clinical phenotype of HCM in recent years.%肥厚型心肌病(hypertrophic cardiomyopathy,HCM)是以心肌肥厚尤其是左心室不对称性心肌肥厚、心肌纤维肥大、排列紊乱为病理特征的原发性心肌病,是目前年轻人和运动员常见的猝死原因之一.目前HCM通常被认为是一种基因突变所导致的常染色体疾病,呈显性遗传.最近研究发现心脏肌节蛋白基因以及相关的线粒体基因与修饰基因的基因突变,超过900种不同的基因突变类型与HCM发生发展以及临床表型有关.本文主要就近年来关于HCM常见的基因突变与其临床意义的研究作一综述.

  11. Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

    Science.gov (United States)

    Ablorh, Naa-Adjeley D.; Thomas, David D.

    2015-01-01

    We review the recent development of novel biochemical and spectroscopic methods to determine the site-specific phosphorylation, expression, mutation, and structural dynamics of phospholamban (PLB), in relation to its function (inhibition of the cardiac calcium pump, SERCA2a), with specific focus on cardiac physiology, pathology, and therapy. In the cardiomyocyte, SERCA2a actively transports Ca2+ into the sarcoplasmic reticulum (SR) during relaxation (diastole) to create the concentration gradient that drives the passive efflux of Ca2+ required for cardiac contraction (systole). Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes the structure of PLB to relieve SERCA2a inhibition. Because insufficient SERCA2a activity is a hallmark of heart failure, SERCA2a activation (by gene therapy (Andino et al. 2008; Fish et al. 2013; Hoshijima et al. 2002; Jessup et al. 2011) or drug therapy (Ferrandi et al. 2013; Huang 2013; Khan et al. 2009; Rocchetti et al. 2008; Zhang et al. 2012)) is a widely sought goal for treatment of heart failure. This review describes rational approaches to this goal. Novel biophysical assays, using site-directed labeling and high-resolution spectroscopy, have been developed to resolve the structural states of SERCA2a-PLB complexes in vitro and in living cells. Novel biochemical assays, using synthetic standards and multidimensional immunofluorescence, have been developed to quantitate PLB expression and phosphorylation states in cells and human tissues. The biochemical and biophysical properties of U-PLB, P-PLB, and mutant PLB will ultimately resolve the mechanisms of loss of inhibition and gain of inhibition to guide therapeutic development. These assays will be powerful tools for investigating human tissue samples from the Sydney Heart Bank, for the purpose of analyzing and diagnosing specific disorders. PMID:25774229

  12. Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation

    Science.gov (United States)

    Huang, Wei-Lin; Chou, Shih-Jie; Chang, Wei-Chao; Chang, Yuh-Lih; Leu, Hsin-Bang; Chen, Kuan-Hsuan; Wang, Kang-Ling; Lai, Ying-Hsiu; Liu, Yung-Yang; Lu, Kai-Hsi; Li, Hsin-Yang; Sung, Yen-Jen; Jong, Yuh-Jyh; Chen, Yann-Jang; Chen, Chung-Hsuan; Yu, Wen-Chung

    2016-01-01

    Rationale A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. Objective Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. Results and methods The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients’ sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. Conclusion Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation. PMID:27888626

  13. Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca(2+)-sensitivity and suppress the modulation of Ca(2+)-sensitivity by troponin I phosphorylation.

    Science.gov (United States)

    Messer, Andrew E; Bayliss, Christopher R; El-Mezgueldi, Mohammed; Redwood, Charles S; Ward, Douglas G; Leung, Man-Ching; Papadaki, Maria; Dos Remedios, Cristobal; Marston, Steven B

    2016-07-01

    We investigated the effect of 7 Hypertrophic Cardiomyopathy (HCM)-causing mutations in troponin T (TnT) on troponin function in thin filaments reconstituted with actin and human cardiac tropomyosin. We used the quantitative in vitro motility assay to study Ca(2+)-regulation of unloaded movement and its modulation by troponin I phosphorylation. Troponin from a patient with the K280N TnT mutation showed no difference in Ca(2+)-sensitivity when compared with donor heart troponin and the Ca(2+)-sensitivity was also independent of the troponin I phosphorylation level (uncoupled). The recombinant K280N TnT mutation increased Ca(2+)-sensitivity 1.7-fold and was also uncoupled. The R92Q TnT mutation in troponin from transgenic mouse increased Ca(2+)-sensitivity and was also completely uncoupled. Five TnT mutations (Δ14, Δ28 + 7, ΔE160, S179F and K273E) studied in recombinant troponin increased Ca(2+)-sensitivity and were all fully uncoupled. Thus, for HCM-causing mutations in TnT, Ca(2+)-sensitisation together with uncoupling in vitro is the usual response and both factors may contribute to the HCM phenotype. We also found that Epigallocatechin-3-gallate (EGCG) can restore coupling to all uncoupled HCM-causing TnT mutations. In fact the combination of Ca(2+)-desensitisation and re-coupling due to EGCG completely reverses both the abnormalities found in troponin with a TnT HCM mutation suggesting it may have therapeutic potential.

  14. Genetics Home Reference: familial restrictive cardiomyopathy

    Science.gov (United States)

    ... AV. Malignant and benign mutations in familial cardiomyopathies: insights into mutations linked to complex cardiovascular phenotypes. J ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  15. DNA analysis in inherited cardiomyopathies : Current status and clinical relevance

    NARCIS (Netherlands)

    Van Spaendonck-Zwarts, Karin Y.; Van den Berg, Maarten P.; Van Tintelen, J. Peter

    2008-01-01

    Most hypertrophic cardiomyopathies and a subset of dilated and arrhythmogenic right ventricular cardiomyopathies are familial diseases. They generally show an autosomal dominant pattern of inheritance and have underlying mutations in genes encoding sarcomeric, cytoskeletal, nuclear envelope, and des

  16. Prediction of disease-related mutations affecting protein localization

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    Laurila Kirsti

    2009-03-01

    Full Text Available Abstract Background Eukaryotic cells contain numerous compartments, which have different protein constituents. Proteins are typically directed to compartments by short peptide sequences that act as targeting signals. Translocation to the proper compartment allows a protein to form the necessary interactions with its partners and take part in biological networks such as signalling and metabolic pathways. If a protein is not transported to the correct intracellular compartment either the reaction performed or information carried by the protein does not reach the proper site, causing either inactivation of central reactions or misregulation of signalling cascades, or the mislocalized active protein has harmful effects by acting in the wrong place. Results Numerous methods have been developed to predict protein subcellular localization with quite high accuracy. We applied bioinformatics methods to investigate the effects of known disease-related mutations on protein targeting and localization by analyzing over 22,000 missense mutations in more than 1,500 proteins with two complementary prediction approaches. Several hundred putative localization affecting mutations were identified and investigated statistically. Conclusion Although alterations to localization signals are rare, these effects should be taken into account when analyzing the consequences of disease-related mutations.

  17. Connecting Sarcomere Protein Mutations to Pathogenesis in Cardiomyopathies: The Development of ‘Disease in a Dish’ Models

    Directory of Open Access Journals (Sweden)

    Rebecca Zaunbrecher

    2016-11-01

    Full Text Available Recent technological and protocol developments have greatly increased the ability to utilize stem cells transformed into cardiomyocytes as models to study human heart muscle development and how this is affected by disease associated mutations in a variety of sarcomere proteins. In this perspective we provide an overview of these emerging technologies and how they are being used to create better models of ‘disease in a dish’ for both research and screening assays. We also consider the value of these assays as models to explore the seminal processes in initiation of the disease development and the possibility of early interventions.

  18. The classical pink-eyed dilution mutation affects angiogenic responsiveness.

    Science.gov (United States)

    Rogers, Michael S; Boyartchuk, Victor; Rohan, Richard M; Birsner, Amy E; Dietrich, William F; D'Amato, Robert J

    2012-01-01

    Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis.

  19. The classical pink-eyed dilution mutation affects angiogenic responsiveness.

    Directory of Open Access Journals (Sweden)

    Michael S Rogers

    Full Text Available Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis.

  20. Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant.

    Science.gov (United States)

    Charif, Majida; Titah, Salah Mohamed Cherif; Roubertie, Agathe; Desquiret-Dumas, Valérie; Gueguen, Naig; Meunier, Isabelle; Leid, Jean; Massal, Frédéric; Zanlonghi, Xavier; Mercier, Jacques; Raynaud de Mauverger, Eric; Procaccio, Vincent; Mousson de Camaret, Bénédicte; Lenaers, Guy; Hamel, Christian P

    2015-10-01

    We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease.

  1. The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

    Energy Technology Data Exchange (ETDEWEB)

    Al-Saaidi, Rasha [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark); Rasmussen, Torsten B. [Department of Cardiology, Aarhus University Hospital, Aarhus (Denmark); Palmfeldt, Johan [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark); Nissen, Peter H. [Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus (Denmark); Beqqali, Abdelaziz [Heart Failure Research Center, Academic Medical Center, Amsterdam (Netherlands); Hansen, Jakob [Department of Forensic Medicine, Bioanalytical Unit, University of Aarhus (Denmark); Pinto, Yigal M. [Heart Failure Research Center, Academic Medical Center, Amsterdam (Netherlands); Boesen, Thomas [Department of Molecular Biology and Genetics, University of Aarhus (Denmark); Mogensen, Jens [Department of Cardiology, Odense University Hospital, Odense (Denmark); Bross, Peter, E-mail: peter.bross@ki.au.dk [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark)

    2013-11-15

    Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by cardiac chamber enlargement and reduced systolic function of the left ventricle. Mutations in the LMNA gene represent the most frequent known genetic cause of DCM associated with disease of the conduction systems. The LMNA gene generates two major transcripts encoding the nuclear lamina major components lamin A and lamin C by alternative splicing. Both haploinsuffiency and dominant negative effects have been proposed as disease mechanism for premature termination codon (PTC) mutations in LMNA. These mechanisms however are still not clearly established. In this study, we used a representative LMNA nonsense mutation, p.Arg321Ter, to shed light on the molecular disease mechanisms. Cultured fibroblasts from three DCM patients carrying this mutation were analyzed. Quantitative reverse transcriptase PCR and sequencing of these PCR products indicated that transcripts from the mutant allele were degraded by the nonsense-mediated mRNA decay (NMD) mechanism. The fact that no truncated mutant protein was detectable in western blot (WB) analysis strengthens the notion that the mutant transcript is efficiently degraded. Furthermore, WB analysis showed that the expression of lamin C protein was reduced by the expected approximately 50%. Clearly decreased lamin A and lamin C levels were also observed by immunofluorescence microscopy analysis. However, results from both WB and nano-liquid chromatography/mass spectrometry demonstrated that the levels of lamin A protein were more reduced suggesting an effect on expression of lamin A from the wild type allele. PCR analysis of the ratio of lamin A to lamin C transcripts showed unchanged relative amounts of lamin A transcript suggesting that the effect on the wild type allele was operative at the protein level. Immunofluorescence microscopy analysis showed no abnormal nuclear morphology of patient fibroblast cells. Based on these data, we propose that

  2. Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

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    Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

    2015-03-01

    We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

  3. Takotsubo cardiomyopathy associated with severe hypothyroidism in an elderly female

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    Jorge A Brenes-Salazar

    2016-01-01

    Full Text Available Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a syndrome that affects predominantly postmenopausal women. Despite multiple described mechanisms, intense, neuroadrenergic myocardial stimulation appears to be the main trigger. Hyperthyroidism, but rarely hypothyroidism, has been described in association with Takotsubo cardiomyopathy. Herein, we present a case of stress cardiomyopathy in the setting of symptomatic hypothyroidism.

  4. A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.

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    Rubattu, Speranza; Bozzao, Cristina; Pennacchini, Ermelinda; Pagannone, Erika; Musumeci, Beatrice Maria; Piane, Maria; Germani, Aldo; Savio, Camilla; Francia, Pietro; Volpe, Massimo; Autore, Camillo; Chessa, Luciana

    2016-07-30

    Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective.

  5. Mitochondrial DNA m.3242G > A mutation, an under diagnosed cause of hypertrophic cardiomyopathy and renal tubular dysfunction?

    NARCIS (Netherlands)

    Wortmann, S.B.; Champion, M.P.; Heuvel, L.P. van den; Barth, H.; Trutnau, B.; Craig, K.; Lammens, M.M.; Schreuder, M.F.; Taylor, R.W.; Smeitink, J.A.M.; Wevers, R.A.; Rodenburg, R.J.T.; Morava, E.

    2012-01-01

    We present two new patients with the recently described mitochondrial m.3242G > A mutation. Although the mutation is situated next to the well known m.3243A > G mutation, the most common alteration associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode

  6. Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy.

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    Kramer, Christopher M; Appelbaum, Evan; Desai, Milind Y; Desvigne-Nickens, Patrice; DiMarco, John P; Friedrich, Matthias G; Geller, Nancy; Heckler, Sarahfaye; Ho, Carolyn Y; Jerosch-Herold, Michael; Ivey, Elizabeth A; Keleti, Julianna; Kim, Dong-Yun; Kolm, Paul; Kwong, Raymond Y; Maron, Martin S; Schulz-Menger, Jeanette; Piechnik, Stefan; Watkins, Hugh; Weintraub, William S; Wu, Pan; Neubauer, Stefan

    2015-08-01

    Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.

  7. The subaortic tendon as a mimic of hypertrophic cardiomyopathy

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    Ker James

    2009-07-01

    Full Text Available Abstract Originally described by Brock and Teare, today hypertrophic cardiomyopathy is clinically defined as left (or right ventricular hypertrophy without a known cardiac or systemic cause, such as systemic hypertension, Fabry's disease or aortic stenosis. Also appreciated today is the enormous genotypic and phenotypic heterogeneity of this disease with more than 300 mutations over more than 24 genes, encoding various sarcomeric, mitochondrial and calcium-handling proteins, all as genetic causes for hypertrophic cardiomyopathy. Phenotypically, the disease can vary from negligible to extreme hypertrophy, affecting either the left and/or right ventricle in an apical, midventricular or subaortic location. Left ventricular false tendons are thin, fibrous or fibromuscular structures that traverse the left ventricular cavity. Recently, a case report was presented where it was shown that such a false tendon, originating from a subaortic location, was responsible for striking ST-segment elevation on the surface electrocardiogram. In this case report, a case is presented where such a subaortic tendon led to the classic echocardiographic appearance of hypertrophic cardiomyopathy, thus in the assessment of hypertrophic cardiomyopathy, this entity needs to be excluded in order to prevent a false positive diagnosis of hypertrophic cardiomyopathy.

  8. Dilated cardiomyopathy mutation (R134W in mouse cardiac troponin T induces greater contractile deficits against α-myosin heavy chain than against β-myosin heavy chain

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    Sampath K Gollapudi

    2016-10-01

    Full Text Available Many studies have demonstrated that depressed myofilament Ca2+ sensitivity is common to dilated cardiomyopathy (DCM in humans. However, it remains unclear whether a single determinant — such as myofilament Ca2+ sensitivity — is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms that underlie disparate effects of DCM mutations on cardiac phenotypes. Dynamic features are dominated by myofilament cooperativity that stem from different sources. One such source is the strong tropomyosin binding region in troponin T (TnT, which is known to modulate crossbridge (XB recruitment dynamics in a myosin heavy chain (MHC-dependent manner. Therefore, we hypothesized that the effects of DCM-linked mutations in TnT on contractile dynamics would be differently modulated by α- and β-MHC. After reconstitution with the mouse TnT equivalent (TnTR134W of the human DCM mutation (R131W, we measured dynamic contractile parameters in detergent-skinned cardiac muscle fiber bundles from normal (α-MHC and transgenic mice (β-MHC. TnTR134W significantly attenuated the rate constants of tension redevelopment, XB recruitment dynamics, XB distortion dynamics, and the magnitude of length-mediated XB recruitment only in α-MHC fiber bundles. TnTR134W decreased myofilament Ca2+ sensitivity to a greater extent in α-MHC (0.14 pCa units than in β-MHC fiber bundles (0.08 pCa units. Thus, our data demonstrate that TnTR134W induces a more severe DCM-like contractile phenotype against α-MHC than against β-MHC background.

  9. Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis

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    Xu, Zhenyan; Zhu, Wengen; Wang, Cen; Huang, Lin; Zhou, Qiongqiong; Hu, Jinzhu; Cheng, Xiaoshu; Hong, Kui

    2017-01-01

    The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1–3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1–3 leads and a strong family history of ARVC. PMID:28120905

  10. Importance of genetic evaluation and testing in pediatric cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Muhammad; Tariq; Stephanie; M; Ware

    2014-01-01

    Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders that are responsible for significant morbidity and mortality. Phenotypes include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction and arrhythmogenic right ventricular cardiomyopathy. There is substantial evidence for a genetic contribution to pediatric cardiomyopathy. To date, more than 100 genes have been implicated in cardiomyopathy, but comprehensive genetic diagnosis has been problematic because of the large number of genes, the private nature of mutations, and difficulties in interpreting novel rare variants. This review will focus on current knowledge on the genetic etiologies of pediatric cardiomyopathy and their diagnostic relevance in clinical settings. Recent developments in sequencing technologies are greatly impacting the pace of gene discovery and clinical diagnosis. Understanding the genetic basis for pediatric cardiomyopathy and establishing genotypephenotype correlations may help delineate the molecular and cellular events necessary to identify potential novel therapeutic targets for heart muscle dysfunction in children.

  11. Cardiomyopathy in becker muscular dystrophy:Overview

    Institute of Scientific and Technical Information of China (English)

    Rady Ho; My-Le Nguyen; Paul Mather

    2016-01-01

    Becker muscular dystrophy(BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.

  12. Comparative cardiac pathological changes of Atlantic salmon (Salmo salar L.) affected with heart and skeletal muscle inflammation (HSMI), cardiomyopathy syndrome (CMS) and pancreas disease (PD)

    DEFF Research Database (Denmark)

    Yousaf, Muhammad Naveed; Koppang, Erling Olaf; Skjødt, Karsten

    2013-01-01

    The heart is considered the powerhouse of the cardiovascular system. Heart and skeletal muscle inflammation (HSMI), cardiomyopathy syndrome (CMS) and pancreas disease (PD) are cardiac diseases of marine farmed Atlantic salmon (Salmo salar) which commonly affect the heart in addition to the skeletal......) and TUNEL, and moderate levels of caspase 3 immuno-reactivity suggested a high cell turnover where DNA damage/repair might be occurring in the diseased hearts. Interestingly, the apparently similar cardiac diseases exhibited differences in the immunopathological responses in Atlantic salmon....

  13. Peripartum cardiomyopathy: a review

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    Capriola M

    2012-12-01

    Full Text Available Michael CapriolaThomasville Medical Center, Department of Emergency Medicine, Thomasville Medical Center, Thomasville, NC, USAAbstract: Peripartum cardiomyopathy (PPCM is a form of dilated cardiomyopathy of unclear etiology affecting women without preexisting heart disease during the last month of pregnancy or during the first 5 months postpartum. Its incidence shows marked geographic and ethnic variation, being most common in Africa and among women of African descent. Most women present in the first month postpartum with typical heart failure symptoms such as dyspnea, lower extremity edema, and fatigue. These symptoms are often initially erroneously diagnosed as part of the normal puerperal process. Diagnosis can be aided by the finding of a significantly elevated serum brain natriuretic peptide. The etiology of PPCM is unclear; however, recent research suggests abnormal prolactin metabolism is seminal in its development, and prolactin antagonism with bromocriptine shows promise as a novel treatment for PPCM.Keywords: pregnancy, pregnancy complications, cardiovascular, cardiomyopathy, dilated

  14. Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy.

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    Mariotti, C; Tiranti, V; Carrara, F; Dallapiccola, B; DiDonato, S; Zeviani, M

    1994-01-01

    We studied the physiometabolic effects of a mitochondrial DNA (mtDNA) heteroplasmic point mutation, the A-->G3260 transition associated with maternally inherited myopathy and cardiomyopathy. To eliminate the possible influence of the autochthonous nuclear gene set, we fused myoblast-derived cytoplasts of a patient with a human tumoral cell line deprived of mtDNA (Rho degrees). The presence and amount of the mutant G3260 vs the wild-type A3260 were measured by solid phase minisequencing. We observed a marked reduction of the percentage of mutant mtDNA in the culture system compared with that measured in the donor's muscle biopsy, suggesting the presence of negative selection against the mutation. Furthermore, stable mitotic segregation of the two mtDNA populations was observed in 18 of 19 transformant clones, suggesting the presence of intraorganelle and possibly intracellular homoplasmy in the precursor cells of the donor. Several indexes of mtDNA-related respiratory capacity, including oxygen consumption, complex I- and complex IV-specific activities, and lactate production, were markedly abnormal in the clones containing a high proportion of mutant mtDNA, as compared with those containing homoplasmic wild-type mtDNA, possibly because of impaired mitochondrial protein synthesis. We conclude that (a) the A-->G3260 transition is indeed responsible for the mitochondrial disorder identified in the donor patient, and (b) transformant cybrid system gives direct evidence of the mitochondrial origin of a genetic disorder and should be adopted for the evaluation of the pathogenic potential of the mtDNA mutations. Images PMID:8132749

  15. A Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy Associated Mutation in Human Cardiac Troponin I (K206I)

    Science.gov (United States)

    Warren, Chad M.; Karam, Chehade N.; Wolska, Beata M.; Kobayashi, Tomoyoshi; de Tombe, Pieter P.; Arteaga, Grace M.; Bos, J. Martijn; Ackerman, Michael J.; Solaro, R. John

    2015-01-01

    Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease characterized by thickening of ventricular walls and decreased left ventricular chamber volume. The majority of HCM-associated mutations are found in genes encoding sarcomere proteins. Herein, we set out to functionally characterize a novel HCM-associated mutation (K206I-TNNI3), and elucidate the mechanism of dysfunction at the level of myofilament proteins. Methods and Results The male index case was diagnosed with HCM after an out-of-hospital cardiac arrest which was followed by comprehensive clinical evaluation, transthoracic echocardiography, and clinical genetic testing. To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca2+ dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system comparing wildtype human troponin complex, 50% mix of K206I/wildtype, or 100% K206I. We also exchanged native troponin detergent extracted fibers with reconstituted troponin containing either wildtype or a 65% mix of K206I/wildtype, and measured force generation. The Ca2+ sensitivity of the myofilaments containing the K206I variant was significantly increased, and when treated with 20 μM EGCG (green tea) was restored back to wildtype levels in ATPase and force measurements. The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of Ca-hcTnC (calcium-bound-human cardiac troponin C). The ability of Ca-hcTnC to neutralize the inhibition of K206I was greater than with wildtype TnI. Conclusions Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM. PMID:26553696

  16. Peripartum cardiomyopathy

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    Rodolfo Citro

    2011-07-01

    Full Text Available Peripartum cardiomyopathy is an uncommon form of congestive heart failure associated with systolic dysfunction of left ventricle. The onset is characterised by symptoms of heart failure occurring between the last month of pregnancy and 5-6 months postpartum. The early diagnosis and the institution of medical treatment for this disease are essential because the inadequate management may affect the patient’s long-term prognosis and can lead to severe complications, including death.Currently its aetiology is not completely understood. Many aetiopathogenetic hypotheses have been formulated: inflammation, viral agents, autoimmune processes. In the last years, evidences aroused for a role of prolactin and its 16 kDa metabolite in reducing cardiomyocite metabolic activity and contraction. In this article we have reviewed the current literature with special emphasis on the role of prolactin and the related current treatment strategies. In particular, bromocriptine appears promising, even if women need to be informed that the drug stops the production of breastmilk. Further researchers, such as large multicenter trials, are needed to decide the best treatment for the women suffering of this disease.

  17. Mutations affecting the chemosensory neurons of Caenorhabditis elegans

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    Starich, T.A.; Herman, R.K.; Kari, C.K. [Univ. of Minnesota, St. Paul, MN (United States)] [and others

    1995-01-01

    We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS. All of the mutations result in defects in one or more chemosensory responses, such as chemotaxis to ammonium chloride or formation of dauer larvae under conditions of starvation and overcrowding. Seventy-five of the mutations are alleles of 12 previously defined genes, mutations which were previously shown to lead to defects in amphid ultrastructure. We have assigned 20 mutations to 13 new genes, called dyf-1 through dyf-13. We expect that the genes represented by dye-filling defective mutants are important for the differentiation of amphid and phasmid chemosensilla. 58 refs., 3 figs., 6 tabs.

  18. An explicitly solvated full atomistic model of the cardiac thin filament and application on the calcium binding affinity effects from familial hypertrophic cardiomyopathy linked mutations

    Science.gov (United States)

    Williams, Michael; Schwartz, Steven

    2015-03-01

    The previous version of our cardiac thin filament (CTF) model consisted of the troponin complex (cTn), two coiled-coil dimers of tropomyosin (Tm), and 29 actin units. We now present the newest revision of the model to include explicit solvation. The model was developed to continue our study of genetic mutations in the CTF proteins which are linked to familial hypertrophic cardiomyopathies. Binding of calcium to the cTnC subunit causes subtle conformational changes to propagate through the cTnC to the cTnI subunit which then detaches from actin. Conformational changes propagate through to the cTnT subunit, which allows Tm to move into the open position along actin, leading to muscle contraction. Calcium disassociation allows for the reverse to occur, which results in muscle relaxation. The inclusion of explicit TIP3 water solvation allows for the model to get better individual local solvent to protein interactions; which are important when observing the N-lobe calcium binding pocket of the cTnC. We are able to compare in silica and in vitro experimental results to better understand the physiological effects from mutants, such as the R92L/W and F110V/I of the cTnT, on the calcium binding affinity compared to the wild type.

  19. Genetic biomarkers in hypertrophic cardiomyopathy.

    Science.gov (United States)

    Coats, Caroline J; Elliott, Perry M

    2013-08-01

    Hypertrophic cardiomyopathy is a common inherited heart muscle disorder associated with sudden cardiac death, arrhythmias and heart failure. Genetic mutations can be identified in approximately 60% of patients; these are commonest in genes that encode proteins of the cardiac sarcomere. Similar to other Mendelian diseases these mutations are characterized by incomplete penetrance and variable clinical expression. Our knowledge of this genetic diversity is rapidly evolving as high-throughput DNA sequencing technology is now used to characterize an individual patient's disease. In addition, the genomic basis of several multisystem diseases associated with a hypertrophic cardiomyopathy phenotype has been elucidated. Genetic biomarkers can be helpful in making an accurate diagnosis and in identifying relatives at risk of developing the condition. In the clinical setting, genetic testing and genetic screening should be used pragmatically with appropriate counseling. Here we review the current role of genetic biomarkers in hypertrophic cardiomyopathy, highlight recent progress in the field and discuss future challenges.

  20. Genotype phenotype correlations of cardiac beta-myosin heavy chain mutations in Indian patients with hypertrophic and dilated cardiomyopathy

    DEFF Research Database (Denmark)

    Rai, Taranjit Singh; Ahmad, Shamim; Bahl, Ajay;

    2009-01-01

    consecutive patients diagnosed with HCM or DCM (69 with HCM and 61 with DCM) attending the cardiology clinic of Post Graduate Institute of Medical Education and Research were screened for mutations in the MYH7 gene. The control group for genetic studies consisted of 100 healthy subjects. We report 14...

  1. Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

    DEFF Research Database (Denmark)

    Andersen, Paal Skytt; Havndrup, Ole; Hougs, Lotte;

    2008-01-01

    persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants...

  2. Three-dimensional speckle tracking echocardiography for left atrial and left ventricular function in hypertrophic cardiomyopathy mutation carriers

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    Mohammad Abdulghani Abdulzaher

    2014-03-01

    Conclusion: HCM mutation carriers could be distinguished from healthy subjects using 3DSTE through detection of LA dysfunction that might indicate subtle LV dysfunction. No differences were found in LV systolic myocardial deformation between both groups. The exact clinical value of 3DSTE in family screening for HCM needs to be further evaluated.

  3. [Peripartum cardiomyopathy].

    Science.gov (United States)

    Mouquet, Frédéric; Bouabdallaoui, Nadia

    2015-01-01

    The peripartum cardiomyopathy is a rare form of dilated cardiomyopathy resulting from alteration of angiogenesis toward the end of pregnancy. The diagnosis is based on the association of clinical heart failure and systolic dysfunction assessed by echocardiography or magnetic resonance imaging. Diagnoses to rule out are myocardial infarction, amniotic liquid embolism, myocarditis, inherited cardiomyopathy, and history of treatment by anthracycline. Risk factors are advance maternal age (>30), multiparity, twin pregnancy, African origin, obesity, preeclampsia, gestational hypertension, and prolonged tocolytic therapy. Treatment of acute phase is identical to usual treatment of acute systolic heart failure. After delivery, VKA treatment should be discussed in case of systolic function <25% because of higher risk of thrombus. A specific treatment by bromocriptine can be initiated on a case-by-case basis. Complete recovery of systolic function is observed in 50% of cases. The mortality risk is low. Subsequent pregnancy should be discouraged, especially if systolic function did not recover.

  4. A Genetic Variants Database for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

    NARCIS (Netherlands)

    van der Zwaag, Paul A.; Jongbloed, Jan D. H.; van den Berg, Maarten P.; van der Smagt, Jasper J.; Jongbloed, Roselie; Bikker, Hennie; Hofstra, Robert M. W.; van Tintelen, J. Peter

    2009-01-01

    Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a hereditary cardiomyopathy characterized by fibrofatty replacement of cardiomyocytes, ventricular tachyarrhythmias and sudden death. ARVD/C is mainly caused by mutations in genes encoding desmosomal proteins. However, the pathoge

  5. Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death.

    Science.gov (United States)

    Zaragoza, Michael V; Fung, Lianna; Jensen, Ember; Oh, Frances; Cung, Katherine; McCarthy, Linda A; Tran, Christine K; Hoang, Van; Hakim, Simin A; Grosberg, Anna

    2016-01-01

    The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10) with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85%) located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51%) variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency.

  6. Exome Sequencing Identifies a Novel LMNA Splice-Site Mutation and Multigenic Heterozygosity of Potential Modifiers in a Family with Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death.

    Directory of Open Access Journals (Sweden)

    Michael V Zaragoza

    Full Text Available The goals are to understand the primary genetic mechanisms that cause Sick Sinus Syndrome and to identify potential modifiers that may result in intrafamilial variability within a multigenerational family. The proband is a 63-year-old male with a family history of individuals (>10 with sinus node dysfunction, ventricular arrhythmia, cardiomyopathy, heart failure, and sudden death. We used exome sequencing of a single individual to identify a novel LMNA mutation and demonstrated the importance of Sanger validation and family studies when evaluating candidates. After initial single-gene studies were negative, we conducted exome sequencing for the proband which produced 9 gigabases of sequencing data. Bioinformatics analysis showed 94% of the reads mapped to the reference and identified 128,563 unique variants with 108,795 (85% located in 16,319 genes of 19,056 target genes. We discovered multiple variants in known arrhythmia, cardiomyopathy, or ion channel associated genes that may serve as potential modifiers in disease expression. To identify candidate mutations, we focused on ~2,000 variants located in 237 genes of 283 known arrhythmia, cardiomyopathy, or ion channel associated genes. We filtered the candidates to 41 variants in 33 genes using zygosity, protein impact, database searches, and clinical association. Only 21 of 41 (51% variants were validated by Sanger sequencing. We selected nine confirmed variants with minor allele frequencies G, a novel heterozygous splice-site mutation as the primary mutation with rare or novel variants in HCN4, MYBPC3, PKP4, TMPO, TTN, DMPK and KCNJ10 as potential modifiers and a mechanism consistent with haploinsufficiency.

  7. Fast diastolic swinging motion of the mitral valve as a clinical marker of familial hypertrophic cardiomyopathy in genetically affected young children without left ventricular hypertrophy: a new role for noninvasive imaging?

    Science.gov (United States)

    Udink ten Cate, Floris E A; Junghaenel, Shino; Brockmeier, Konrad; Sreeram, Narayanswami

    2013-08-01

    Structural mitral valve (MV) abnormalities are common in patients with hypertrophic cardiomyopathy (HCM). This is the first report demonstrating MV abnormalities in very young children as the sole overt clinical feature of a known HCM-causing sarcomere protein gene mutation. Due to MV leaflet elongation, we also noticed a typical fast diastolic swinging motion of the MV in our patients. This novel echocardiographic feature may be used as a clinical marker of HCM disease in the absence of left ventricular hypertrophy.

  8. LMNA cardiomyopathy: cell biology and genetics meet clinical medicine

    Directory of Open Access Journals (Sweden)

    Jonathan T. Lu

    2011-09-01

    Full Text Available Mutations in the LMNA gene, which encodes A-type nuclear lamins (intermediate filament proteins expressed in most differentiated somatic cells, cause a diverse range of diseases, called laminopathies, that selectively affect different tissues and organ systems. The most prevalent laminopathy is cardiomyopathy with or without different types of skeletal muscular dystrophy. LMNA cardiomyopathy has an aggressive clinical course with higher rates of deadly arrhythmias and heart failure than most other heart diseases. As awareness among physicians increases, and advances in DNA sequencing methods make the genetic diagnosis of LMNA cardiomyopathy more common, cardiologists are being faced with difficult questions regarding patient management. These questions concern the optimal use of intracardiac cardioverter defibrillators to prevent sudden death from arrhythmias, and medical interventions to prevent heart damage and ameliorate heart failure symptoms. Data from a mouse model of LMNA cardiomyopathy suggest that inhibitors of mitogen-activated protein kinase (MAPK signaling pathways are beneficial in preventing and treating cardiac dysfunction; this basic research discovery needs to be translated to human patients.

  9. LMNA cardiomyopathy: cell biology and genetics meet clinical medicine.

    Science.gov (United States)

    Lu, Jonathan T; Muchir, Antoine; Nagy, Peter L; Worman, Howard J

    2011-09-01

    Mutations in the LMNA gene, which encodes A-type nuclear lamins (intermediate filament proteins expressed in most differentiated somatic cells), cause a diverse range of diseases, called laminopathies, that selectively affect different tissues and organ systems. The most prevalent laminopathy is cardiomyopathy with or without different types of skeletal muscular dystrophy. LMNA cardiomyopathy has an aggressive clinical course with higher rates of deadly arrhythmias and heart failure than most other heart diseases. As awareness among physicians increases, and advances in DNA sequencing methods make the genetic diagnosis of LMNA cardiomyopathy more common, cardiologists are being faced with difficult questions regarding patient management. These questions concern the optimal use of intracardiac cardioverter defibrillators to prevent sudden death from arrhythmias, and medical interventions to prevent heart damage and ameliorate heart failure symptoms. Data from a mouse model of LMNA cardiomyopathy suggest that inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways are beneficial in preventing and treating cardiac dysfunction; this basic research discovery needs to be translated to human patients.

  10. Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature.

    Science.gov (United States)

    Hedberg-Oldfors, Carola; Glamuzina, Emma; Ruygrok, Peter; Anderson, Lisa J; Elliott, Perry; Watkinson, Oliver; Occleshaw, Chris; Abernathy, Malcolm; Turner, Clinton; Kingston, Nicola; Murphy, Elaine; Oldfors, Anders

    2017-01-01

    We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.

  11. Mutations in NRXN1 in a family multiply affected with brain disorders

    DEFF Research Database (Denmark)

    Duong, Linh; Klitten, Laura L; Møller, Rikke S

    2012-01-01

    Mutation of the neurexin1-gene, NRXN1, interrupting the expression of neurexin1 has been associated with schizophrenia, autism, and intellectual disability. We have identified a family multiply affected with psychiatric, neurological, and somatic disorders along with an intricate co-segregation o......Mutation of the neurexin1-gene, NRXN1, interrupting the expression of neurexin1 has been associated with schizophrenia, autism, and intellectual disability. We have identified a family multiply affected with psychiatric, neurological, and somatic disorders along with an intricate co......-segregation of NRXN1 mutations. The proband suffered from autism, mental retardation, and epilepsy and on genotyping it was revealed that he carried a compound heterozygous mutation in the NRXN1 consisting of a 451¿kb deletion, affecting the promoter and first introns in addition to a point mutation, predicted...

  12. New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy.

    Science.gov (United States)

    Alonso-Montes, Cristina; Naves-Diaz, Manuel; Fernandez-Martin, Jose Luis; Rodriguez-Reguero, Julian; Moris, Cesar; Coto, Eliecer; Cannata-Andia, Jorge B; Rodriguez, Isabel

    2012-09-01

    Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomeric proteins. Its variable phenotype suggests the existence of modifier genes. Myocyte enhancer factor (MEF) 2C could be important in this process given its role as transcriptional regulator of several cardiac genes. Any variant affecting MEF2C expression and/or function may impact on hypertrophic cardiomyopathy clinical manifestations. In this candidate gene approach, we screened 209 Caucasian hypertrophic cardiomyopathy patients and 313 healthy controls for genetic variants in MEF2C gene by single-strand conformation polymorphism analysis and direct sequencing. Functional analyses were performed with transient transfections of luciferase reporter constructions. Three new variants in non-coding exon 1 were found both in patients and controls with similar frequencies. One-way ANOVA analyses showed a greater left ventricular outflow tract obstruction (p = 0.011) in patients with 10C+10C genotype of the c.-450C(8_10) variant. Moreover, one patient was heterozygous for two rare variants simultaneously. This patient presented thicker left ventricular wall than her relatives carrying the same sarcomeric mutation. In vitro assays additionally showed a slightly increased transcriptional activity for both rare MEF2C alleles. In conclusion, our data suggest that 15 bp-deletion and C-insertion in the 5'UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C and therefore, the expression of their target cardiac proteins that are implicated in the hypertrophic process.

  13. Alcoholic cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Gonzalo; Guzzo-Merello; Marta; Cobo-Marcos; Maria; Gallego-Delgado; Pablo; Garcia-Pavia

    2014-01-01

    Alcohol is the most frequently consumed toxic substance in the world. Low to moderate daily intake of alcohol has been shown to have beneficial effects on the cardiovascular system. In contrast, exposure to high levels of alcohol for a long period could lead to progressive cardiac dysfunction and heart failure. Cardiac dysfunction associated with chronic and excessive alcohol intake is a specific cardiac disease known as alcoholic cardiomyopathy(ACM). In spite of its clinical importance, data on ACM and how alcohol damages the heart are limited. In this review, we evaluate available evidence linking excessive alcohol consumption with heart failure and dilated cardiomyopathy. Additionally, we discuss the clinical presentation, prognosis and treatment of ACM.

  14. Takotsubo cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Sénior, Juan Manuel

    2015-04-01

    Full Text Available Takotsubo cardiomyopathy or stress-induced cardiomyopathy is often diagnosed as an acute coronary syndrome in postmenopausal women, because its clinical presentation may mimic an acute myocardial infarction: anginal chest pain, changes in the ST segment and T wave in precordial leads and elevated cardiac biomarkers of necrosis. It is characterized by systolic dysfunction with transient ballooning of the apical and middle portions of the left ventricle in the absence of significant coronary disease. Prognosis is good and complete recovery occurs in days to weeks. We report three cases of postmenopausal women with initial diagnosis of acute myocardial infarction; no significant coronary lesions were found in the coronary angiography; apical ballooning, characteristic of this syndrome, was observed on left ventriculography. On follow-up, the three patients had complete recovery of systolic function at six weeks.

  15. Infiltrative Cardiomyopathies

    Science.gov (United States)

    Bejar, David; Colombo, Paolo C; Latif, Farhana; Yuzefpolskaya, Melana

    2015-01-01

    Infiltrative cardiomyopathies can result from a wide spectrum of both inherited and acquired conditions with varying systemic manifestations. They portend an adverse prognosis, with only a few exceptions (ie, glycogen storage disease), where early diagnosis can result in potentially curative treatment. The extent of cardiac abnormalities varies based on the degree of infiltration and results in increased ventricular wall thickness, chamber dilatation, and disruption of the conduction system. These changes often lead to the development of heart failure, atrioventricular (AV) block, and ventricular arrhythmia. Because these diseases are relatively rare, a high degree of clinical suspicion is important for diagnosis. Electrocardiography and echocardiography are helpful, but advanced techniques including cardiac magnetic resonance (CMR) and nuclear imaging are increasingly preferred. Treatment is dependent on the etiology and extent of the disease and involves medications, device therapy, and, in some cases, organ transplantation. Cardiac amyloid is the archetype of the infiltrative cardiomyopathies and is discussed in great detail in this review. PMID:26244036

  16. Peripartum cardiomyopathy : Euro Observational Research Program

    NARCIS (Netherlands)

    Hoes, M. F.; van Hagen, I.; Russo, F.; Van Veldhuisen, D. J.; Van den Berg, M. P.; Roos-Hesselink, J.; van Spaendonck-Zwarts, K. Y.; van der Meer, P.

    2014-01-01

    Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology r

  17. Cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens H

    2010-01-01

    , nitric oxide overproduction, and cannabinoid receptor activation. Systolic incompetence in patients can be revealed by pharmacological or physical strain and during stressful procedures, such as transjugular intrahepatic portosystemic shunt insertion and liver transplantation. Systolic dysfunction has...... and electrophysiological abnormalities. This syndrome is termed cirrhotic cardiomyopathy. Results of experimental studies indicate the involvement of several mechanisms in the pathophysiology, such as reduced beta-adrenergic receptor signal transduction, altered transmembrane currents and electromechanical coupling...

  18. Cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Wiese, Signe; Hove, Jens Dahlgaard; Bendtsen, Flemming;

    2014-01-01

    causes of cardiac disease. This condition is primarily revealed by inducing physical or pharmacological stress, but echocardiography is excellent at revealing diastolic dysfunction and might also be used to detect systolic dysfunction at rest. Furthermore, measurement of circulating levels of cardiac...... in relation to invasive procedures such as shunt insertion and liver transplantation. Current pharmacological treatment is nonspecific and directed towards left ventricular failure, and liver transplantation is currently the only proven treatment with specific effect on cirrhotic cardiomyopathy....

  19. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Directory of Open Access Journals (Sweden)

    Sokolenko Anna P

    2009-01-01

    Full Text Available Abstract Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.

  20. Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

    Science.gov (United States)

    Sokolenko, Anna P; Voskresenskiy, Dmitry A; Iyevleva, Aglaya G; Bit-Sava, Elena M; Gutkina, Nadezhda I; Anisimenko, Maxim S; Yu Sherina, Nathalia; Mitiushkina, Nathalia V; Ulibina, Yulia M; Yatsuk, Olga S; Zaitseva, Olga A; Suspitsin, Evgeny N; Togo, Alexandr V; Pospelov, Valery A; Kovalenko, Sergey P; Semiglazov, Vladimir F; Imyanitov, Evgeny N

    2009-01-01

    Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele. PMID:19338681

  1. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.

    Science.gov (United States)

    Chappuis-Flament, S; Pasini, A; De Vita, G; Ségouffin-Cariou, C; Fusco, A; Attié, T; Lenoir, G M; Santoro, M; Billaud, M

    1998-12-03

    The RET gene encodes a receptor tyrosine kinase whose function is essential during the development of kidney and the intestinal nervous system. Germline mutations affecting one of five cysteines (Cys609, 611, 618, 620 and 634) located in the juxtamembrane domain of the RET receptor are responsible for the vast majority of two cancer-prone disorders, multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). These mutations lead to the replacement of a cysteine by an alternate amino acid. Mutations of the RET gene are also the underlying genetic cause of Hirschsprung disease (HSCR), a congenital aganglionosis of the hindgut. In a fraction of kindreds, MEN 2A cosegregate with HSCR and affected individuals carry a single mutation at codons 609, 618 or 620. To examine the consequences of cysteine substitution on RET function, we have introduced a Cys to Arg mutation into the wild-type RET at either codons 609, 618, 620, 630 or 634. We now report that each mutation induces a constitutive catalytic activity due to the aberrant disulfide homodimerization of RET. However, mutations 630 and 634 activate RET more strongly than mutations 609, 618 or 620 as demonstrated by quantitative assays in rodent fibroblasts and pheochromocytoma PC12 cells. Biochemical analysis revealed that mutations 618 and 620, and to a lesser extent mutation 609, result in a marked reduction of the level of RET at the cell surface and as a consequence decrease the amount of RET covalent dimer. These findings provide a molecular basis explaining the range of phenotype engendered by alterations of RET cysteines and suggest a novel mechanism whereby mutations of cysteines 609, 618 and 620 exert both activating and inactivating effects.

  2. Diaphanous gene mutation affects spiral cleavage and chirality in snails

    Science.gov (United States)

    Kuroda, Reiko; Fujikura, Kohei; Abe, Masanori; Hosoiri, Yuji; Asakawa, Shuichi; Shimizu, Miho; Umeda, Shin; Ichikawa, Futaba; Takahashi, Hiromi

    2016-01-01

    L-R (left and right) symmetry breaking during embryogenesis and the establishment of asymmetric body plan are key issues in developmental biology, but the onset including the handedness-determining gene locus still remains unknown. Using pure dextral (DD) and sinistral (dd) strains of the pond snail Lymnaea stagnalis as well as its F2 through to F10 backcrossed lines, the single handedness-determining-gene locus was mapped by genetic linkage analysis, BAC cloning and chromosome walking. We have identified the actin-related diaphanous gene Lsdia1 as the strongest candidate. Although the cDNA and derived amino acid sequences of the tandemly duplicated Lsdia1 and Lsdia2 genes are very similar, we could discriminate the two genes/proteins in our molecular biology experiments. The Lsdia1 gene of the sinistral strain carries a frameshift mutation that abrogates full-length LsDia1 protein expression. In the dextral strain, it is already translated prior to oviposition. Expression of Lsdia1 (only in the dextral strain) and Lsdia2 (in both chirality) decreases after the 1-cell stage, with no asymmetric localization throughout. The evolutionary relationships among body handedness, SD/SI (spiral deformation/spindle inclination) at the third cleavage, and expression of diaphanous proteins are discussed in comparison with three other pond snails (L. peregra, Physa acuta and Indoplanorbis exustus). PMID:27708420

  3. Hypertrophic cardiomyopathy: a heart in need of an energy bar?

    Directory of Open Access Journals (Sweden)

    Styliani eVakrou

    2014-08-01

    Full Text Available Hypertrophic cardiomyopathy (HCM has been recently recognized as the most common inherited cardiovascular disorder, affecting 1 in 500 adults worldwide. HCM is characterized by myocyte hypertrophy resulting in thickening of the ventricular wall, myocyte disarray, interstitial and/or replacement fibrosis, decreased ventricular cavity volume and diastolic dysfunction. HCM is also the most common cause of sudden death in the young. A large proportion of patients diagnosed with HCM have mutations in sarcomeric proteins. However, it is unclear how these mutations lead to the cardiac phenotype, which is variable even in patients carrying the same causal mutation. Abnormalities in calcium cycling, oxidative stress, mitochondrial dysfunction and energetic deficiency have been described, constituting the basis of therapies in experimental models of HCM and HCM patients. This review focuses on evidence supporting the role of cellular metabolism and mitochondria in HCM.

  4. Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women

    DEFF Research Database (Denmark)

    Havndrup, Ole; Christiansen, Michael; Stoevring, Birgitte

    2010-01-01

    AIMS: Fabry disease, an X-linked storage disorder caused by defective lysosomal enzyme alpha-galactosidase A activity, may resemble sarcomere-gene-associated hypertrophic cardiomyopathy (HCM). The 'cardiac variant' of Fabry disease which only affects the heart may be missed unless specifically...... tested for. METHODS AND RESULTS: We evaluated 90 consecutively recruited HCM probands and their relatives. Probands without sarcomere-gene mutations were tested for alpha-galactosidase A gene (GLA) mutations. Of the 90 families, 31 (34%) had sarcomere gene mutations and were therefore excluded...... without sarcomere gene mutations. GLA mutations were found in 3/90 (3%) of HCM families and in 2/20 (10%) of females without sarcomere-gene mutations. None of the probands presented other indices of Fabry disease. This, in combination with putative reversibility of cardiac changes by enzyme replacement...

  5. Cocaine cardiomyopathy: A case report

    Directory of Open Access Journals (Sweden)

    Georgiev Antonio

    2014-12-01

    Full Text Available Cocaine is the second most common illicit drug used and the most frequent cause of drug related deaths. The use of cocaine is associated with both, acute and chronic complications, that may involve any system, but the most common system affected is cardiovascular one. Cocaine cardiomyopathy may result from the use of cocaine. This article presents a first case in Republic of Macedonia of 24-year-old male with reversible cocaine-related cardiomyopathy. Clinical presentation, laboratory, X-ray, ultrasound findings and treatment are reviewed.

  6. Mitochondrial DNA variant discovery and evaluation in human Cardiomyopathies through next-generation sequencing.

    Directory of Open Access Journals (Sweden)

    Michael V Zaragoza

    Full Text Available Mutations in mitochondrial DNA (mtDNA may cause maternally-inherited cardiomyopathy and heart failure. In homoplasmy all mtDNA copies contain the mutation. In heteroplasmy there is a mixture of normal and mutant copies of mtDNA. The clinical phenotype of an affected individual depends on the type of genetic defect and the ratios of mutant and normal mtDNA in affected tissues. We aimed at determining the sensitivity of next-generation sequencing compared to Sanger sequencing for mutation detection in patients with mitochondrial cardiomyopathy. We studied 18 patients with mitochondrial cardiomyopathy and two with suspected mitochondrial disease. We "shotgun" sequenced PCR-amplified mtDNA and multiplexed using a single run on Roche's 454 Genome Sequencer. By mapping to the reference sequence, we obtained 1,300x average coverage per case and identified high-confidence variants. By comparing these to >400 mtDNA substitution variants detected by Sanger, we found 98% concordance in variant detection. Simulation studies showed that >95% of the homoplasmic variants were detected at a minimum sequence coverage of 20x while heteroplasmic variants required >200x coverage. Several Sanger "misses" were detected by 454 sequencing. These included the novel heteroplasmic 7501T>C in tRNA serine 1 in a patient with sudden cardiac death. These results support a potential role of next-generation sequencing in the discovery of novel mtDNA variants with heteroplasmy below the level reliably detected with Sanger sequencing. We hope that this will assist in the identification of mtDNA mutations and key genetic determinants for cardiomyopathy and mitochondrial disease.

  7. Troponin Ⅰ,cardiac diastolic dysfunction and restrictive cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Xu-pei HUANG; Jian-feng DU

    2004-01-01

    Cardiomyopathies are diseases of heart muscle that are associated with cardiac dysfunction. Molecular genetic studies performed to date have demonstrated that the damage or mutations in several sarcomeric contractile protein genes are associated with the development of the diseases. In this review, cardiac troponin Ⅰ, one of the sarcomeric thin filament protein, will be discussed regarding its role in cardiac function, its deficiency-related diastolic dysfunction, and the mutation of this protein-mediated restrictive cardiomyopathy.

  8. Pregnancy, cardiomyopathies, and genetics

    NARCIS (Netherlands)

    Van Tintelen, J. Peter; Pieper, Petronella G.; Van Spaendonck-Zwarts, Karin Y.; Van den Berg, Maarten P.

    2014-01-01

    Although familial forms of cardiomyopathy such as hypertrophic or dilated cardiomyopathy have been recognized for decades, it is only recently that much of the genetic basis of these inherited cardiomyopathies has been elucidated. This has provided important insights into the pathophysiological mech

  9. A novel mutation in TFL1 homolog affecting determinacy in cowpea (Vigna unguiculata).

    Science.gov (United States)

    Dhanasekar, P; Reddy, K S

    2015-02-01

    Mutations in the widely conserved Arabidopsis Terminal Flower 1 (TFL1) gene and its homologs have been demonstrated to result in determinacy across genera, the knowledge of which is lacking in cowpea. Understanding the molecular events leading to determinacy of apical meristems could hasten development of cowpea varieties with suitable ideotypes. Isolation and characterization of a novel mutation in cowpea TFL1 homolog (VuTFL1) affecting determinacy is reported here for the first time. Cowpea TFL1 homolog was amplified using primers designed based on conserved sequences in related genera and sequence variation was analysed in three gamma ray-induced determinate mutants, their indeterminate parent "EC394763" and two indeterminate varieties. The analyses of sequence variation exposed a novel SNP distinguishing the determinate mutants from the indeterminate types. The non-synonymous point mutation in exon 4 at position 1,176 resulted from transversion of cytosine (C) to adenine (A) leading to an amino acid change (Pro-136 to His) in determinate mutants. The effect of the mutation on protein function and stability was predicted to be detrimental using different bioinformatics/computational tools. The functionally significant novel substitution mutation is hypothesized to affect determinacy in the cowpea mutants. Development of suitable regeneration protocols in this hitherto recalcitrant crop and subsequent complementation assay in mutants or over-expressing assay in parents could decisively conclude the role of the SNP in regulating determinacy in these cowpea mutants.

  10. Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB-crystallinopathies.

    Science.gov (United States)

    van der Smagt, J J; Vink, A; Kirkels, J H; Nelen, M; ter Heide, H; Molenschot, M M C; Weger, R A; Schellekens, P A W; Hoogendijk, J; Dooijes, D

    2014-04-01

    Mutations in the αB-crystallin gene (CRYAB) have been reported in desmin-related myopathies, with or without cardiac involvement. Mutations in this gene have also been documented in large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC). In these congenital cataract families no cardiac or muscular phenotype was reported. This report describes a family with an unusual read-through mutation in CRYAB, leading to the elongation of the normal αB-crystallin protein with 19 amino acid residues. Affected family members combine a CPPC with an adult onset dilated cardiomyopathy (DCM), thereby expanding the αB-crystallinopathy phenotype. Repolarisation abnormalities preceded the onset of cardiomyopathy and were already present in childhood. No skeletal myopathy was observed. This report illustrates that congenital cataract can be a prelude to more severe disease even outside the context of inborn errors of metabolism. The identification of a CRYAB mutation in this family supports the notion that mutations in this gene are a rare cause of genetically determined DCM. The combined congenital cataract/cardiomyopathy phenotype adds to our understanding of the complex phenotypic spectrum of αB-crystallinopathies.

  11. Identification and Functional Characterization of GAA Mutations in Colombian Patients Affected by Pompe Disease.

    Science.gov (United States)

    Niño, Mónica Yasmín; Mateus, Heidi Eliana; Fonseca, Dora Janeth; Kroos, Marian A; Ospina, Sandra Yaneth; Mejía, Juan Fernando; Uribe, Jesús Alfredo; Reuser, Arnold J J; Laissue, Paul

    2013-01-01

    Pompe disease (PD) is a recessive metabolic disorder characterized by acid α-glucosidase (GAA) deficiency, which results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD clinical course is mainly determined by the nature of the GAA mutations. Although ~400 distinct GAA sequence variations have been described, the genotype-phenotype correlation is not always evident.In this study, we describe the first clinical and genetic analysis of Colombian PD patients performed in 11 affected individuals. GAA open reading frame sequencing revealed eight distinct mutations related to PD etiology including two novel missense mutations, c.1106 T > C (p.Leu369Pro) and c.2236 T > C (p.Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations did not inhibit the synthesis of the 110 kD GAA precursor form but affected the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p.Trp746Gly, p.Trp746Cys, p.Trp746Ser, p.Trp746X) revealed new insights in the molecular basis of PD. Notably, we found that p.Trp746Cys mutation, which was previously described as a polymorphism as well as a causal mutation, displayed a mild deleterious effect. Interestingly and by chance, our study argues in favor of a remarkable Afro-American and European ancestry of the Colombian population. Taken together, our report provides valuable information on the PD genotype-phenotype correlation, which is expected to facilitate and improve genetic counseling of affected individuals and their families.

  12. Prevalence of hypertrophic cardiomyopathy in China

    Institute of Scientific and Technical Information of China (English)

    Tsung O Cheng

    2004-01-01

    @@ To the Editor: I read with interest the recent article on cardiac troponin T (TNNT2) mutations in Chinese patients with hypertrophic cardiomyopathy (HCM) by Wu et al.1 The authors cited a prevalence of HCM of 0.2% in general population, but did not indicate whether it referred to the general population in China or some other countries.

  13. MeCP2 Rett mutations affect large scale chromatin organization

    DEFF Research Database (Denmark)

    Gupta, Noopur Agarwal; Becker, Annette; Jost, K Laurence

    2011-01-01

    Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene...... expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two......-thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl-binding domain...

  14. Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain.

    Science.gov (United States)

    Vernengo, Luis; Chourbagi, Oussama; Panuncio, Ana; Lilienbaum, Alain; Batonnet-Pichon, Sabrina; Bruston, Francine; Rodrigues-Lima, Fernando; Mesa, Rosario; Pizzarossa, Carlos; Demay, Laurence; Richard, Pascale; Vicart, Patrick; Rodriguez, Maria-Mirta

    2010-03-01

    Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.

  15. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

    Directory of Open Access Journals (Sweden)

    Akinori Nakamura

    2015-06-01

    Full Text Available X-linked dilated cardiomyopathy (XLDCM is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment.

  16. A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.

    Science.gov (United States)

    Davis, Jennifer; Davis, L Craig; Correll, Robert N; Makarewich, Catherine A; Schwanekamp, Jennifer A; Moussavi-Harami, Farid; Wang, Dan; York, Allen J; Wu, Haodi; Houser, Steven R; Seidman, Christine E; Seidman, Jonathan G; Regnier, Michael; Metzger, Joseph M; Wu, Joseph C; Molkentin, Jeffery D

    2016-05-19

    The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

  17. Two different cardiomyopathies in a single patient : hypertrophic cardiomyopathy and left ventricular noncompaction.

    Science.gov (United States)

    Sunbul, M; Ozben, B; Mutlu, B

    2013-05-01

    Hypertrophic cardiomyopathy is a complex and relatively common genetic disorder characterized by left ventricular (LV) hypertrophy, usually associated with a nondilated and hyperdynamic chamber with heterogeneous phenotypic expression and clinical course. On the other hand, LV noncompaction is an uncommon cardiomyopathy characterized by the persistence of fetal myocardium with a pattern of prominent trabecular meshwork and deep intertrabecular recesses, systolic dysfunction, and LV dilatation. We report a 29-year-old man with these two different inherent conditions. Our case raises the possibility of a genetic mutation common to these two clinical entities or different gene mutations existing in the same individual.

  18. Private mitochondrial DNA variants in danish patients with hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Hagen, Christian M; Aidt, Frederik H; Havndrup, Ole;

    2015-01-01

    Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM....... Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446......>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM....

  19. Mutations affecting mitotic recombination frequency in haploids and diploids of the filamentous fungus Aspergillus nidulans.

    Science.gov (United States)

    Parag, Y; Parag, G

    1975-01-01

    A haploid strain of Asp. nidulans with a chromosome segment in duplicate (one in normal position on chromosome I, one translocated to chromosome II) shows mitotic recombination, mostly by conversion, in adE in a frequency slightly higher than in the equivalent diploid. A method has been devised, using this duplication, for the selection of rec and uvs mutations. Six rec mutations have been found which decrease recombination frequency in the haploid. One mutation selected as UV sensitive showed a hundred fold increase in recombination frequency in the haploid (pop mutation) and probably the same in diploids. The increased frequency is both in gene conversion and in crossing over, and the exchanges appear in clusters of two or more. pop is allelic to uvsB (Jansen, 1970) which had been found to affect mitotic but not meiotic recombination. It is suggested that mutations of this type interfere with the control mechanism which determines that high recombination is confirmed to the meiotic nuclei and avoided in somatic nuclei.

  20. Mutations affecting extracellular protease production in the filamentous fungus Aspergillus nidulans.

    Science.gov (United States)

    Katz, M E; Flynn, P K; vanKuyk, P A; Cheetham, B F

    1996-04-10

    The extracellular proteases of Aspergillus nidulans are known to be regulated by carbon, nitrogen and sulphur metabolite repression. In this study, a mutant with reduced levels of extracellular protease was isolated by screening for loss of halo production on milk plates. Genetic analysis of the mutant showed that it contains a single, recessive mutation, in a gene which we have designated xprE, located on chromosome VI. The xprE1 mutation affected the production of extracellular proteases in response to carbon, nitrogen and, to a lesser extent, sulphur limitation. Three reversion mutations, xprF1, xprF2 and xprG1, which suppress xprE1, were characterised. Both xprF and xprG map to chromosome VII but the two genes are unlinked. The xprF1, xprF2 and xprG1 mutants showed high levels of milk-clearing activity on medium containing milk as a carbon source but reduced growth on a number of nitrogen sources. Evidence is presented that the xprE1 and xprG1 mutations alter expression of more than one protease and affect levels of alkaline protease gene mRNA.

  1. Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency

    Science.gov (United States)

    Toderici, Mara; de la Morena-Barrio, María Eugenia; Padilla, José; Miñano, Antonia; Antón, Ana Isabel; Iniesta, Juan Antonio; Herranz, María Teresa; Fernández, Nuria; Vicente, Vicente; Corral, Javier

    2016-01-01

    Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63–78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments. PMID:27003919

  2. Mutations in the human adenosine deaminase gene that affect protein structure and RNA splicing

    Energy Technology Data Exchange (ETDEWEB)

    Akeson, A.L.; Wiginton, D.A.; States, C.J.; Perme, C.M.; Dusing, M.R.; Hutton, J.J.

    1987-08-01

    Adenosine deaminase deficiency is one cause of the genetic disease severe combined immunodeficiency. To identify mutations responsible for ADA deficiency, the authors synthesized cDNAs to ADA mRNAs from two cell lines, GM2756 and GM2825A, derived from ADA-deficient immunodeficient patients. Sequence analysis of GM2756 cDNA clones revealed a different point mutation in each allele that causes amino acid changes of alanine to valine and arginine to histidine. One allele of GM2825A also has a point mutation that causes an alanine to valine substitution. The other allele of GM2825A was found to produce an mRNA in which exon 4 had been spliced out but had no other detrimental mutations. S1 nuclease mapping of GM2825A mRNA showed equal abundance of the full-length ADA mRNA and the ADA mRNA that was missing exon 4. Several of the ADA cDNA clones extended 5' of the major initiation start site, indicating multiple start sites for ADA transcription. The point mutations in GM2756 and GM2825A and the absence of exon 4 in GM2825A appear to be directly responsible for the ADA deficiency. Comparison of a number of normal and mutant ADA cDNA sequences showed a number of changes in the third base of codons. These change do not affect the amino acid sequence. Analyses of ADA cDNAs from different cell lines detected aberrant RNA species that either included intron 7 or excluded exon 7. Their presence is a result of aberrant splicing of pre-mRNAs and is not related to mutations that cause ADA deficiency.

  3. Distant and new mutations in CTX-M-1 beta-lactamase affect cefotaxime hydrolysis.

    Science.gov (United States)

    Pérez-Llarena, Francisco José; Kerff, Frédéric; Abián, Olga; Mallo, Susana; Fernández, María Carmen; Galleni, Moreno; Sancho, Javier; Bou, Germán

    2011-09-01

    The CTX-M β-lactamases are an increasingly prevalent group of extended-spectrum β-lactamases (ESBL). Point mutations in CTX-M β-lactamases are considered critical for enhanced hydrolysis of cefotaxime. In order to clarify the structural determinants of the activity against cefotaxime in CTX-M β-lactamases, screening for random mutations was carried out to search for decreased activity against cefotaxime, with the CTX-M-1 gene as a model. Thirteen single mutants with a considerable reduction in cefotaxime MICs were selected for biochemical and stability studies. The 13 mutated genes of the CTX-M-1 β-lactamase were expressed, and the proteins were purified for kinetic studies against cephalothin and cefotaxime (as the main antibiotics). Some of the positions, such as Val103Asp, Asn104Asp, Asn106Lys, and Pro107Ser, are located in the (103)VNYN(106) loop, which had been described as important in cefotaxime hydrolysis, although this has not been experimentally confirmed. There are four mutations located close to catalytic residues-Thr71Ile, Met135Ile, Arg164His, and Asn244Asp-that may affect the positioning of these residues. We show here that some distant mutations, such as Ala219Val, are critical for cefotaxime hydrolysis and highlight the role of this loop at the top of the active site. Other distant substitutions, such as Val80Ala, Arg191, Ala247Ser, and Val260Leu, are in hydrophobic cores and may affect the dynamics and flexibility of the enzyme. We describe here, in conclusion, new residues involved in cefotaxime hydrolysis in CTX-M β-lactamases, five of which are in positions distant from the catalytic center.

  4. Peripartum Cardiomyopathy Presenting as Bradycardia

    Science.gov (United States)

    Rose, Carl H.; Tweet, Marysia S.; Hayes, Sharonne N.; Best, Patricia J. M.; Blauwet, Lori A.

    2017-01-01

    Peripartum cardiomyopathy (PPCM) is a disease that typically affects young otherwise healthy women. As PPCM is associated with significant mortality, timely diagnosis is necessary to ensure appropriate care. To our knowledge, this represents the first reported case of PPCM presenting as symptomatic bradycardia. We describe the patient's clinical presentation and relevant findings and review the potential etiology and ramifications of bradycardia in patients with PPCM.

  5. Peripartum Cardiomyopathy: A Case Report

    Directory of Open Access Journals (Sweden)

    Afzal Azim

    2009-04-01

    Full Text Available Peripartum cardiomyopathy (PPCM is an uncommon but life threatening disease that affects women in the last month of pregnancy or within the first five months after delivery. Very few Indian case reports are available. However, it is essential for the practitioner dealing with such population to have a high degree of clinical suspicion for early diagnosis and management. Echocardiography is used to diagnose this entity and monitor the therapy.

  6. Peripartum Cardiomyopathy Presenting as Bradycardia

    Directory of Open Access Journals (Sweden)

    Elisabeth Codsi

    2017-01-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a disease that typically affects young otherwise healthy women. As PPCM is associated with significant mortality, timely diagnosis is necessary to ensure appropriate care. To our knowledge, this represents the first reported case of PPCM presenting as symptomatic bradycardia. We describe the patient’s clinical presentation and relevant findings and review the potential etiology and ramifications of bradycardia in patients with PPCM.

  7. Mendelian and non-mendelian mutations affecting surface antigen expression in Paramecium tetraurelia

    Energy Technology Data Exchange (ETDEWEB)

    Epstein, L.M.; Forney, J.D.

    1984-08-01

    A screening procedure was devised for the isolation of X-ray-induced mutations affecting the expression of the A immobilization antigen (i-antigen) in Paramecium tetraurelia. Two of the mutations isolated by this procedure proved to be in modifier genes. The two genes are unlinked to each other and unlinked to the structural A i-antigen gene. These are the first modifier genes identified in a Paramecium sp. that affect surface antigen expression. Another mutation was found to be a deletion of sequences just downstream from the A i-antigen gene. In cells carrying this mutation, the A i-antigen gene lies in close proximity to the end of a macronuclear chromosome. The expression of the A i-antigen is not affected in these cells, demonstrating that downstream sequences are not important for the regulation and expression of the A i-antigen gene. A stable cell line was also recovered which shows non-Mendelian inheritance of a macronuclear deletion of the A i-antigen gene. This mutant does not contain the gene in its macronucleus, but contains a complete copy of the gene in its micronucleus. In the cytoplasm of wild-type animals, the micronuclear gene is included in the developing macronucleus; in the cytoplasm of the mutant, the incorporation of the A i-antigen gene into the macronucleus is inhibited. This is the first evidence that a mechanism is available in ciliates to control the expression of a gene by regulating its incorporation into developing macronuclei.

  8. The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes

    Directory of Open Access Journals (Sweden)

    Saúl Gómez-Manzo

    2014-11-01

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PD deficiency is the most common enzyme deficiency worldwide, causing a wide spectrum of conditions with severity classified from the mildest (Class IV to the most severe (Class I. To correlate mutation sites in the G6PD with the resulting phenotypes, we studied four naturally occurring G6PD variants: Yucatan, Nashville, Valladolid and Mexico City. For this purpose, we developed a successful over-expression method that constitutes an easier and more precise method for obtaining and characterizing these enzymes. The kcat (catalytic constant of all the studied variants was lower than in the wild-type. The structural rigidity might be the cause and the most evident consequence of the mutations is their impact on protein stability and folding, as can be observed from the protein yield, the T50 (temperature where 50% of its original activity is retained values, and differences on hydrophobic regions. The mutations corresponding to more severe phenotypes are related to the structural NADP+ region. This was clearly observed for the Classes III and II variants, which became more thermostable with increasing NADP+, whereas the Class I variants remained thermolabile. The mutations produce repulsive electric charges that, in the case of the Yucatan variant, promote increased disorder of the C-terminus and consequently affect the binding of NADP+, leading to enzyme instability.

  9. Mutations in the West Nile prM protein affect VLP and virion secretion in vitro.

    Science.gov (United States)

    Calvert, Amanda E; Huang, Claire Y-H; Blair, Carol D; Roehrig, John T

    2012-11-10

    Mutation of the West Nile virus-like particle (WN VLP) prM protein (T20D, K31A, K31V, or K31T) results in undetectable VLP secretion from transformed COS-1 cells. K31 mutants formed intracellular prM-E heterodimers; however these proteins remained in the ER and ER-Golgi intermediary compartments of transfected cells. The T20D mutation affected glycosylation, heterodimer formation, and WN VLP secretion. When infectious viruses bearing the same mutations were used to infect COS-1 cells, K31 mutant viruses exhibited delayed growth and reduced infectivity compared to WT virus. Epitope maps of WN VLP and WNV prM were also different. These results suggest that while mutations in the prM protein can reduce or eliminate secretion of WN VLPs, they have less effect on virus. This difference may be due to the quantity of prM in WN VLPs compared to WNV or to differences in maturation, structure, and symmetry of these particles.

  10. [Arrhythmic cardiomyopathy. Case report].

    Science.gov (United States)

    Streangă, Violeta; Dimitriu, A G; Iordache, C; Georgescu, G; Grecu, Mihaela

    2004-01-01

    An 11 year-old boy was admitted with incessant sinus node reentrant tachycardia and secondary dilated arrhythmic cardiomyopathy, treated by radiofrequency ablation. Two years later he was admitted with incessant automatic atrial tachycardia and arrhythmic cardiomyopathy; a second catheter ablation procedure failed, but the third one, performed four month later, was successfully and resulted in a restoration of a normal sinus rhythm and a complete regression of arrhythmic cardiomyopathy.

  11. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study.

    Science.gov (United States)

    Penicka, Martin; Gregor, Pavel; Kerekes, Roman; Marek, Dan; Curila, Karol; Krupicka, Jiri

    2009-01-01

    Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.

  12. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

    Science.gov (United States)

    Ware, James S; Li, Jian; Mazaika, Erica; Yasso, Christopher M; DeSouza, Tiffany; Cappola, Thomas P; Tsai, Emily J; Hilfiker-Kleiner, Denise; Kamiya, Chizuko A; Mazzarotto, Francesco; Cook, Stuart A; Halder, Indrani; Prasad, Sanjay K; Pisarcik, Jessica; Hanley-Yanez, Karen; Alharethi, Rami; Damp, Julie; Hsich, Eileen; Elkayam, Uri; Sheppard, Richard; Kealey, Angela; Alexis, Jeffrey; Ramani, Gautam; Safirstein, Jordan; Boehmer, John; Pauly, Daniel F; Wittstein, Ilan S; Thohan, Vinay; Zucker, Mark J; Liu, Peter; Gorcsan, John; McNamara, Dennis M; Seidman, Christine E; Seidman, Jonathan G; Arany, Zoltan

    2016-01-21

    Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

  13. Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing

    Energy Technology Data Exchange (ETDEWEB)

    Wong, A.; Boutis, P.; Hekimi, S. [McGill Univ., Quebec (Canada)

    1995-03-01

    We have identified three allelic, maternal-effect mutations that affect developmental and behavioral timing in Caenorhabditis elegans. They result in a mean lengthening of embryonic and postembryonic development, the cell cycle period and life span, as well as the periods of the defecation, swimming and pumping cycles. These mutants also display a number of additional phenotypes related to timing. For example, the variability in the length of embryonic development is several times larger in the mutants than in the wild type, resulting in the occasional production of mutant embryos developing more rapidly than the most rapidly developing wild-type embryos. In addition, the duration of embryonic development of the mutants, but not of the wild type, depends on the temperature at which their parents were raised. Finally, individual variations in the severity of distinct mutant phenotypes are correlated in a counterintuitive way. For example, the animals with the shortest embryonic development have the longest defecation cycle and those with the longest embryonic development have the shortest defecation cycle. Most of the features affected by these mutations are believed to be controlled by biological clocks, and we therefore call the gene defined by these mutations clk-1, for {open_quotes}abnormal function of biological clocks.{close_quotes} 52 refs., 5 figs., 4 tabs.

  14. Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

    Directory of Open Access Journals (Sweden)

    Yusuke Echigoya

    Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

  15. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

    Science.gov (United States)

    Mills, Philippa B.; Camuzeaux, Stephane S.M.; Footitt, Emma J.; Mills, Kevin A.; Gissen, Paul; Fisher, Laura; Das, Krishna B.; Varadkar, Sophia M.; Zuberi, Sameer; McWilliam, Robert; Stödberg, Tommy; Plecko, Barbara; Baumgartner, Matthias R.; Maier, Oliver; Calvert, Sophie; Riney, Kate; Wolf, Nicole I.; Livingston, John H.; Bala, Pronab; Morel, Chantal F.; Feillet, François; Raimondi, Francesco; Del Giudice, Ennio; Chong, W. Kling; Pitt, Matthew

    2014-01-01

    The first described patients with pyridox(am)ine 5’-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5’-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5’-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5’-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5’-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5’-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5’-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin

  16. Identification of a mutation in the CHAT gene of Old Danish Pointing Dogs affected with congenital myasthenic syndrome

    DEFF Research Database (Denmark)

    Proschowsky, Helle Friis; Flagstad, Annette; Cirera, Susanna;

    2007-01-01

    to decreased activity of the enzyme choline acetyltransferase. We sequenced exons 5-18 of the gene encoding choline acetyltransferase (CHAT) in 2 affected and 2 unaffected dogs and identified a G to A missense mutation in exon 6. The mutation causes a valine to methionine substitution and segregates...

  17. Mutations that affect vacuole biogenesis inhibit proliferation of the endoplasmic reticulum in Saccharomyces cerevisiae.

    Science.gov (United States)

    Koning, Ann J; Larson, Lynnelle L; Cadera, Emily J; Parrish, Mark L; Wright, Robin L

    2002-04-01

    In yeast, increased levels of the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase isozyme, Hmg1p, induce assembly of nuclear-associated ER membranes called karmellae. To identify additional genes involved in karmellae assembly, we screened temperature-sensitive mutants for karmellae assembly defects. Two independently isolated, temperature-sensitive strains that were also defective for karmellae biogenesis carried mutations in VPS16, a gene involved in vacuolar protein sorting. Karmellae biogenesis was defective in all 13 other vacuole biogenesis mutants tested, although the severity of the karmellae assembly defect varied depending on the particular mutation. The hypersensitivity of 14 vacuole biogenesis mutants to tunicamycin was well correlated with pronounced defects in karmellae assembly, suggesting that the karmellae assembly defect reflected alteration of ER structure or function. Consistent with this hypothesis, seven of eight mutations causing defects in secretion also affected karmellae assembly. However, the vacuole biogenesis mutants were able to proliferate their ER in response to Hmg2p, indicating that the mutants did not have a global defect in the process of ER biogenesis.

  18. Keshan disease and mitochondrial cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    YANG Fuyu

    2006-01-01

    Keshan disease (KD) is a potentially fatal form of cardiomyopathy (disease of the heart muscle) endemic in certain areas of China. From 1984 to 1986, a national comprehensive scientific investigation on KD in Chuxiong region of Yunnan Province in the southwest China was conducted. The investigation team was composed of epidemiologists, clinic doctors, pathologists, biochemists, biophysicists and specialists in ecological environment. Results of pathological, biochemical and biophysical as well as clinical studies showed: an obvious increase of enlarged and swollen mitochondria with distended crista membranes in myocardium from patients with KD; significant reductions in the activity of oxidative phosphorylation (succinate dehydrogenase, cytochrome oxidase, succinate oxidase, H+-ATPase) of affected mitochondria; decrease in CoQ, cardiolipin, Se and GSHPx activity, while obvious increase in the Ca2+ content. So, it was suggested that mitochondria are the predominant target of the pathogenic factors of KD. Before Chuxiong KD survey only a few cases of mitochondrial cardiomyopathy were studied. During the multidisciplinary scientific investigation on KD in Chuxiong a large amount of samples from KD cases and the positive controls were examined. On the basis of the results obtained it was suggested that KD might be classified as a "Mitochondrial Cardiomyopathy" endemic in China. This is one of the achievements in the three years' survey in Chuxiong and is valuable not only to the deeper understanding of pathogenic mechanism of KD but also to the study of mitochondrial cardiomyopathy in general.Keshan disease is not a genetic disease, but is closely related to the malnutrition (especially microelement Se deficiency). KD occurs along a low Se belt, and Se supplementation has been effective in prevention of such disease. The incidence of KD has sharply decreased along with the steady raise of living standard and realization of preventive measures. At present, patients of

  19. MSH2 ATPase domain mutation affects CTG*CAG repeat instability in transgenic mice.

    Directory of Open Access Journals (Sweden)

    Stéphanie Tomé

    2009-05-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is associated with one of the most highly unstable CTG*CAG repeat expansions. The formation of further repeat expansions in transgenic mice carrying expanded CTG*CAG tracts requires the mismatch repair (MMR proteins MSH2 and MSH3, forming the MutSbeta complex. It has been proposed that binding of MutSbeta to CAG hairpins blocks its ATPase activity compromising hairpin repair, thereby causing expansions. This would suggest that binding, but not ATP hydrolysis, by MutSbeta is critical for trinucleotide expansions. However, it is unknown if the MSH2 ATPase activity is dispensible for instability. To get insight into the mechanism by which MSH2 generates trinucleotide expansions, we crossed DM1 transgenic mice carrying a highly unstable >(CTG(300 repeat tract with mice carrying the G674A mutation in the MSH2 ATPase domain. This mutation impairs MSH2 ATPase activity and ablates base-base MMR, but does not affect the ability of MSH2 (associated with MSH6 to bind DNA mismatches. We found that the ATPase domain mutation of MSH2 strongly affects the formation of CTG expansions and leads instead to transmitted contractions, similar to a Msh2-null or Msh3-null deficiency. While a decrease in MSH2 protein level was observed in tissues from Msh2(G674 mice, the dramatic reduction of expansions suggests that the expansion-biased trinucleotide repeat instability requires a functional MSH2 ATPase domain and probably a functional MMR system.

  20. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm.

    Science.gov (United States)

    Chetaille, Philippe; Preuss, Christoph; Burkhard, Silja; Côté, Jean-Marc; Houde, Christine; Castilloux, Julie; Piché, Jessica; Gosset, Natacha; Leclerc, Séverine; Wünnemann, Florian; Thibeault, Maryse; Gagnon, Carmen; Galli, Antonella; Tuck, Elizabeth; Hickson, Gilles R; El Amine, Nour; Boufaied, Ines; Lemyre, Emmanuelle; de Santa Barbara, Pascal; Faure, Sandrine; Jonzon, Anders; Cameron, Michel; Dietz, Harry C; Gallo-McFarlane, Elena; Benson, D Woodrow; Moreau, Claudia; Labuda, Damian; Zhan, Shing H; Shen, Yaoqing; Jomphe, Michèle; Jones, Steven J M; Bakkers, Jeroen; Andelfinger, Gregor

    2014-11-01

    The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-β signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

  1. A fatal case of peripartum cardiomyopathy.

    Science.gov (United States)

    Cohen, Ronny; Mallet, Thierry; Mirrer, Brooks; Loarte, Pablo; Gale, Michael; Kastell, Paul

    2014-06-01

    Peripartum cardiomyopathy is a life-threatening cardiac condition affecting pregnant women either late in pregnancy or early in the post-partum period. The latest studies show a dramatic improvement in the mortality rates of women affected with this disorder, which has been correlated with advances in medical therapy for heart failure. However, patients continue to die of this condition. The following case report describes a typical patient with peripartum cardiomyopathy diagnosed on clinical grounds, along with echocardiogram findings of severe systolic dysfunction and global hypokinesis consistent with dilated cardiomyopathy. Emergency cesarean delivery had to be performed for fetal distress. There was significant improvement of the patient's condition with standard pharmacological management for heart failure at the time of discharge. However, five weeks after discharge, fatal cardiac arrest occurred. It is hoped that this article will raise awareness about this rare but potentially fatal condition and promote understanding of its main clinical features, diagnostic criteria, and conventional pharmacological management.

  2. PERIPARTUM CARDIOMYOPATHY: A MANAGEMENT DILEMMA

    Directory of Open Access Journals (Sweden)

    Niranjan Kumar

    2014-07-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a form of dilated cardiomyopathy of unclear etiology, affecting women without pre-existing cardiac diseases, during the last month of pregnancy or up to five postpartum months1 As with other form of dilated cardiomyopathies, PPCM involves the systolic dysfunction of the heart with a decrease in Left Ventricular Ejection Fraction (LVEF <40, associated with congestive heart failure and with an increased risk of supra ventricular or ventricular arrhythmias, thromboembolism and even sudden cardiac death. PPCM is diagnosed by exclusion, where the patient has no history of previous heart disease, coincides with the pregnancy period (one month pre-operative to five months post- operative, and where no other possible cause of heart failure present. Diagnosis of Peripartum cardiomyopathy is a dilemma for the obstetricians, physicians, cardiologists, and the general physicians, as most of these patients are hurriedly diagnosed and treated first as a case of Left Ventricular Failure (LVF of some cardiac origin. Specific treatment is started late or not at all. So, relapses are very common with the treatment line of Left Ventricular Failure of cardiac origin only without any specific treatment and no precautions taken, thereafter. Although the exact cause of PPCM is unknown, yet (a some cardio tropic virus (b immune system dysfunction8, (c genetic factors 1, (d deficiency of micro-nutrients or trace elements (e some cardio-toxins may serve as a trigger to malfunction of immune system that may be responsible in the development of PPCM. Recently two cases of PPCM were transferred to our ICU from the obstetrics and gynecology department immediately after deliveries for acute left ventricular failure in quick succession and were diagnosed as PPCM and successfully managed with Diuretic, ACE inhibitor, Beta blocker and Nitrates with mechanical ventilation. After discharge from the hospital they are being followed up and are put

  3. SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

    Science.gov (United States)

    Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A; Landau, Daniel; Birk, Ohad S

    2017-02-09

    A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through

  4. Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene.

    Directory of Open Access Journals (Sweden)

    Rocio Toro

    Full Text Available Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64 in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased, 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.

  5. Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.

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    Alexandra F S Breitenkamp

    Full Text Available Autism Spectrum Disorders (ASD are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C and CaVβ2 (CACNB2 were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L found in ASD-affected families, two of them described here for the first time (G167S and F240L. All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells. Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.

  6. Mutations of the Drosophila myosin regulatory light chain affect courtship song and reduce reproductive success.

    Science.gov (United States)

    Chakravorty, Samya; Vu, Hien; Foelber, Veronica; Vigoreaux, Jim O

    2014-01-01

    The Drosophila indirect flight muscles (IFM) rely on an enhanced stretch-activation response to generate high power output for flight. The IFM is neurally activated during the male courtship song, but its role, if any, in generating the small amplitude wing vibrations that produce the song is not known. Here, we examined the courtship song properties and mating behavior of three mutant strains of the myosin regulatory light chain (DMLC2) that are known to affect IFM contractile properties and impair flight: (i) Dmlc2(Δ2-46) (Ext), an N-terminal extension truncation; (ii) Dmlc2(S66A,S67A) (Phos), a disruption of two MLC kinase phosphorylation sites; and (iii) Dmlc2(Δ2-46;S66A,S67A) (Dual), expressing both mutations. Our results show that the Dmlc2 gene is pleiotropic and that mutations that have a profound effect on flight mechanics (Phos and Dual) have minimal effects on courtship song. None of the mutations affect interpulse interval (IPI), a determinant of species-specific song, and intrapulse frequency (IPF) compared to Control (Dmlc2 (+) rescued null strain). However, abnormalities in the sine song (increased frequency) and the pulse song (increased cycles per pulse and pulse length) evident in Ext males are not apparent in Dual males suggesting that Ext and Phos interact differently in song and flight mechanics, given their known additive effect on the latter. All three mutant males produce a less vigorous pulse song and exhibit impaired mating behavior compared to Control males. As a result, females are less receptive to Ext, Phos, and Dual males when a Control male is present. These results open the possibility that DMLC2, and perhaps contractile protein genes in general, are partly under sexual selection. That mutations in DMLC2 manifest differently in song and flight suggest that this protein fulfills different roles in song and flight and that stretch activation plays a smaller role in song production than in flight.

  7. Genetic and clinical profile of Indian patients of idiopathic restrictive cardiomyopathy with and without hypertrophy

    DEFF Research Database (Denmark)

    Rai, Taranjit Singh; Ahmad, Shamim; Ahluwalia, Tarun Veer Singh

    2009-01-01

    Both idiopathic restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) are part of the same disease spectrum and are due to sarcomeric gene mutations. A patient with restrictive physiology without left ventricular hypertrophy (LVH) would be diagnosed as IRCM, while one with LVH...

  8. Cardiomyopathies in children

    Directory of Open Access Journals (Sweden)

    Young Mi Hong

    2013-02-01

    Full Text Available Cardiomyopathy (CMP is a heterogeneous disease caused by a functional abnormality of the cardiac muscle. CMP is of 2 major types, dilated and hypertrophic, and is further classified as either primary or secondary. Secondary CMP is caused by extrinsic factors, including infection, ischemia, hypertension, and metabolic disorders. Primary CMP is diagnosed when the extrinsic factors of secondary CMP are absent. Furthermore, the World Health Organization, American Heart Association, and European Cardiology Association have different systems for clinically classifying primary CMP. Primary CMP is rare and associated with a family history of the disease, implying that genetic factors might affect its incidence. In addition, the incidence of CMP varies widely according to patient ethnicity. Genetic testing plays an important role in the care of patients with CMP and their families because it confirms diagnosis, determines the appropriate care for the patient, and possibly affects patient prognosis. The diagnosis and genetic identification of CMP in patients’ families allow the possibility to identify novel genes that may lead to new treatments. This review focuses on the epidemiology, pathophysiology, diagnosis, and treatment of CMP, with the aim of providing pediatricians with insights that may be helpful in the early identification and management of idiopathic CMP in children.

  9. Combined use of in silico and in vitro splicing assays for interpretation of genomic variants of unknown significance in cardiomyopathies and channelopathies

    Directory of Open Access Journals (Sweden)

    Hervé Crehalet

    2012-06-01

    Full Text Available The identification of molecular anomalies in patients with inherited arrhythmias or cardiomyopathies is a multi challenge due to: i the number of genes involved; ii the number of polymorphisms and the fact that most mutations are private; and iii the variable degree of penetrance which complicates family segregation study. Consequently, a number of unclassified variants (UV are found in patients’ DNA and some (outside the canonical GT/AG may affect splicing. Mutational screening on the most prevalent genes involved in arrythmias syndromes or in cardiomyopathies was performed on a cohort made up of 740 unrelated French index probands. To identify splice variants among the identified UVs, a combination of available in silico and in vitro tools were used since transcript is not available. Using this approach, 10 previously identified UVs were reclassified as disease-causing mutations and, more precisely, as haploinsufficiency mutations rather than dominant-negative mutations. Most of them (7 of 10 were observed in MYBPC3. Our study highlighted the importance of the combined use of in silico and in vitro splicing assays to improve the prediction of the functional impact of identified genetic variants. The primary challenge now, with new sequencing technologies, is to distinguish between background polymorphisms and pathogenic mutations. Since splice site mutations can account for almost 50% of disease-causing mutations, recognizing them from among other variations is essential.

  10. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency.

    Science.gov (United States)

    Manco, L; Ribeiro, M L; Máximo, V; Almeida, H; Costa, A; Freitas, O; Barbot, J; Abade, A; Tamagnini, G

    2000-09-01

    Mutations in the PKLR gene responsible for pyruvate kinase (PK)-deficient anaemia are mainly located in the coding regions: 11 are in the splicing sites and, recently, three mutations have been described in the promoter region. We now report a novel point mutation A-->G on nucleotide 72, upstream from the initiation codon of the PKLR gene, in four Portuguese PK-deficient patients. This new regulatory mutation occurs within the most proximal of the four GATA motifs (GATA-A element) in the R-type promoter region. In two patients who were homozygous for this mutation, a semiquantitative reverse transcription polymerase chain reaction (PCR) procedure was used to evaluate the amount of R-PK mRNA transcript in the reticulocytes. The mRNA level was about five times lower than in normal controls, demonstrating that the PKLR gene transcription is severely affected, most probably because the -72A-->G point mutation disables the binding of the erythroid transcription factor GATA-1 to the GATA-A element. Supporting these data, the two patients homozygous for the -72A-->G mutation had severe haemolytic anaemia and were transfusion dependent until splenectomy. Two other patients who were compound heterozygous for this mutation and the previously described missense mutation 1456C-->T had a mild condition.

  11. Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment.

    Science.gov (United States)

    Lupsa, Beatrice C; Sachdev, Vandana; Lungu, Andreea O; Rosing, Douglas R; Gorden, Phillip

    2010-07-01

    Lipodystrophy is a rare disorder characterized by loss of adipose tissue and low leptin levels. This condition is characterized by severe dyslipidemia, insulin resistance, diabetes mellitus, and steatohepatitis. Another phenotypic feature that occurs with considerable frequency in generalized lipodystrophy is cardiomyopathy. We report here the cardiac findings in a cohort of patients with generalized congenital and acquired lipodystrophy, and present a literature review of the cardiac findings in patients with generalized lipodystrophy. We studied 44 patients with generalized congenital and acquired lipodystrophy, most of them enrolled in a clinical trial of leptin therapy. Patients underwent electrocardiograms and transthoracic echocardiograms to evaluate their cardiac status. We followed these patients for an extended time period, some of them up to 8 years. Evaluation of our cohort of patients with generalized lipodystrophy shows that cardiomyopathy is a frequent finding in this population. Most of our patients had hypertrophic cardiomyopathy, and only a small number had features of dilated cardiomyopathy. Hypertrophic cardiomyopathy was more frequent in patients with seipin mutation, a finding consistent with the literature. The underlying mechanism for cardiomyopathy in lipodystrophy is not clear. Extreme insulin resistance and the possibility of a "lipotoxic cardiomyopathy" should be entertained as possible explanations.

  12. Mutation in fucose synthesis gene of Klebsiella pneumoniae affects capsule composition and virulence in mice.

    Science.gov (United States)

    Pan, Po-Chang; Chen, Hui-Wen; Wu, Po-Kuan; Wu, Yu-Yang; Lin, Chun-Hung; Wu, June H

    2011-02-01

    The emerging pathogenicity of Klebsiella pneumoniae (KP) is evident by the increasing number of clinical cases of liver abscess (LA) due to KP infection. A unique property of KP is its thick mucoid capsule. The bacterial capsule has been found to contain fucose in KP strains causing LA but not in those causing urinary tract infections. The products of the gmd and wcaG genes are responsible for converting mannose to fucose in KP. A KP strain, KpL1, which is known to have a high death rate in infected mice, was mutated by inserting an apramycin-resistance gene into the gmd. The mutant expressed genes upstream and downstream of gmd, but not gmd itself, as determined by reverse transcriptase polymerase chain reaction. The DNA mapping confirmed the disruption of the gmd gene. This mutant decreased its ability to kill infected mice and showed decreased virulence in infected HepG2 cells. Compared with wild-type KpL1, the gmd mutant lost fucose in capsular polysaccharides, increased biofilm formation and interacted more readily with macrophages. The mutant displayed morphological changes with long filament forms and less uniform sizes. The mutation also converted the serotype from K1 of wild-type to K2 and weak K3. The results indicate that disruption of the fucose synthesis gene affected the pathophysiology of this bacterium and may be related to the virulence of this KpL1 strain.

  13. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia.

    Directory of Open Access Journals (Sweden)

    Ferdos Alaa El Din

    Full Text Available Hereditary Hemorrhagic Telangiectasia syndrome (HHT or Rendu-Osler-Weber (ROW syndrome is an autosomal dominant vascular disorder. Two most common forms of HHT, HHT1 and HHT2, have been linked to mutations in the endoglin (ENG and activin receptor-like kinase 1 (ACVRL1or ALK1 genes respectively. This work was designed to examine the pathogenicity of 23 nucleotide variations in ACVRL1 gene detected in more than 400 patients. Among them, 14 missense mutations and one intronic variant were novels, and 8 missense mutations were previously identified with questionable implication in HHT2. The functionality of missense mutations was analyzed in response to BMP9 (specific ligand of ALK1, the maturation of the protein products and their localization were analyzed by western blot and fluorescence microscopy. The splicing impairment of the intronic and of two missense mutations was examined by minigene assay. Functional analysis showed that 18 out of 22 missense mutations were defective. Splicing analysis revealed that one missense mutation (c.733A>G, p.Ile245Val affects the splicing of the harboring exon 6. Similarly, the intronic mutation outside the consensus splicing sites (c.1048+5G>A in intron 7 was seen pathogenic by splicing study. Both mutations induce a frame shift creating a premature stop codon likely resulting in mRNA degradation by NMD surveillance mechanism. Our results confirm the haploinsufficiency model proposed for HHT2. The affected allele of ACVRL1 induces mRNA degradation or the synthesis of a protein lacking the receptor activity. Furthermore, our data demonstrate that functional and splicing analyses together, represent two robust diagnostic tools to be used by geneticists confronted with novel or conflicted ACVRL1 mutations.

  14. Sex differences in cardiomyopathies

    NARCIS (Netherlands)

    Meyer, Sven; van der Meer, Peter; van Tintelen, J. Peter; van den Berg, Maarten P.

    2014-01-01

    Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RC

  15. Children's Cardiomyopathy Foundation

    Science.gov (United States)

    ... families living with cardiomyopathy through CCF’s new online Coffee & Chat event. On Wednesday, November 16, CCF will be hosting "Navigating Disability Benefits," a webinar to provide an overview of disability ...

  16. Error-prone and error-restrictive mutations affecting ribosomal protein S12.

    Science.gov (United States)

    Agarwal, Deepali; Gregory, Steven T; O'Connor, Michael

    2011-07-01

    Ribosomal protein S12 plays a pivotal role in decoding functions on the ribosome. X-ray crystallographic analyses of ribosomal complexes have revealed that S12 is involved in the inspection of codon-anticodon pairings in the ribosomal A site, as well as in the succeeding domain rearrangements of the 30S subunit that are essential for accommodation of aminoacyl-tRNA. A role for S12 in tRNA selection is also well supported by classical genetic analyses; mutations affecting S12 are readily isolated in bacteria and organelles, since specific alterations in S12 confer resistance to the error-inducing antibiotic streptomycin, and the ribosomes from many such streptomycin-resistant S12 mutants display decreased levels of miscoding. However, substitutions that confer resistance to streptomycin likely represent a very distinct class of all possible S12 mutants. Until recently, the technical difficulties in generating random, unselectable mutations in essential genes in complex operons have generally precluded the analysis of other classes of S12 alterations. Using a recombineering approach, we have targeted the Escherichia coli rpsL gene, encoding S12, for random mutagenesis and screened the resulting mutants for effects on decoding fidelity. We have recovered over 40 different substitutions located throughout the S12 protein that alter the accuracy of translation without substantially affecting the sensitivity to streptomycin. Moreover, this collection includes mutants that promote miscoding, as well as those that restrict decoding errors. These results affirm the importance of S12 in decoding processes and indicate that alterations in this essential protein can have diverse effects on the accuracy of decoding.

  17. Segmental overgrowth syndrome due to an activating PIK3CA mutation identified in affected muscle tissue by exome sequencing

    DEFF Research Database (Denmark)

    Rasmussen, Maria; Sunde, Lone; Weigert, Karen Petra;

    2014-01-01

    Mosaic PIK3CA-mutations have been described in an increasing number of overgrowth syndromes. We describe a patient with a previously unreported segmental overgrowth syndrome with the mutation, PIKCA3 c.3140A>G (p.His1047Arg) in affected tissue diagnosed by exome sequencing. This PIK3CA-associated......-associated segmental overgrowth syndrome overlaps with CLOVES syndrome and fibroadipose hyperplasia but is distinct from each of these entities....

  18. Familial hypertrophic cardiomyopathy related cardiac troponin C L29Q mutation alters length-dependent activation and functional effects of phosphomimetic troponin I*.

    Directory of Open Access Journals (Sweden)

    Alison Y Li

    Full Text Available The Ca(2+ binding properties of the FHC-associated cardiac troponin C (cTnC mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca(2+ binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca(2+ affinity by 27% in the steady-state measurement and increased the Ca(2+ dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations suggest that L29Q destabilizes the conformation of cNTnC in the presence of phosphomimetic cTnI and potentially modulates the Ca(2+ sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca(2+ sensitivity in a highly sarcomere length (SL-dependent manner. The well-established reduction of Ca(2+ sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca(2+ sensitivity. This might result from its modified interaction with cTnI which altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. This study demonstrates that the L29Q mutation alters the contractility and the functional effects of the phosphomimetic cTnI in both thin filament and single skinned cardiomyocytes and importantly that this effect is highly sarcomere length dependent.

  19. Biventricular Takotsubo Cardiomyopathy

    Science.gov (United States)

    Daoko, Joseph; Rajachandran, Manu; Savarese, Ronald; Orme, Joseph

    2013-01-01

    Biventricular takotsubo cardiomyopathy is associated with more hemodynamic instability than is isolated left ventricular takotsubo cardiomyopathy; medical management is more invasive and the course of hospitalization is longer. In March 2011, a 62-year-old woman presented at our emergency department with abdominal pain, nausea, and vomiting. On hospital day 2, she experienced chest pain. An electrocardiogram and cardiac enzyme levels suggested an acute myocardial infarction. She underwent cardiac angiography and was found to have severe left ventricular systolic dysfunction involving the mid and apical segments, which resulted in a left ventricular ejection fraction of 0.10 to 0.15 in the absence of obstructive coronary artery disease. Her hospital course was complicated by cardiogenic shock that required hemodynamic support with an intra-aortic balloon pump and dobutamine. A transthoracic echocardiogram revealed akinesis of the mid-to-distal segments of the left ventricle and mid-to-apical dyskinesis of the right ventricular free wall characteristic of biventricular takotsubo cardiomyopathy. After several days of medical management, the patient was discharged from the hospital in stable condition. To the best of our knowledge, this is the first review of the literature on biventricular takotsubo cardiomyopathy that compares its hemodynamic instability and medical management requirements with those of isolated left ventricular takotsubo cardiomyopathy. Herein, we discuss the case of our patient, review the pertinent medical literature, and convey the prevalence and importance of right ventricular involvement in patients with takotsubo cardiomyopathy. PMID:23914028

  20. The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

    DEFF Research Database (Denmark)

    Al-Saaidi, Rasha; Rasmussen, Torsten Bloch; Palmfeldt, Johan

    2013-01-01

    degraded. Furthermore, WB analysis showed that the expression of lamin C protein was reduced by the expected approximately 50%. Clearly decreased lamin A and lamin C levels were also observed by immunofluorescence microscopy analysis. However, results from both WB and nano-liquid chromatography....... The LMNA gene generates two major transcripts encoding the nuclear lamina major components lamin A and lamin C by alternative splicing. Both haploinsuffiency and dominant negative effects have been proposed as disease mechanism for premature termination codon (PTC) mutations in LMNA. These mechanisms....../mass spectrometry demonstrated that the levels of lamin A protein were more reduced suggesting an effect on expression of lamin A from the wild type allele. PCR analysis of the ratio of lamin A to lamin C transcripts showed unchanged relative amounts of lamin A transcript suggesting that the effect on the wild type...

  1. New perspectives in Hypertrophic Cardiomyopathy

    NARCIS (Netherlands)

    M.J.M. Kofflard (Marcel)

    1998-01-01

    textabstractHypertrophic cardiomyopathy is a primary cardiac disorder with a heterogeneous expression. Although relatively uncommon, the disease has been studied extensively as appears from the numerous studies that have explored specific facets of hypertrophic cardiomyopathy. This review will focus

  2. Effects of calcium binding and the hypertrophic cardiomyopathy A8V mutation on the dynamic equilibrium between closed and open conformations of the regulatory N-domain of isolated cardiac troponin C.

    Science.gov (United States)

    Cordina, Nicole M; Liew, Chu K; Gell, David A; Fajer, Piotr G; Mackay, Joel P; Brown, Louise J

    2013-03-19

    Troponin C (TnC) is the calcium-binding subunit of the troponin complex responsible for initiating striated muscle contraction in response to calcium influx. In the skeletal TnC isoform, calcium binding induces a structural change in the regulatory N-domain of TnC that involves a transition from a closed to open structural state and accompanying exposure of a large hydrophobic patch for troponin I (TnI) to subsequently bind. However, little is understood about how calcium primes the N-domain of the cardiac isoform (cTnC) for interaction with the TnI subunit as the open conformation of the regulatory domain of cTnC has been observed only in the presence of bound TnI. Here we use paramagnetic relaxation enhancement (PRE) to characterize the closed to open transition of isolated cTnC in solution, a process that cannot be observed by traditional nuclear magnetic resonance methods. Our PRE data from four spin-labeled monocysteine constructs of isolated cTnC reveal that calcium binding triggers movement of the N-domain helices toward an open state. Fitting of the PRE data to a closed to open transition model reveals the presence of a small population of cTnC molecules in the absence of calcium that possess an open conformation, the level of which increases substantially upon Ca(2+) binding. These data support a model in which calcium binding creates a dynamic equilibrium between the closed and open structural states to prime cTnC for interaction with its target peptide. We also used PRE data to assess the structural effects of a familial hypertrophic cardiomyopathy point mutation located within the N-domain of cTnC (A8V). The PRE data show that the Ca(2+) switch mechanism is perturbed by the A8V mutation, resulting in a more open N-domain conformation in both the apo and holo states.

  3. Isolation of mutations affecting neural circuitry required for grooming behavior in Drosophila melanogaster.

    Science.gov (United States)

    Phillis, R W; Bramlage, A T; Wotus, C; Whittaker, A; Gramates, L S; Seppala, D; Farahanchi, F; Caruccio, P; Murphey, R K

    1993-03-01

    We have developed a screen for the isolation of mutations that produce neural defects in adult Drosophila melanogaster. In this screen, we identify mutants as flies unable to remove a light coating of applied dust in a 2-hr period. We have recovered and characterized six mutations and have found that they produce coordination defects and some have reduced levels of reflex responsiveness to the stimulation of single tactile sensory bristles. The grooming defects produced by all six of the mutations are recessive, and each of the mutations has been genetically mapped. We have also used our assay to test the grooming ability of stocks containing mutations that produce known neural defects.

  4. Functional assessment of human coding mutations affecting skin pigmentation using zebrafish.

    Directory of Open Access Journals (Sweden)

    Zurab R Tsetskhladze

    Full Text Available A major challenge in personalized medicine is the lack of a standard way to define the functional significance of the numerous nonsynonymous, single nucleotide coding variants that are present in each human individual. To begin to address this problem, we have used pigmentation as a model polygenic trait, three common human polymorphisms thought to influence pigmentation, and the zebrafish as a model system. The approach is based on the rescue of embryonic zebrafish mutant phenotypes by "humanized" zebrafish orthologous mRNA. Two hypomorphic polymorphisms, L374F in SLC45A2, and A111T in SLC24A5, have been linked to lighter skin color in Europeans. The phenotypic effect of a second coding polymorphism in SLC45A2, E272K, is unclear. None of these polymorphisms had been tested in the context of a model organism. We have confirmed that zebrafish albino fish are mutant in slc45a2; wild-type slc45a2 mRNA rescued the albino mutant phenotype. Introduction of the L374F polymorphism into albino or the A111T polymorphism into slc24a5 (golden abolished mRNA rescue of the respective mutant phenotypes, consistent with their known contributions to European skin color. In contrast, the E272K polymorphism had no effect on phenotypic rescue. The experimental conclusion that E272K is unlikely to affect pigmentation is consistent with a lack of correlation between this polymorphism and quantitatively measured skin color in 59 East Asian humans. A survey of mutations causing human oculocutaneous albinism yielded 257 missense mutations, 82% of which are theoretically testable in zebrafish. The developed approach may be extended to other model systems and may potentially contribute to our understanding the functional relationships between DNA sequence variation, human biology, and disease.

  5. Psychological Distress, Anxiety, and Depression of Cancer-Affected BRCA1/2 Mutation Carriers: a Systematic Review.

    Science.gov (United States)

    Ringwald, Johanna; Wochnowski, Christina; Bosse, Kristin; Giel, Katrin Elisabeth; Schäffeler, Norbert; Zipfel, Stephan; Teufel, Martin

    2016-10-01

    Understanding the intermediate- and long-term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer-affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate- and long-term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer-affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate- and long-term studies focusing on distress, anxiety, and depression symptoms among cancer-affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer-affected mutation carriers experienced a negative effect in relation to psychological well-being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate- and long-term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer-affected mutation carriers. We concluded that current well-implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate- and long-term psychological impact of a positive test disclosure.

  6. Mutations in the CRE pocket of bacterial RNA polymerase affect multiple steps of transcription.

    Science.gov (United States)

    Petushkov, Ivan; Pupov, Danil; Bass, Irina; Kulbachinskiy, Andrey

    2015-07-13

    During transcription, the catalytic core of RNA polymerase (RNAP) must interact with the DNA template with low-sequence specificity to ensure efficient enzyme translocation and RNA extension. Unexpectedly, recent structural studies of bacterial promoter complexes revealed specific interactions between the nontemplate DNA strand at the downstream edge of the transcription bubble (CRE, core recognition element) and a protein pocket formed by core RNAP (CRE pocket). We investigated the roles of these interactions in transcription by analyzing point amino acid substitutions and deletions in Escherichia coli RNAP. The mutations affected multiple steps of transcription, including promoter recognition, RNA elongation and termination. In particular, we showed that interactions of the CRE pocket with a nontemplate guanine immediately downstream of the active center stimulate RNA-hairpin-dependent transcription pausing but not other types of pausing. Thus, conformational changes of the elongation complex induced by nascent RNA can modulate CRE effects on transcription. The results highlight the roles of specific core RNAP-DNA interactions at different steps of RNA synthesis and suggest their importance for transcription regulation in various organisms.

  7. Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor [gamma] chain gene in SCIDX1 that differently affect the mRNA processing

    Energy Technology Data Exchange (ETDEWEB)

    Markiewicz, S.; Fischer, A.; Saint Basile, G. de (INSERM, Paris (France)); Subtil, A.; Dautry-Varsat, A. (Institut Pasteur, Paris (France))

    1994-05-01

    The interleukin-2 receptor [gamma] (IL-2R[gamma]) chain gene encodes a 64-kDa protein that not only composes the high-affinity form of the IL-2 binding receptor in association with the 2R [alpha] and [beta] chains, but also participates in at least the IL-4 and IL-7 receptor complexes. Mutations in this gene have recently been shown to cause X-linked severe combined immunodeficiency (SCIDX1). This disease of the immune system results from an early block of T lymphocyte and natural killer (NK) cell differentiation, which leads to a severe cellular and humoral immune defect that is lethal unless treated by bone marrow transplantation. Analysis of the IL-2R[gamma] gene in SCIDX1 patients has revealed the presence of heterogeneous mutations principally located in the extracellular domain of the molecule. We report here three intraexonic mutations and one deletion in the IL-2R[gamma] gene in four SCIDX1 patients. These mutations appear to differentially affect RNA processing, either by decreasing IL-2R[gamma] mRNA level or by the skipping of a constitutive exon. 16 refs., 1 fig.

  8. FIRING PROPERTY OF INFERIOR COLLICULUS NEURONS AFFECTED BY FMR1 GENE MUTATION

    Institute of Scientific and Technical Information of China (English)

    Brittany Mott; SUN Wei

    2014-01-01

    Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syn-drome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product FMRP. Impairment in the nor-mal functioning of FMRP leads to learning and memory deficits and heightened sensitivity to sensory stimuli, including sound (hyperacusis). The molecular basis of fragile X syndrome is thoroughly understood;however, the neural mechanisms underly-ing hyperacusis have not yet been determined. As the inferior colliculus (IC) is the principal midbrain nucleus of the auditory pathway, the current study addresses the questions underlying the neural mechanism of hyperacusis within the IC of fragile X mice. Acute experiments were performed in which electrophysiological recordings of the IC in FMR1-KO and WT mice were measured. Results showed that Q-values for WT were significantly larger than that of FMR-1 KO mice, indicating that WT mice exhibit sharper tuning curves than FMR1-KO mice. We also found the ratio of the monotonic neurons in the KO mice was much higher than the WT mice. These results suggest that lack of FMRP in the auditory system affects the developmental maturation and function of structures within the auditory pathway, and in this case specifically the IC. The dysfunction ob-served within the auditory neural pathway and in particular the IC may be related to the increased susceptibility to sound as seen in individuals with fragile X syndrome. Our study may help on understanding the mechanisms of the fragile X syndrome and hyperacusis.

  9. Treatment of Chagas Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Fernando A. Botoni

    2013-01-01

    Full Text Available Chagas' disease (ChD, caused by the protozoa Trypanosoma cruzi (T. cruzi, was discovered and described by the Brazilian physician Carlos Chagas in 1909. After a century of original description, trypanosomiasis still brings much misery to humanity and is classified as a neglected tropical disease prevalent in underdeveloped countries, particularly in South America. It is an increasing worldwide problem due to the number of cases in endemic areas and the migration of infected subjects to more developed regions, mainly North America and Europe. Despite its importance, chronic chagas cardiomyopathy (CCC pathophysiology is yet poorly understood, and independently of its social, clinical, and epidemiological importance, the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Therefore, the objective of this review is to describe the treatment of Chagas cardiomyopathy with emphasis on its peculiarities.

  10. Tako-tsubo cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Yan Zhuang; Di Xu

    2009-01-01

    Tako-tsubo cardiomyopathy(TC) is a recently described acute cardiac syndrome, which the latest cardiomyopathy classification of the European Society of Cardiology describes as an unclassified cardiomyopathy. TC mimics acute myocardial infarction(AMI) and is characterised by ischaemic chest symptoms, an elevated electrocardiogram ST-segment, and moderately increased levels of cardiac disease markers. However, patients with TC have no coronary angiogram-detectable or non-obstructive coronary arterial disease(CAD), and left ventriculography documents transient left apical and middle ventricular wall dysfunction. In this review, we describe TC and evaluate epidemiological, clinical and instrumental features, pathophysiological mechanisms, therapy and prognosis of this syndrome, with a view to raising awareness of the disease.

  11. Arrhythmias in peripartum cardiomyopathy.

    Science.gov (United States)

    Honigberg, Michael C; Givertz, Michael M

    2015-06-01

    Peripartum cardiomyopathy (PPCM) is a complication of late pregnancy and the early postpartum period characterized by dilated cardiomyopathy and heart failure with reduced ejection fraction. Approximately half of women fail to recover left ventricular function. Standard management of heart failure is indicated, with some exceptions for women who are predelivery or breastfeeding. Atrial and ventricular arrhythmias are reported in PPCM, but the frequency of arrhythmias in this condition is not well characterized. Management of PPCM-associated arrhythmias may include antiarrhythmic drugs, catheter ablation, and wearable or implantable cardioverter-defibrillators. Further research is needed on the prevalence, natural history, and optimal management of arrhythmias in PPCM.

  12. Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology.

    Science.gov (United States)

    Uhlmann, Wendy R; Peñaherrera, Maria S; Robinson, Wendy P; Milunsky, Jeff M; Nicholson, Jane M; Albin, Roger L

    2015-05-01

    Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full HTT mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full HTT mutations. Most had one HTT allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT allele has ≤40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non-identical expanded HTT alleles.

  13. Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability.

    Science.gov (United States)

    Fontanesi, Flavia; Palmieri, Luigi; Scarcia, Pasquale; Lodi, Tiziana; Donnini, Claudia; Limongelli, Anna; Tiranti, Valeria; Zeviani, Massimo; Ferrero, Iliana; Viola, Anna Maria

    2004-05-01

    Autosomal dominant and recessive forms of progressive external ophthalmoplegia (adPEO and arPEO) are mitochondrial disorders characterized by the presence of multiple deletions of mitochondrial DNA in affected tissues. Four adPEO-associated missense mutations have been identified in the ANT1 gene. In order to investigate their functional consequences on cellular physiology, we introduced three of them at equivalent positions in AAC2, the yeast orthologue of human ANT1. We demonstrate here that expression of the equivalent mutations in aac2-defective haploid strains of Saccharomyces cerevisiae results in (a) a marked growth defect on non-fermentable carbon sources, and (b) a concurrent reduction of the amount of mitochondrial cytochromes, cytochrome c oxidase activity and cellular respiration. The efficiency of ATP and ADP transport was variably affected by the different AAC2 mutations. However, irrespective of the absolute level of activity, the AAC2 pathogenic mutants showed a significant defect in ADP versus ATP transport compared with wild-type AAC2. In order to study whether a dominant phenotype, as in humans, could be observed, the aac2 mutant alleles were also inserted in combination with the endogenous wild-type AAC2 gene. The heteroallelic strains behaved as recessive for oxidative growth and petite-negative phenotype. In contrast, reduction in cytochrome content and increased mtDNA instability appeared to behave as dominant traits in heteroallelic strains. Our results indicate that S. cerevisiae is a suitable in vivo model to study the pathogenicity of the human ANT1 mutations and the pathophysiology leading to impairment of oxidative phosphorylation and damage of mtDNA integrity, as found in adPEO.

  14. Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

    Science.gov (United States)

    Mistri, Mehul; Tamhankar, Parag M; Sheth, Frenny; Sanghavi, Daksha; Kondurkar, Pratima; Patil, Swapnil; Idicula-Thomas, Susan; Gupta, Sarita; Sheth, Jayesh

    2012-01-01

    Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

  15. Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

    Directory of Open Access Journals (Sweden)

    Mehul Mistri

    Full Text Available Tay Sachs disease (TSD is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients. Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K, c.964 G>A (p.D322N, c.964 G>T (p.D322Y, c.1178C>G (p.R393P and c.1385A>T (p.E462V, c.1432 G>A (p.G478R and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W. The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

  16. Cardiomyopathy Following Latrodectus Envenomation

    Directory of Open Access Journals (Sweden)

    Levine, Michael

    2010-12-01

    Full Text Available Latrodectus envenomations are common throughout the United States and the world. While many envenomations can result in catecholamine release with resultant hypertension and tachycardia, myocarditis is very rare. We describe a case of a 22- year-old male who sustained a Latrodectus envenomation complicated by cardiomyopathy. [West J Emerg Med. 2010; 11(5:521-523.

  17. Application of Echocardiography on Transgenic Mice with Cardiomyopathies

    Directory of Open Access Journals (Sweden)

    G. Chen

    2012-01-01

    Full Text Available Cardiomyopathies are common cardiac disorders that primarily affect cardiac muscle resulting in cardiac dysfunction and heart failure. Transgenic mouse disease models have been developed to investigate the cellular mechanisms underlying heart failure and sudden cardiac death observed in cardiomyopathy cases and to explore the therapeutic outcomes in experimental animals in vivo. Echocardiography is an essential diagnostic tool for accurate and noninvasive assessment of cardiac structure and function in experimental animals. Our laboratory has been among the first to apply high-frequency research echocardiography on transgenic mice with cardiomyopathies. In this work, we have summarized our and other studies on assessment of systolic and diastolic dysfunction using conventional echocardiography, pulsed Doppler, and tissue Doppler imaging in transgenic mice with various cardiomyopathies. Estimation of embryonic mouse hearts has been performed as well using this high-resolution echocardiography. Some technical considerations in mouse echocardiography have also been discussed.

  18. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

    Science.gov (United States)

    Depienne, Christel; Bouteiller, Delphine; Keren, Boris; Cheuret, Emmanuel; Poirier, Karine; Trouillard, Oriane; Benyahia, Baya; Quelin, Chloé; Carpentier, Wassila; Julia, Sophie; Afenjar, Alexandra; Gautier, Agnès; Rivier, François; Meyer, Sophie; Berquin, Patrick; Hélias, Marie; Py, Isabelle; Rivera, Serge; Bahi-Buisson, Nadia; Gourfinkel-An, Isabelle; Cazeneuve, Cécile; Ruberg, Merle; Brice, Alexis; Nabbout, Rima; Leguern, Eric

    2009-02-01

    Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.

  19. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

    Directory of Open Access Journals (Sweden)

    Christel Depienne

    2009-02-01

    Full Text Available Dravet syndrome (DS is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.

  20. Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age

    NARCIS (Netherlands)

    Knauff, Erik A. H.; Richardus, Renate; Eijkemans, Marinus J.; Broekinans, Frank J.; de Jong, Frank J.; Fauser, Bart C. J. M.; Bosch, Annet M.

    2007-01-01

    Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and ea

  1. High prevalence of Arginine to Glutamine Substitution at 98, 141 and 162 positions in Troponin I (TNNI3 associated with hypertrophic cardiomyopathy among Indians

    Directory of Open Access Journals (Sweden)

    Rani Deepa

    2012-08-01

    Full Text Available Abstract Background Troponin I (TNNI3 is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7% in this gene had been reported in hypertrophic cardiomyopathy patients (HCM. However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study. Methods We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM, along with 160 healthy controls, inhabited in the same geographical region of southern India. Results Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM. The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++. The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85% with a rare codon (GAA: 14%. Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing. Conclusion Our study has provided valuable information regarding the prevalence of TNNI3 mutations in

  2. Isolation of Mutations Affecting Neural Circuitry Required for Grooming Behavior in Drosophila Melanogaster

    OpenAIRE

    1993-01-01

    We have developed a screen for the isolation of mutations that produce neural defects in adult Drosophila melanogaster. In this screen, we identify mutants as flies unable to remove a light coating of applied dust in a 2-hr period. We have recovered and characterized six mutations and have found that they produce coordination defects and some have reduced levels of reflex responsiveness to the stimulation of single tactile sensory bristles. The grooming defects produced by all six of the muta...

  3. Peripartum Cardiomyopathy From a Genetic Perspective.

    Science.gov (United States)

    Kamiya, Chizuko A; Yoshimatsu, Jun; Ikeda, Tomoaki

    2016-07-25

    Peripartum cardiomyopathy (PPCM) is a rare, but life-threatening condition that occurs during the peripartum period in previously healthy women. Although its etiology remains unknown, potential risk factors include hypertensive disorders during pregnancy, such as preeclampsia, advanced maternal age, multiparity, multiple gestation, and African descent. Several cohort studies of PPCM revealed that the prevalence of these risk factors was quite similar. Clinically, approximately 40% of PPCM patients are complicated with hypertensive disorders during pregnancy. Because PPCM is a diagnosis of exclusion, heterogeneity is a common element in its pathogenesis. Recent genetic research has given us new aspects of the disease. PPCM and dilated cardiomyopathy (DCM) share genetic predisposition: 15% of PPCM patients were found to have genetic mutations that have been associated with DCM, and they showed a lower recovery rate. Other basic research using PPCM model mice suggests that predisposition genes related to both hypertensive and cardiac disorders via angiogenic imbalance may explain common elements of hypertensive disorders and PPCM. Furthermore, hypertensive disorders during pregnancy are now found to be a risk factor of not only PPCM, but also cardiomyopathy in the future. Understanding genetic variations allows us to stratify PPCM patients and to guide therapy. (Circ J 2016; 80: 1684-1688).

  4. Novel missense mutation in the GALNS gene in an affected patient with severe form of mucopolysaccharidosis type IVA.

    Science.gov (United States)

    Seyedhassani, Seyed Mohammad; Hashemi-Gorji, Feyzollah; Yavari, Mahdieh; Mirfakhraie, Reza

    2015-10-23

    Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A, is an autosomal recessive disorder characterized by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes major skeletal and connective tissue abnormalities and affects multiple organ systems. In this study, one MPS IVA patient with a severe form from consanguine large Iranian family has been investigated. To find a mutation, all of the 14 exons and intron-exon junctions of GALNS gene were sequenced. Sequencing results were analyzed using bioinformatic analysis in order to predict probable pathogenic effect of the variant. One novel homozygous missense mutation in exon 5, c.542A>G (p.Y181C), was found in the proband. That was predicted as being probably pathogenic by bioinformatics analysis. Segregation and familial study confirmed this pathogenic mutation. In conclusion, we have identified the novel mutation responsible for MPS IVA in an Iranian patient to assist in the diagnosis, genetic counseling and prenatal diagnosis of the affected families.

  5. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

    Science.gov (United States)

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

  6. HERC 1 ubiquitin ligase mutation affects neocortical, CA3 hippocampal and spinal cord projection neurons. An ultrastructural study

    Directory of Open Access Journals (Sweden)

    Rocío eRuiz

    2016-04-01

    Full Text Available The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and, hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

  7. Private mitochondrial DNA variants in danish patients with hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Christian M Hagen

    Full Text Available Hypertrophic cardiomyopathy (HCM is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9% non-coding and synonymous variants, a further 109 (24.4% with a global prevalence > 0.1%, three (0.7% haplogroup associated and 19 (2.0% variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.

  8. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): A clue to the pathogenesis of oncocytic cardiomyopathy?

    Energy Technology Data Exchange (ETDEWEB)

    Bird, L.M.; Krous, H.F.; Eichenfield, L.F.; Swalwell, C.I.; Jones, M.C. [Univ. of California, San Diego, CA (United States)

    1994-11-01

    A infant girl had red stellate skin lesions on the cheeks and neck, and mildly short palpebral fissures. Her skin abnormality was typical of microphthalmia with linear skin defects (MLS), a newly recognized syndrome consisting of congenital linear skin defects and ocular abnormalities in females monosomic for Xp22. She died suddenly and unexpectedly at age 4 months; the cause of death was ascribed to oncocytic cardiomyopathy. Oncocytic cardiomyopathy occurs only in young children, who present with refractory arrhythmias leading to cardiac arrest. The coexistence of two rare conditions, one of which is mapped to the X chromosome, and an excess of affected females with oncocytic cardiomyopathy is also X-linked, with Xp22 being a candidate region. Overlapping manifestations in the two conditions (ocular abnormalities in cases of oncocytic cardiomyopathy and arrhythmias in MLS) offer additional support for this hypothesis. 43 refs., 2 figs., 2 tabs.

  9. Screening of mutations affecting protein stability and dynamics of FGFR1—A simulation analysis

    Directory of Open Access Journals (Sweden)

    C. George Priya Doss

    2012-12-01

    Full Text Available Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1 destabilize protein and have been implicated in several genetic disorders like various forms of cancer, Kallamann syndrome, Pfeiffer syndrome, Jackson Weiss syndrome, etc. In order to gain functional insight into mutation caused by amino acid substitution to protein function and expression, special emphasis was laid on molecular dynamics simulation techniques in combination with in silico tools such as SIFT, PolyPhen 2.0, I-Mutant 3.0 and SNAP. It has been estimated that 68% nsSNPs were predicted to be deleterious by I-Mutant, slightly higher than SIFT (37%, PolyPhen 2.0 (61% and SNAP (58%. From the observed results, P722S mutation was found to be most deleterious by comparing results of all in silico tools. By molecular dynamics approach, we have shown that P722S mutation leads to increase in flexibility, and deviated more from the native structure which was supported by the decrease in the number of hydrogen bonds. In addition, biophysical analysis revealed a clear insight of stability loss due to P722S mutation in FGFR1 protein. Majority of mutations predicted by these in silico tools were in good concordance with the experimental results.

  10. ARRHYTHMOGENIC CALMODULIN MUTATIONS AFFECT THE ACTIVATION AND TERMINATION OF CARDIAC RYANODINE RECEPTOR MEDIATED CA2+ RELEASE

    DEFF Research Database (Denmark)

    Søndergaard, Mads Toft; Chazin, Walter J.; Chen, Wayne S.R.;

    We recently identified the first two human missense mutations in a calmodulin (CaM) gene (CALM1) and linked these to catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death in young individuals1. More CaM mutations have since been identified in CALM1 and also......M in the presence of RyR2 CaMBD. The D95V, N97S and D129G mutations lowered the affinity of Ca2+ binding of the C-lobe of CaM, to apparent KDs of ~ 140, 150, and 4000 nM, respectively, consistent with the critical role of these residues in Ca2+ binding to the C-lobe. Thus, we suggest that these mutations may shift...... to an apo-CaM binding state during diastole, leading to dysregulation of RyR2 mediated Ca2+ release. Despite the pronounced impact on RyR2 mediated Ca2+ release, the N-lobe N53I mutation only imposed a small lowering of the N-lobe Ca2+ affinity (KD ~1200 nM). Thus, the RyR2 mediated Ca2+ release is either...

  11. Two desmin gene mutations associated with myofibrillar myopathies in Polish families.

    Directory of Open Access Journals (Sweden)

    Jakub Piotr Fichna

    Full Text Available Desmin is a muscle-specific intermediate filament protein which forms a network connecting the sarcomere, T tubules, sarcolemma, nuclear membrane, mitochondria and other organelles. Mutations in the gene coding for desmin (DES cause skeletal myopathies often combined with cardiomyopathy, or isolated cardiomyopathies. The molecular pathomechanisms of the disease remain ambiguous. Here, we describe and comprehensively characterize two DES mutations found in Polish patients with a clinical diagnosis of desminopathy. The study group comprised 16 individuals representing three families. Two mutations were identified: a novel missense mutation (Q348P and a small deletion of nine nucleotides (A357_E359del, previously described by us in the Polish population. A common ancestry of all the families bearing the A357_E359del mutation was confirmed. Both mutations were predicted to be pathogenic using a bioinformatics approach, including molecular dynamics simulations which helped to rationalize abnormal behavior at molecular level. To test the impact of the mutations on DES expression and the intracellular distribution of desmin muscle biopsies were investigated. Elevated desmin levels as well as its atypical localization in muscle fibers were observed. Additional staining for M-cadherin, α-actinin, and myosin heavy chains confirmed severe disruption of myofibrill organization. The abnormalities were more prominent in the Q348P muscle, where both small atrophic fibers as well large fibers with centrally localized nuclei were observed. We propose that the mutations affect desmin structure and cause its aberrant folding and subsequent aggregation, triggering disruption of myofibrils organization.

  12. Analysis of a mutation affecting the specificity domain for prohead binding of the bacteriophage lambda terminase.

    OpenAIRE

    1992-01-01

    Genetic studies have identified a specificity domain for prohead binding in the C-terminal 32 amino acids of gpA, the large subunit of bacteriophage lambda terminase (S. Frackman, D. A. Siegele, and M. Feiss, J. Mol. Biol. 180:283-300, 1984). In the present work, an amber mutation, Aam42, in the fifth-to-last codon of the A gene was found to be lethal in nonsuppressing hosts. The mutation, expected to generate gpA lacking the last five amino acids, caused the production of a terminase that cu...

  13. Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy.

    Science.gov (United States)

    Roma-Rodrigues, Catarina; Fernandes, Alexandra R

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that occurs mainly due to mutations (>1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people in the general population, is typically inherited in an autosomal dominant pattern, and presents variable expressivity and age-related penetrance. Due to the morphological and pathological heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying mutations on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlighting their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems.

  14. Cardiac troponin and tropomyosin: structural and cellular perspectives to unveil the Hypertrophic Cardiomyopathy phenotype

    Directory of Open Access Journals (Sweden)

    Mayra de A. Marques

    2016-09-01

    Full Text Available Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1,400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the disease of the sarcomere. The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53, seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We

  15. Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy.

    Science.gov (United States)

    Li Mura, Ilena Egle Astrid; Bauce, Barbara; Nava, Andrea; Fanciulli, Manuela; Vazza, Giovanni; Mazzotti, Elisa; Rigato, Ilaria; De Bortoli, Marzia; Beffagna, Giorgia; Lorenzon, Alessandra; Calore, Martina; Dazzo, Emanuela; Nobile, Carlo; Mostacciuolo, Maria Luisa; Corrado, Domenico; Basso, Cristina; Daliento, Luciano; Thiene, Gaetano; Rampazzo, Alessandra

    2013-11-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high-density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.

  16. Saw-tooth cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Karatza Ageliki A

    2009-12-01

    Full Text Available Abstract We present an unusual case of cardiomyopathy in a two month old male infant with a grade-I systolic murmur. Echocardiographic examination disclosed left ventricular (LV, dysplasia with saw-tooth like inwards myocardial projections extending from the lateral walls towards the LV cavity. There was mild LV systolic dysfunction with apical hypokinesia. Cardiovascular magnetic resonance demonstrated in detail these cross bridging muscular projections originating from the inferior interventricular septum and lateral LV wall, along with areas of hypokinesis at the LV septum and apex in a noncoronary distribution, without any late gadolinium enhancement. We have termed this condition saw-tooth cardiomyopathy because of the very characteristic appearance.

  17. MRI of the cardiomyopathies

    Energy Technology Data Exchange (ETDEWEB)

    Di Cesare, Ernesto E-mail: ernesto.dicesare@cc.univaq.it

    2001-06-01

    We examined the potentialities of Magnetic resonance imaging (MRI) in the evaluation of the main cardiomyopathies: hypertrophic, dilated, restrictive and arrhythmogenic right ventricular. The hypertrophic cardiomyopathy is generally adequately investigated by echocardiography, that well defines the myocardial thickening and the obstruction of the left ventricular output. However, by echocardiography we still have difficulties in the evaluation of the apex of the left ventricle and the right ventricle involvement. MRI provides a complete evaluation of the heart with a clear evidence also of the echocardiographic dark zones by means of a clear evidence of the apex of the right ventricle. The dilated form is also well investigated by MRI that provides a clear evaluation of the volumes, mass and ejection fraction by means of the 3D analysis including conditions of the ventricular remodelling. Moreover, this technique helps in the differential diagnosis of acute myocarditis. In the acute phase of myocarditis (first 2 weeks), in fact, the myocardium produces high signal intensity on the T2 weighted sequences due to the presence of oedema. The third form of cardiomyopathy is the restrictive one, characterised by reduced diastolic filling and diastolic volume, normality of the systolic function and parietal thickness, interstitial fibrosis and enlargement of both atria. The mean potentiality of MRI is related to the differential diagnosis with constrictive pericarditis. Only in the former, the pericardium appears irregularly thickened with areas exceeding 4 mm of pericardial thickness. Finally, the right ventricular arrhythmogenic cardiomyopathy represents the main indication to MRI evaluation. With this imaging modality we are can obtain a clear morpho-functional evaluation of the right ventricle and distinguish the intramyocardial adipose substitution characterised by areas of high signal in the myocardium.

  18. Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

    Science.gov (United States)

    Zhang, Mingzhen; Zheng, Jie; Nussinov, Ruth; Ma, Buyong

    2016-09-01

    Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer → dimer → membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer → dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail.

  19. Mutations in MCT8 in patients with Allan-Herndon-Dudley-Syndrome affecting its cellular distribution

    NARCIS (Netherlands)

    S. Kersseboom (Simone); G.J. Kremers (Gert-Jan); E.C.H. Friesema (Edith); W. Edward Visser (W.); W. Klootwijk (Willem); R.P. Peeters (Robin); T.J. Visser (Theo)

    2013-01-01

    textabstractMonocarboxylate transporter 8 (MCT8) is a thyroid hormone (TH)-specific transporter. Mutations in the MCT8 gene are associated with Allan-Herndon-Dudley Syndrome (AHDS), consisting of severe psychomotor retardation and disturbed TH parameters. To study the functional consequences of diff

  20. Structural analysis of tissues affected by cytochrome C oxidase deficiency due to mutations in the SCO2 gene.

    Science.gov (United States)

    Vesela, Katerina; Hulkova, Helena; Hansikova, Hana; Zeman, Jiri; Elleder, Milan

    2008-01-01

    Structural and histochemical studies carried out in a series of seven cases (from five families) with isolated cytochrome c oxidase (COX) deficiency caused by mutations in the SCO2 gene (1, 2) disclosed changes concentrated in the nervous system, skeletal muscle and myocardium. In five patients homozygous for the E140K mutation, the phenotype was predominantly neuromuscular and the average life span ranged between 9 and 15 months. In two cases, the course was more rapid (death at 7 and 11 weeks of life) and featured marked cardiac hypertrophy (3- and 4-fold increase in heart weight). This predominantly cardiomyopathic phenotype was associated with compound heterozygosity (E140K with another nonsense mutation) in the SCO2 gene. Polioencephalopathy with neurodegeneration and neuronal drop out was present in all cases with evidence that retinal neurons might be seriously affected too. Involvement of spinal motoneurons together with cytochrome c oxidase deficiency in muscle represents a "double hit" for the skeletal muscle. The mitochondrial population was not found to be significantly increased or structurally altered, with the exception of two compound heterozygotes in which the cardiac mitochondria were increased in number and size. Our report extends knowledge of the pathology of COX deficiency caused by mutations in the SCO2 gene.

  1. Down Syndrome with Complete Atrioventricular Septal Defect, Hypertrophic Cardiomyopathy, and Pulmonary Vein Stenosis.

    Science.gov (United States)

    Mahadevaiah, Guruprasad; Gupta, Manoj; Ashwath, Ravi

    2015-10-01

    The prevalence of congenital heart disease in infants with Down syndrome is 40%, compared with 0.3% in children who have normal chromosomes. Atrioventricular and ventricular septal defects are often associated with chromosomal aberrations, such as in trisomy 21, whereas hypertrophic cardiomyopathy is chiefly thought to be secondary to specific gene mutations. We found only one reported case of congenital hypertrophic cardiomyopathy and atrioventricular septal defect in an infant with Down syndrome. Here, we report atrioventricular septal defect, hypertrophic cardiomyopathy, and pulmonary vein stenosis in a neonate with Down syndrome-an apparently unique combination. In addition, we discuss the relevant medical literature.

  2. MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST Interactions

    Directory of Open Access Journals (Sweden)

    Damien Duval

    2015-09-01

    Full Text Available Although the genetic basis of mitral valve prolapse (MVP has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1–8 of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP.

  3. Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy

    NARCIS (Netherlands)

    van Spaendonck-Zwarts, Karin Y.; van Tintelen, J. Peter; van Veldhuisen, Dirk J.; van der Werf, Rik; Jongbloed, Jan D. H.; Paulus, Walter J.; Dooijes, Dennis; van den Berg, Maarten P.

    2010-01-01

    Background-Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of

  4. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy

    NARCIS (Netherlands)

    K.Y. van Spaendonck-Zwarts (Karin); J.P. van Tintelen (Peter); D.J. van Veldhuisen (Dirk); R. van der Werf (Rik); J.D.H. Jongbloed (Jan); W.J. Paulus (Walter); D. Dooijes (Dennis); M.P. van den Berg (Maarten)

    2010-01-01

    textabstractBACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that

  5. Comparison Between Clinical and Echocardiographic Findings in Infants and Children Diagnosed with Hypertrophic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Cristina Blesneac

    2015-06-01

    Full Text Available Background: Hypertrophic cardiomyopathy is a rather common hereditary disease with an autozomal dominant character, caused by mutations of genes that code for proteins of the cardiac sarcomere. The observed prevalence of this disease is much lower in pediatric patients compared to adults, because it’s late gene expression. Hypertrophic cardiomyopathy presenting in infancy has been shown to have a very high mortality.

  6. Mutations of Cx43 that affect B cell spreading in response to BCR signaling

    Directory of Open Access Journals (Sweden)

    Letitia Falk

    2014-07-01

    Full Text Available The gap junction (GJ protein connexin 43 (Cx43 is both necessary and sufficient for B cell receptor (BCR-mediated cell spreading. To address how Cx43 mediates this effect, we blocked its function genetically, by expressing mutants of Cx43, and pharmacologically, by using chemical inhibitors. While various point mutations of Cx43 inhibited B cell spreading, treatment with channel blocking drugs did not, suggesting that this response was independent of channel function. The critical region of Cx43 appears to be the cytoplasmic carboxyl-terminal (CT domain, which has previously been shown to be important for B cell spreading. Consistent with this, mutations of either tyrosine 247 or 265 found in the CT were sufficient to inhibit spreading. Thus Cx43 may influence B cell spreading by mechanisms requiring protein binding to, or modification of, these sites in the CT tail.

  7. Clinical findings in four Brazilian families affected by Saethre-Chotzen syndrome without TWIST mutations

    OpenAIRE

    2004-01-01

    Objective: To analyze the dysmorphological variability and to investigate the presence of mutations in the exon 1 of TWIST gene using direct sequencing in Brazilian families presenting with Saethre-Chotzen Syndrome (SCS). Methods: Four families with 24 patients diagnosed as having features of SCS were studied. Phenotypic characteristics of all patients were inventoried. The investigation protocol included anamnesis, dysmorphological examination, abdominal ultrasound, spine and cranium x-ray, ...

  8. Mutations in Durum Wheat SBEII Genes affect Grain Yield Components, Quality, and Fermentation Responses in Rats.

    Science.gov (United States)

    Hazard, Brittany; Zhang, Xiaoqin; Naemeh, Mahmoudreza; Hamilton, M Kristina; Rust, Bret; Raybould, Helen E; Newman, John W; Martin, Roy; Dubcovsky, Jorge

    2015-01-01

    Increased amylose in wheat (Triticum ssp.) starch is associated with increased resistant starch, a fermentable dietary fiber. Fermentation of resistant starch in the large intestine produces short-chain fatty acids that are associated with human health benefits. Since wheat foods are an important component of the human diet, increases in amylose and resistant starch in wheat grains have the potential to deliver health benefits to a large number of people. In three replicated field trials we found that mutations in starch branching enzyme II genes (SBEIIa and SBEIIb) in both A and B genomes (SBEIIa/b-AB) of durum wheat [T. turgidum L. subsp. durum (Desf.) Husn.] resulted in large increases of amylose and resistant starch content. The presence of these four mutations was also associated with an average 5% reduction in kernel weight (P = 0.0007) and 15% reduction in grain yield (P = 0.06) compared to the wild type. Complete milling and pasta quality analysis showed that the mutant lines have an acceptable quality with positive effects on pasta firmness and negative effects on semolina extraction and pasta color. Positive fermentation responses were detected in rats (Rattus spp.) fed with diets incorporating mutant wheat flour. This study quantifies benefits and limitations associated with the deployment of the SBEIIa/b-AB mutations in durum wheat and provides the information required to develop realistic strategies to deploy durum wheat varieties with increased levels of amylose and resistant starch.

  9. Myotonia congenita-associated mutations in chloride channel-1 affect zebrafish body wave swimming kinematics.

    Directory of Open Access Journals (Sweden)

    Wei Cheng

    Full Text Available Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1. Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita.

  10. Myotonia Congenita-Associated Mutations in Chloride Channel-1 Affect Zebrafish Body Wave Swimming Kinematics

    Science.gov (United States)

    Cheng, Wei; Tian, Jing; Burgunder, Jean-Marc; Hunziker, Walter; Eng, How-Lung

    2014-01-01

    Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita. PMID:25083883

  11. Analysis of a mutation affecting the specificity domain for prohead binding of the bacteriophage lambda terminase.

    Science.gov (United States)

    Sippy, J; Feiss, M

    1992-02-01

    Genetic studies have identified a specificity domain for prohead binding in the C-terminal 32 amino acids of gpA, the large subunit of bacteriophage lambda terminase (S. Frackman, D. A. Siegele, and M. Feiss, J. Mol. Biol. 180:283-300, 1984). In the present work, an amber mutation, Aam42, in the fifth-to-last codon of the A gene was found to be lethal in nonsuppressing hosts. The mutation, expected to generate gpA lacking the last five amino acids, caused the production of a terminase that cut cos efficiently both in vivo and in vitro but was defective in DNA packaging. lambda Aam42 lysates contained unused proheads, consistent with a defect in prohead binding. Aam42 terminase was more strongly dependent than wild-type terminase on gpFI, the catalyst of prohead binding. Like wild-type terminase, Aam42 terminase did not cut cos in vivo when prohead assembly was blocked by a mutation in one of the genes encoding the prohead.

  12. Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies

    Science.gov (United States)

    Frisso, Giulia; Detta, Nicola; Coppola, Pamela; Mazzaccara, Cristina; Pricolo, Maria Rosaria; D’Onofrio, Antonio; Limongelli, Giuseppe; Calabrò, Raffaele; Salvatore, Francesco

    2016-01-01

    Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families. PMID:27834932

  13. Role of neuropeptides in cardiomyopathies.

    Science.gov (United States)

    Dvorakova, Magdalena Chottova; Kruzliak, Peter; Rabkin, Simon W

    2014-11-01

    The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides--Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy--diabetic, ischemic, inflammatory, stress-induced or restrictive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies.

  14. Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations.

    Science.gov (United States)

    Dalakas, Marinos C; Dagvadorj, Ayush; Goudeau, Bertrand; Park, Kye-Yoon; Takeda, Kazuyo; Simon-Casteras, Monique; Vasconcelos, Olavo; Sambuughin, Nyamkhishig; Shatunov, Alexey; Nagle, James W; Sivakumar, Kumaraswamy; Vicart, Patrick; Goldfarb, Lev G

    2003-03-01

    Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.

  15. A novel COL11A1 mutation affecting splicing in a patient with Stickler syndrome.

    Science.gov (United States)

    Kohmoto, Tomohiro; Naruto, Takuya; Kobayashi, Haruka; Watanabe, Miki; Okamoto, Nana; Masuda, Kiyoshi; Imoto, Issei; Okamoto, Nobuhiko

    2015-01-01

    Stickler syndrome is a clinically and genetically heterogeneous collagenopathy characterized by ocular, auditory, skeletal and orofacial abnormalities, commonly occurring as an autosomal dominant trait. We conducted target resequencing to analyze candidate genes associated with known clinical phenotypes from a 4-year-old girl with Stickler syndrome. We detected a novel heterozygous intronic mutation (NM_001854.3:c.3168+5G>A) in COL11A1 that may impair splicing, which was suggested by in silico prediction and a minigene assay.

  16. Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle

    Energy Technology Data Exchange (ETDEWEB)

    Argaw, Takele; Wilson, Carolyn A., E-mail: carolyn.wilson@fda.hhs.gov

    2015-01-15

    Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. - Highlights: • Env cleavage signal impacts infectivity of gammaretroviruses. • Non-infectious mutants have hyper-glycosylated envelope that bind target cells. • Non-infectious mutants have defects in the formation of the double-stranded DNA. • Env cleavage motif has functions beyond cleavage of the env precursor.

  17. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy

    DEFF Research Database (Denmark)

    Riisager, Maria; Duno, M; Hansen, Flemming Juul;

    2013-01-01

    to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due...... to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations...

  18. Mutations in eukaryotic 18S ribosomal RNA affect translational fidelity and resistance to aminoglycoside antibiotics.

    Science.gov (United States)

    Chernoff, Y O; Vincent, A; Liebman, S W

    1994-02-15

    Mutations have been created in the Saccharomyces cerevisiae 18S rRNA gene that correspond to those known to be involved in the control of translational fidelity or antibiotic resistance in prokaryotes. Yeast strains, in which essentially all chromosomal rDNA repeats are deleted and all cellular rRNAs are encoded by plasmid, have been constructed that contain only mutant 18S rRNA. In Escherichia coli, a C-->U substitution at position 912 of the small subunit rRNA causes streptomycin resistance. Eukaryotes normally carry U at the corresponding position and are naturally resistant to streptomycin. We show that a U-->C transition (rdn-4) at this position of the yeast 18S rRNA gene decreases resistance to streptomycin. The rdn-4 mutation also increases resistance to paromomycin and G-418, and inhibits nonsense suppression induced by paromomycin. The same phenotypes, as well as a slow growth phenotype, are also associated with rdn-2, whose prokaryotic counterpart, 517 G-->A, manifests itself as a suppressor rather than an antisuppressor. Neither rdn-2- nor rdn-4-related phenotypes could be detected in the presence of the normal level of wild-type rDNA repeats. Our data demonstrate that eukaryotic rRNA is involved in the control of translational fidelity, and indicate that rRNA features important for interactions with aminoglycosides have been conserved throughout evolution.

  19. A mutation in protein phosphatase 2A regulatory subunit A affects auxin transport in Arabidopsis

    Science.gov (United States)

    Garbers, C.; DeLong, A.; Deruere, J.; Bernasconi, P.; Soll, D.; Evans, M. L. (Principal Investigator)

    1996-01-01

    The phytohormone auxin controls processes such as cell elongation, root hair development and root branching. Tropisms, growth curvatures triggered by gravity, light and touch, are also auxin-mediated responses. Auxin is synthesized in the shoot apex and transported through the stem, but the molecular mechanism of auxin transport is not well understood. Naphthylphthalamic acid (NPA) and other inhibitors of auxin transport block tropic curvature responses and inhibit root and shoot elongation. We have isolated a novel Arabidopsis thaliana mutant designated roots curl in NPA (rcn1). Mutant seedlings exhibit altered responses to NPA in root curling and hypocotyl elongation. Auxin efflux in mutant seedlings displays increased sensitivity to NPA. The rcn1 mutation was transferred-DNA (T-DNA) tagged and sequences flanking the T-DNA insert were cloned. Analysis of the RCN1 cDNA reveals that the T-DNA insertion disrupts a gene for the regulatory A subunit of protein phosphatase 2A (PP2A-A). The RCN1 gene rescues the rcn1 mutant phenotype and also complements the temperature-sensitive phenotype of the Saccharomyces cerevisiae PP2A-A mutation, tpd3-1. These data implicate protein phosphatase 2A in the regulation of auxin transport in Arabidopsis.

  20. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.

    Science.gov (United States)

    Peters, Heidi; Buck, Nicole; Wanders, Ronald; Ruiter, Jos; Waterham, Hans; Koster, Janet; Yaplito-Lee, Joy; Ferdinandusse, Sacha; Pitt, James

    2014-11-01

    Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

  1. Systematic review of pregnancy in women with inherited cardiomyopathies

    NARCIS (Netherlands)

    Krul, Sebastien P. J.; van der Smagt, Jasper J.; van den Berg, Maarten P.; Sollie, Krystyna M.; Pieper, Petronella G.; van Spaendonck-Zwarts, Karin Y.

    2011-01-01

    Pregnancy exposes women with inherited cardiomyopathies to increased risk for heart failure and arrhythmias. In this paper, we review the clinical course and management of pregnant women with the following inherited cardiomyopathies: hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogeni

  2. Single amino acid mutation in alpha-helical peptide affect second harmonic generation hyperpolarizability

    Science.gov (United States)

    Wei, Jing; Wang, Jin-Yun; Zhang, Min-Yi; Chai, Guo-Liang; Lin, Chen-Sheng; Cheng, Wen-Dan

    2013-01-01

    We investigate the effect of side chain on the first-order hyperpolarizability in α-helical polyalanine peptide with the 10th alanine mutation (Acetyl(ala)9X(ala)7NH2). Structures of various substituted peptides are optimized by ONIOM (DFT: AM1) scheme, and then linear and nonlinear optical properties are calculated by SOS//CIS/6-31G∗ method. The polarizability and first-order hyperpolarizability increase obviously only when 'X' represents phenylalanine, tyrosine and tryptophan. We also discuss the origin of nonlinear optical response and determine what caused the increase of first-order hyperpolarizability. Our results strongly suggest that side chains containing benzene, phenol and indole have important contributions to first-order hyperpolarizability.

  3. Takotsubo cardiomyopathy (Broken heart syndrome).

    Science.gov (United States)

    Javed, Aqib; Chitkara, Kamal; Mahmood, Arslan; Kainat, Aleesha

    2015-11-01

    Takotsubo cardiomyopathy is an acute reversible cardiomyopathy characterised by transient regional left ventricular (LV) motion abnormalities. It is diagnosed on a coronary angiography and left ventriculography. We report the case of a 50-year-old lady who presented with sudden onset of chest pain, with no history of cardiac disease and no risk factors. Remarkably though, she had lost her husband the previous night. Coronary and LV angiography was done which revealed findings typical of takotsubo cardiomyopathy. We report this case for its rarity. Informed consent was taken from the patient before undertaking and reporting this study.

  4. Experimental and molecular dynamics studies showed that CBP KIX mutation affects the stability of CBP:c-Myb complex.

    Science.gov (United States)

    Odoux, Anne; Jindal, Darren; Tamas, Tamara C; Lim, Benjamin W H; Pollard, Drake; Xu, Wu

    2016-06-01

    The coactivators CBP (CREBBP) and its paralog p300 (EP300), two conserved multi-domain proteins in eukaryotic organisms, regulate gene expression in part by binding DNA-binding transcription factors. It was previously reported that the CBP/p300 KIX domain mutant (Y650A, A654Q, and Y658A) altered both c-Myb-dependent gene activation and repression, and that mice with these three point mutations had reduced numbers of platelets, B cells, T cells, and red blood cells. Here, our transient transfection assays demonstrated that mouse embryonic fibroblast cells containing the same mutations in the KIX domain and without a wild-type allele of either CBP or p300, showed decreased c-Myb-mediated transcription. Dr. Wright's group solved a 3-D structure of the mouse CBP:c-Myb complex using NMR. To take advantage of the experimental structure and function data and improved theoretical calculation methods, we performed MD simulations of CBP KIX, CBP KIX with the mutations, and c-Myb, as well as binding energy analysis for both the wild-type and mutant complexes. The binding between CBP and c-Myb is mainly mediated by a shallow hydrophobic groove in the center where the side-chain of Leu302 of c-Myb plays an essential role and two salt bridges at the two ends. We found that the KIX mutations slightly decreased stability of the CBP:c-Myb complex as demonstrated by higher binding energy calculated using either MM/PBSA or MM/GBSA methods. More specifically, the KIX mutations affected the two salt bridges between CBP and c-Myb (CBP-R646 and c-Myb-E306; CBP-E665 and c-Myb-R294). Our studies also revealed differing dynamics of the hydrogen bonds between CBP-R646 and c-Myb-E306 and between CBP-E665 and c-Myb-R294 caused by the CBP KIX mutations. In the wild-type CBP:c-Myb complex, both of the hydrogen bonds stayed relatively stable. In contrast, in the mutant CBP:c-Myb complex, hydrogen bonds between R646 and E306 showed an increasing trend followed by a decreasing trend, and hydrogen

  5. Genetic heterogeneity of left-ventricular noncompaction cardiomyopathy.

    Science.gov (United States)

    Moric-Janiszewska, Ewa; Markiewicz-Łoskot, Grazyna

    2008-05-01

    Isolated noncompaction of the ventricular myocardium (INVM) sometimes referred to as spongy myocardium is a rare, congenital and also acquired cardiomyopathy. It appears to divide the presentation into neonatal, childhood and adult forms of which spongy myocardium and systolic dysfunction is the commonality. The disorder is characterized by a left ventricular hypertrophy with deep trabeculations, and with diminished systolic function, with or without associated left ventricular dilation. In half or more of the cases, the right ventricle is also affected. The sporadic type, however, in some patients, may be due to chromosomal abnormalities and the occurrence of familial incidence. Isolated noncompaction of the left ventricular myocardium in the majority of adult patients is an autosomal dominant disorder. The familial and X-linked disorders have been described by various authors. We here describe the genetic background of this disorder: some of the most mutated genes that are responsible for the disease are (G4.5 (tafazzin gene): alpha-dystrobrevin gene (DTNA); FKBP-12 gene; lamin A/C gene; Cypher/ZASP (LIM, LDB3) gene); and some genotype-phenotype correlations (Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy or Barth syndrome) based on the literature review.

  6. Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

    Science.gov (United States)

    Li, Monica X; Hwang, Peter M

    2015-10-25

    In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

  7. Genetic bases of arrhythmogenic right ventricular cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Alessandra Rampazzo

    2010-05-01

    Full Text Available Arrhythmogenic right ventricular cardiomyopathy (ARVC is a heart muscle disease in which the pathological substrate is a fibro-fatty replacement of the right ventricular myocardium. The major clinical features are different types of arrhythmias with a left branch block pattern. ARVC shows autosomal dominant inheritance with incomplete penetrance. Recessive forms were also described, although in association with skin disorders. Ten genetic loci have been discovered so far and mutations were reported in five different genes. ARVD1 was associated with regulatory mutations of transforming growth factor beta-3 (TGFβ3, whereas ARVD2, characterized by effort-induced polymorphic arrhythmias, was associated with mutations in cardiac ryanodine receptor-2 (RYR2. All other mutations identified to date have been detected in genes encoding desmosomal proteins: plakoglobin (JUP which causes Naxos disease (a recessive form of ARVC associated with palmoplantar keratosis and woolly hair; desmoplakin (DSP which causes the autosomal dominant ARVD8 and plakophilin-2 (PKP2 involved in ARVD9. Desmosomes are important cell-to-cell adhesion junctions predominantly found in epidermis and heart; they are believed to couple cytoskeletal elements to plasma membrane in cell-to-cell or cell-to-substrate adhesions.

  8. Right ventricular cardiomyopathies: a multidisciplinary approach to diagnosis.

    Science.gov (United States)

    Limongelli, Giuseppe; Rea, Alessandra; Masarone, Daniele; Francalanci, M Paola; Anastasakis, Aris; Calabro', Raffaele; Giovanna, Russo Maria; Bossone, Eduardo; Elliott, Perry Mark; Pacileo, Giuseppe

    2015-01-01

    The physiological importance of the right ventricle (RV) has been underestimated over the past years. Finally in the early 1950s through the 1970s, cardiac surgeons recognized the importance of RV function. Since then, the importance of RV function has been recognized in many acquired cardiac heart disease. RV can be mainly or together with left ventricle (LV) affected by inherited or acquired cardiomyopathy. In fact, RV morphological and functional remodeling occurs more common during cardiomyopathies than in ischemic cardiomyopathies and more closely parallels LV dysfunction. Moreover, there are some cardiomyopathy subtypes showing a predominant or exclusive involvement of the RV, and they are probably less known by cardiologists. The clinical approach to right ventricular cardiomyopathies is often challenging. Imaging is the first step to raise the suspicion and to guide the diagnostic process. In the differential diagnosis, cardiologists should consider athlete's heart, congenital heart diseases, multisystemic disorders, and inherited arrhythmias. However, a multiparametric and multidisciplinary approach, involving cardiologists, experts in imaging, geneticists, and pathologists with a specific expertise in these heart muscle disorders is required.

  9. Late presentation of arrhythmogenic right ventricular cardiomyopathy: a case report

    Directory of Open Access Journals (Sweden)

    Papaioannou Georgios I

    2009-08-01

    Full Text Available Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy is an inherited myocardial disease affecting predominantly young people and manifests as sustained ventricular tachycardia with left bundle branch block morphology, sudden death or isolated right or biventricular heart failure. However, its first manifestation as sustained ventricular tachycardia in older patients without preceding symptoms of heart failure is infrequent. To our knowledge, our patient is among the oldest reported in the literature presenting with ventricular tachycardia because of arrhythmogenic right ventricular cardiomyopathy without preceding symptoms of heart failure. Case presentation We present an unusual case of a very late presentation of a right ventricular cardiomyopathy in a 72-year-old white Caucasian man. The patient was admitted with symptoms of weakness, dizziness and chest discomfort for several hours. His electrocardiogram showed a wide-complex tachycardia with left bundle branch block morphology and left axis deviation. Because of continuing hemodynamic instability, the patient was cardioverted to sinus rhythm with a single 300 J shock. His post-cardioversion electrocardiogram, cardiac echocardiogram, coronary angiogram, magnetic resonance imaging and electrophysiological study confirmed the diagnosis of arrhythmogenic right ventricular cardiomyopathy. The patient was treated with an implantable cardioverter defibrillator and discharged on sotalol. Conclusion This case report demonstrates that arrhythmogenic right ventricular cardiomyopathy may have a very late presentation and this diagnosis should be considered as a potential cause of sustained ventricular tachycardia of right ventricular origin among the elderly and should be treated accordingly.

  10. Point mutation of H3/H4 histones affects acetic acid tolerance in Saccharomyces cerevisiae.

    Science.gov (United States)

    Liu, Xiangyong; Zhang, Xiaohua; Zhang, Zhaojie

    2014-10-10

    The molecular mechanism of acetic acid tolerance in yeast remains unclear despite of its importance for efficient cellulosic ethanol production. In this study, we examined the effects of histone H3/H4 point mutations on yeast acetic acid tolerance by comprehensively screening a histone H3/H4 mutant library. A total of 24 histone H3/H4 mutants (six acetic acid resistant and 18 sensitive) were identified. Compared to the wild-type strain, the histone acetic acid-resistant mutants exhibited improved ethanol fermentation performance under acetic acid stress. Genome-wide transcriptome analysis revealed that changes in the gene expression in the acetic acid-resistant mutants H3 K37A and H4 K16Q were mainly related to energy production, antioxidative stress. Our results provide novel insights into yeast acetic acid tolerance on the basis of histone, and suggest a novel approach to improve ethanol production by altering the histone H3/H4 sequences.

  11. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore.

    Science.gov (United States)

    Zhang, Zhifen; Park, Minyoung; Tam, John; Auger, Anick; Beilhartz, Greg L; Lacy, D Borden; Melnyk, Roman A

    2014-03-11

    Disease associated with Clostridium difficile infection is caused by the actions of the homologous toxins TcdA and TcdB on colonic epithelial cells. Binding to target cells triggers toxin internalization into acidified vesicles, whereupon cryptic segments from within the 1,050-aa translocation domain unfurl and insert into the bounding membrane, creating a transmembrane passageway to the cytosol. Our current understanding of the mechanisms underlying pore formation and the subsequent translocation of the upstream cytotoxic domain to the cytosol is limited by the lack of information available regarding the identity and architecture of the transmembrane pore. Here, through systematic perturbation of conserved sites within predicted membrane-insertion elements of the translocation domain, we uncovered highly sensitive residues--clustered between amino acids 1,035 and 1,107--that when individually mutated, reduced cellular toxicity by as much as >1,000-fold. We demonstrate that defective variants are defined by impaired pore formation in planar lipid bilayers and biological membranes, resulting in an inability to intoxicate cells through either apoptotic or necrotic pathways. These findings along with the unexpected similarities uncovered between the pore-forming "hotspots" of TcdB and the well-characterized α-helical diphtheria toxin translocation domain provide insights into the structure and mechanism of formation of the translocation pore for this important class of pathogenic toxins.

  12. Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy.

    Science.gov (United States)

    Ikon, Nikita; Ryan, Robert O

    2017-02-01

    The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.

  13. New insights into cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Søren; Hove, Jens D; Dixen, Ulrik

    2013-01-01

    Cirrhotic cardiomyopathy designates a cardiac dysfunction, which includes reduced cardiac contractility with systolic and diastolic dysfunction, and presence of electrophysiological abnormalities in particular prolongation of the QT interval. Several pathophysiological mechanisms including reduce...

  14. Takotsubo cardiomyopathy following subarachnoid haemorrhage.

    Science.gov (United States)

    Maekawa, Hidetsugu; Hadeishi, Hiromu

    2014-08-01

    A 67-year-old woman was admitted with aneurysmal subarachnoid haemorrhage and a 12-lead ECG showed ST segment elevation. Transthoracic echocardiography confirmed akinesis of the left ventricular mid-apical segment, with an ejection fraction of 26%, features characteristic of takotsubo cardiomyopathy. Five days later, we identified thrombus in the apex of the left ventricle. Sixteen days after onset, the thrombus had disappeared and wall motion improved (ejection fraction 58%) without evidence of cardioembolism. Takotsubo cardiomyopathy is a cause of cardiac dysfunction after stroke, including SAH. It is characterised by transiently depressed contractile function of the left mid and apical ventricle, without obstructive coronary artery disease. Clinicians should suspect takotsubo cardiomyopathy in patients with subarachnoid haemorrhage who have an ECG abnormality. Echocardiography is needed to detect the distinctive regional wall motion abnormality. Despite its severity in the acute phase, takotsubo cardiomyopathy is self-limiting and its management is conservative.

  15. Electrocardiographic abnormalities and uremic cardiomyopathy

    NARCIS (Netherlands)

    Stewart, GA; Gansevoort, RT; Mark, PB; Rooney, E; McDonagh, TA; Dargie, HJ; Stuart, R; Rodger, C; Jardine, AG

    2005-01-01

    Background. Progressive renal disease is associated with an increased risk of cardiovascular death, specifically sudden death. We investigated the link between uremic cardiomyopathy, QT interval and dispersal, and arrhythmias (by ambulatory ECG monitoring) in patients at different stages of progress

  16. Genetics of cardiomyopathies in children

    Directory of Open Access Journals (Sweden)

    Matteo Vatta

    2011-08-01

    Full Text Available Cardiomyopathies are diseases of the heart muscle leading to heart failure and/or an increased risk of arrhythmogenic sudden cardiac death. These disorders represent a major cause of morbidity and mortality in children. In childhood forms of cardiomyopathy, genetic etiologies are frequent, but non-genetic or acquired causes, such viral infection, also play a significant role. In the last twenty years, the genetic causes of cardiomyopathies have been increasingly identified and clinical correlations are beginning to be defined. Here we present an overview of the recent advances in our understanding of the genetics of cardiomyopathies in children and what is known about the pathophysiological mechanisms underlying these gene-related forms of disease.

  17. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

    Science.gov (United States)

    Gripp, Karen W; Lin, Angela E; Stabley, Deborah L; Nicholson, Linda; Scott, Charles I; Doyle, Daniel; Aoki, Yoko; Matsubara, Yoichi; Zackai, Elaine H; Lapunzina, Pablo; Gonzalez-Meneses, Antonio; Holbrook, Jennifer; Agresta, Cynthia A; Gonzalez, Iris L; Sol-Church, Katia

    2006-01-01

    Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

  18. An obstetric emergency called peripartum cardiomyopathy!

    Directory of Open Access Journals (Sweden)

    Shaikh Nissar

    2010-01-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a rare obstetric emergency affecting women in late pregnancy or up to five months of postpartum period. The etiology of PPCM is still not known. It has potentially devastating effects on mother and fetus if not treated early. The signs, symptoms and treatment of PPCM are similar to that of heart failure. Early diagnosis and proper management is the corner stone for better outcome of these patients. The only way to prevent PPCM is to avoid further pregnancies.

  19. Collecting, Analyzing, and Publishing Massive Data about the Hypertrophic Cardiomyopathy

    Science.gov (United States)

    Montserrat, Lorenzo; Cotelo-Lema, Jose Antonio; Luaces, Miguel R.; Seco, Diego

    We present in this paper the architecture and some implementation details of a Document Management System and Workflow to help in the diagnosis of the hypertrophic cardiomyopathy, one of the most frequent genetic cardiovascular diseases. The system allows a gradual and collaborative creation of a knowledge base about the mutations associated with this disease. The system manages both the original documents of the scientific papers and the data extracted from these papers by the experts. Furthermore, a semiautomatic report generation module exploits this knowledge base to create high quality reports about the studied mutations.

  20. Mutations in HISTONE ACETYLTRANSFERASE1 affect sugar response and gene expression in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Timothy J Heisel

    2013-07-01

    Full Text Available Nutrient response networks are likely to have been among the first response networks to evolve, as the ability to sense and respond to the levels of available nutrients is critical for all organisms. Although several forward genetic screens have been successful in identifying components of plant sugar-response networks, many components remain to be identified. Towards this end, a reverse genetic screen was conducted in Arabidopsis thaliana to identify additional components of sugar-response networks. This screen was based on the rationale that some of the genes involved in sugar-response networks are likely to be themselves sugar regulated at the steady-state mRNA level and to encode proteins with activities commonly associated with response networks. This rationale was validated by the identification of hac1 mutants that are defective in sugar response. HAC1 encodes a histone acetyltransferase. Histone acetyltransferases increase transcription of specific genes by acetylating histones associated with those genes. Mutations in HAC1 also cause reduced fertility, a moderate degree of resistance to paclobutrazol and altered transcript levels of specific genes. Previous research has shown that hac1 mutants exhibit delayed flowering. The sugar-response and fertility defects of hac1 mutants may be partially explained by decreased expression of AtPV42a and AtPV42b, which are putative components of plant SnRK1 complexes. SnRK1 complexes have been shown to function as central regulators of plant nutrient and energy status. Involvement of a histone acetyltransferase in sugar response provides a possible mechanism whereby nutritional status could exert long-term effects on plant development and metabolism.

  1. Takotsubo or Stress Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    J. P. Bounhoure

    2012-01-01

    Full Text Available Many case reports have been published of reversible left ventricular dysfunction precipitated by sudden emotional stress. We have evaluated 10 women hospitalized for acute chest pain and dyspnea, mimicking an acute coronary syndrome, after a severe emotional trigger. Those patients, postmenopausal women, presented ST segment alterations on the EKG, minor elevations of cardiac enzymes, and biomarkers levels. At the coronarography there was not coronary thrombosis or severe stenosis, but the ventriculography showed wall motion abnormalities involving the left ventricular apex and midventricle, in the absence of significant obstructive coronary disease. The course was benign without complication, with a full recovery of left ventricular function in some weeks. These observations, like other reports, demonstrate the impact of emotional stress on left ventricular function and the risk of cardiovascular disease. The cause of this cardiomyopathy is still unknown, and several mechanisms have been proposed: catecholamine myocardial damage, microvascular spasm, or neural mediated myocardial stunning.

  2. PERIPARTUM CARDIOMYOPATHY: A REVIEW

    Directory of Open Access Journals (Sweden)

    Rajat

    2016-05-01

    Full Text Available Peripartum Cardiomyopathy is a pregnancy associated rare but severe myocardial disease. The incidence of PPCM is about 1 in 3186 live births in United States. Causes include viral infections, toxins, environmental and geographic factors, familial predisposition, Hormonal abnormalities, haemodynamic burden of pregnancy, malnutrition, inflammation, etc. NT-proBNP, Cathepsin D, tyrosine kinase SFlt1 may be elevated and can be used as biomarkers to diagnose PPCM. Restriction of dietary sodium, beta-blockers, diuretics-thiazide and furosemide, in lowest possible doses can be given for symptomatic management. Prognosis of PPCM is positively related to the recovery of ventricular failure. Only about 50% women with PPCM recover baseline ventricular function within 6 months of delivery. Failure of heart size to return to normal is associated with increased mortality and morbidity. Future pregnancies are not recommended in patient with PPCM, as there is an increased risk for recurrence of PPCM in the subsequent pregnancy

  3. A Gain-of-Function Mutation in OsIAA11 Affects Lateral Root Development in Rice

    Institute of Scientific and Technical Information of China (English)

    Zhen-Xing Zhu; Yu Liu; Shao-Jun Liu; Chuan-Zao Mao; Yun-Rong Wu; Ping Wu

    2012-01-01

    Lateral roots are important to plants for the uptake of nutrients and water.Several members of the Aux/IAA family have been shown to play crucial roles in lateral root development.Here,a member of the rice Aux/IAA family genes,OsIAA11 (LOC_Os03g43400),was isolated from a rice mutant defective in lateral root development.The gain-of-function mutation in OsIAA 11 strictly blocks the initiation of lateral root primordia,but it does not affect crown root development.The expression of OsIAA11 is defined in root tips,lateral root caps,steles,and lateral root primordia.The auxin reporter DR5-GUS (β-glucuronidase) was expressed at lower levels in the mutant than in wild-type,indicating that OsIAA11 is involved in auxin signaling in root caps.The transcript abundance of both OsPIN1b and OsPIN10a was diminished in root tips of the Osiaa11 mutant.Taken together,the results indicate that the gain-of-function mutation in OsIAA11 caused the inhibition of lateral root development in rice.

  4. Mutation increasing β-carotene concentrations does not adversely affect concentrations of essential mineral elements in pepper fruit

    Science.gov (United States)

    Thompson, Jacqueline A.; Penchev, Emil A.; Nielen, Stephan

    2017-01-01

    Vitamin and mineral deficiencies are prevalent in human populations throughout the world. Vitamin A deficiency affects hundreds of millions of pre-school age children in low income countries. Fruits of pepper (Capsicum annuum L.) can be a major dietary source of precursors to Vitamin A biosynthesis, such as β-carotene. Recently, pepper breeding programs have introduced the orange-fruited (of) trait of the mutant variety Oranzheva kapiya, which is associated with high fruit β-carotene concentrations, to the mutant variety Albena. In this manuscript, concentrations of β-carotene and mineral elements (magnesium, phosphorus, sulphur, potassium, zinc, calcium, manganese, iron and copper) were compared in fruit from P31, a red-fruited genotype derived from the variety Albena, and M38, a genotype developed by transferring the orange-fruited mutation (of) into Albena. It was observed that fruit from M38 plants had greater β-carotene concentration at both commercial and botanical maturity (4.9 and 52.7 mg / kg fresh weight, respectively) than fruit from P31 plants (2.3 and 30.1 mg / kg fresh weight, respectively). The mutation producing high β-carotene concentrations in pepper fruits had no detrimental effect on the concentrations of mineral elements required for human nutrition. PMID:28207797

  5. A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain.

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    Wenyuan Zhao

    Full Text Available Familial hypertrophic cardiomyopathy (HCM is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2 strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6 reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including β-myosin heavy chain (MHC, atrial natriuretic peptide (ANP, brain natriuretic peptide (BNP, and skeletal muscle alpha actin (α1-actin. Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens.

  6. STN1 OB Fold Mutation Alters DNA Binding and Affects Selective Aspects of CST Function

    Science.gov (United States)

    Bhattacharjee, Anukana; Stewart, Jason; Chaiken, Mary; Price, Carolyn M.

    2016-01-01

    Mammalian CST (CTC1-STN1-TEN1) participates in multiple aspects of telomere replication and genome-wide recovery from replication stress. CST resembles Replication Protein A (RPA) in that it binds ssDNA and STN1 and TEN1 are structurally similar to RPA2 and RPA3. Conservation between CTC1 and RPA1 is less apparent. Currently the mechanism underlying CST action is largely unknown. Here we address CST mechanism by using a DNA-binding mutant, (STN1 OB-fold mutant, STN1-OBM) to examine the relationship between DNA binding and CST function. In vivo, STN1-OBM affects resolution of endogenous replication stress and telomere duplex replication but telomeric C-strand fill-in and new origin firing after exogenous replication stress are unaffected. These selective effects indicate mechanistic differences in CST action during resolution of different replication problems. In vitro binding studies show that STN1 directly engages both short and long ssDNA oligonucleotides, however STN1-OBM preferentially destabilizes binding to short substrates. The finding that STN1-OBM affects binding to only certain substrates starts to explain the in vivo separation of function observed in STN1-OBM expressing cells. CST is expected to engage DNA substrates of varied length and structure as it acts to resolve different replication problems. Since STN1-OBM will alter CST binding to only some of these substrates, the mutant should affect resolution of only a subset of replication problems, as was observed in the STN1-OBM cells. The in vitro studies also provide insight into CST binding mechanism. Like RPA, CST likely contacts DNA via multiple OB folds. However, the importance of STN1 for binding short substrates indicates differences in the architecture of CST and RPA DNA-protein complexes. Based on our results, we propose a dynamic DNA binding model that provides a general mechanism for CST action at diverse forms of replication stress. PMID:27690379

  7. Arabidopsis AtADF1 is Functionally Affected by Mutations on Actin Binding Sites

    Institute of Scientific and Technical Information of China (English)

    Chun-Hai Dong; Wei-Ping Tang; Jia-Yao Liu

    2013-01-01

    The plant actin depolymerizing factor (ADF) binds to both monomeric and filamentous actin,and is directly involved in the depolymerization of actin filaments.To better understand the actin binding sites of the Arabidopsis thaliana L.AtADF1,we generated mutants of AtADF1 and investigated their functions in vitro and in vivo.Analysis of mutants harboring amino acid substitutions revealed that charged residues (Arg98 and Lys100) located at the α-helix 3 and forming an actin binding site together with the N-terminus are essential for both G-and F-actin binding.The basic residues on the β-strand 5 (K82/A) and the α-helix 4 (R135/A,R137/A) form another actin binding site that is important for F-actin binding.Using transient expression of CFP-tagged AtADF1 mutant proteins in onion (Allium cepa) peel epidermal cells and transgenic Arabidopsis thaliana L.plants overexpressing these mutants,we analyzed how these mutant proteins regulate actin organization and affect seedling growth.Our results show that the ADF mutants with a lower affinity for actin filament binding can still be functional,unless the affinity foractin monomers is also affected.The G-actin binding activity of the ADF plays an essential role in actin binding,depolymerization of actin polymers,and therefore in the control of actin organization.

  8. The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaochuan; Suphamungmee, Worawit [Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118 (United States); Janco, Miro; Geeves, Michael A. [School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ (United Kingdom); Marston, Steven B. [National Heart and Lung Institute, Imperial College London, London W12 0NN (United Kingdom); Fischer, Stefan, E-mail: stefan.fischer@iwr.uni-heidelberg.de [Computational Biochemistry Group, University of Heidelberg, Heidelberg D-69120 (Germany); Lehman, William, E-mail: wlehman@bu.edu [Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118 (United States)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Well-known tropomyosin mutants, D175N and E180G are linked to cardiomyopathies. Black-Right-Pointing-Pointer The structural mechanics of D175N and E180G tropomyosins have been investigated. Black-Right-Pointing-Pointer D175N and E180G mutations increase both local and global tropomyosin flexibility. Black-Right-Pointing-Pointer In muscle, this increased flexibility will enhance myosin interactions on actin. Black-Right-Pointing-Pointer Extra myosin interaction can alter cardiac Ca{sup 2+}-switching, leading to dysfunction. -- Abstract: Point mutations targeting muscle thin filament proteins are the cause of a number of cardiomyopathies. In many cases, biological effects of the mutations are well-documented, whereas their structural and mechanical impact on filament assembly and regulatory function is lacking. In order to elucidate molecular defects leading to cardiac dysfunction, we have examined the structural mechanics of two tropomyosin mutants, E180G and D175N, which are associated with hypertrophic cardiomyopathy (HCM). Tropomyosin is an {alpha}-helical coiled-coil dimer which polymerizes end-to-end to create an elongated superhelix that wraps around F-actin filaments of muscle and non-muscle cells, thus modulating the binding of other actin-binding proteins. Here, we study how flexibility changes in the E180G and D175N mutants might affect tropomyosin binding and regulatory motion on F-actin. Electron microscopy and Molecular Dynamics simulations show that E180G and D175N mutations cause an increase in bending flexibility of tropomyosin both locally and globally. This excess flexibility is likely to increase accessibility of the myosin-binding sites on F-actin, thus destabilizing the low-Ca{sup 2+} relaxed-state of cardiac muscle. The resulting imbalance in the on-off switching mechanism of the mutants will shift the regulatory equilibrium towards Ca{sup 2+}-activation of cardiac muscle, as is observed in affected

  9. Aging Kit mutant mice develop cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Lei Ye

    Full Text Available Both bone marrow (BM and myocardium contain progenitor cells expressing the c-Kit tyrosine kinase. The aims of this study were to determine the effects of c-Kit mutations on: i. myocardial c-Kit(+ cells counts and ii. the stability of left ventricular (LV contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography in two groups of Kit mutant (W/Wv and W41/W42 and in wild type (WT mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF and LV fractional shortening rates (FS were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit(+ cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit(+ cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal.

  10. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.

    Science.gov (United States)

    Zampieri, Stefania; Montalvo, Annalisa; Blanco, Mariana; Zanin, Irene; Amartino, Hernan; Vlahovicek, Kristian; Szlago, Marina; Schenone, Andrea; Pittis, Gabriela; Bembi, Bruno; Dardis, Andrea

    2012-05-15

    Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.

  11. Cerebral embolic stroke after disappearing takotsubo cardiomyopathy.

    Science.gov (United States)

    Matsuzono, Kosuke; Ikeda, Yoshio; Deguchi, Shoko; Yamashita, Toru; Kurata, Tomoko; Deguchi, Kentaro; Abe, Koji

    2013-11-01

    Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.

  12. [Levosimendan for septic shock with takotsubo cardiomyopathy].

    Science.gov (United States)

    Schlürmann, C-N; Reinöhl, J; Kalbhenn, J

    2016-01-01

    As a stress-induced disease, takotsubo cardiomyopathy can also occur in septic syndromes; however, the hemodynamic management is fundamentally different from the treatment approaches for classical septic cardiomyopathy, as beta mimetics can increase the heart failure symptoms in takotsubo cardiomyopathy. This article reports the case of an 82-year-old female patient who presented with acute abdomen due to adhesion ileus and takotsubo cardiomyopathy, developed severe septic shock with peritonitis and could be successfully hemodynamically stabilized with levosimendan.

  13. Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology.

    Science.gov (United States)

    Yoshikawa, Tsutomu

    2015-03-01

    Takotsubo cardiomyopathy, a new concept of cardiomyopathy, is characterized by transient cardiac dysfunction, commonly triggered by physical or emotional stress. Differential diagnosis is important, since takotsubo cardiomyopathy presents similar images to those shown in acute coronary syndrome, with ST-segment elevation, T-wave inversion, QT-prolongation, and others on electrocardiogram. Typically, apical involvement with hypercontraction of basal left ventricle (apical type) is predominant, but atypical types involving basal, mid-ventricular, and right ventricular myocardium are also described. In-hospital death occurs at similar level with patients with acute coronary syndrome, but it is significantly affected by underlying diseases. This disease presents diverse cardiac complications in acute phase, such as life-threatening ventricular arrhythmias, pump failure, cardiac rupture, and systemic embolism. The pathogenic mechanism of this disease is still unclear but sympathetic hyperactivity, as well as coronary vasospasm, microcirculatory disorder, and estrogen deficiency, have been considered as one of the most likely pathogenic mechanism. Long-term prognosis is also largely unknown. Issues such as establishment of acute phase treatment, prediction of cardiac complications, and prophylactic measures against recurrence need to be further explored.

  14. Morphogenesis in Mucor mucedo: mutations affecting gamone response and organ differentiation.

    Science.gov (United States)

    Wurtz, T; Jockusch, H

    1978-02-27

    Mutants of Mucor mucedo minus strain that are affected in their trisporic acid (TA) mediated zygophore formation have been isolated. We have found mutants with cold sensitive (cs), with temperature sensitive (ts) and without zygophore formation as well as mutants with unstable zygophores (Zst-). From the appearence of certain pleiotropic phenotypes we deduce a one-dimensional sequence of states of competence of the mycelium to form different organs. TA appears to be a growth substance for zygophores acting on one transient state of competence. The fact that all isolates with lowered response to TA also have a lowered response to the mating type specific TA-precursor P strongly suggests that P has to be converted into TA before inducing zygophore growth. Furthermore, one mutant with lowered sensitivity to TA exhibits an excess zygophore formation in the presence of high TA-concentrations, while high concentrations of P cause a depressed zygophore formation (Fig. 6). Our interpretation of this behaviour is that P acts as an antagonist to TA in the regulation of zygophore growth.

  15. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

    DEFF Research Database (Denmark)

    Christensen, Alex Hørby; Benn, Marianne; Tybjærg-Hansen, Anne;

    2010-01-01

    Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported...

  16. Takotsubo cardiomyopathy triggered by alcohol withdrawal.

    Science.gov (United States)

    Alexandre, Joakim; Benouda, Leila; Champ-Rigot, Laure; Labombarda, Fabien

    2011-07-01

    Takotsubo cardiomyopathy is a reversible cardiomyopathy frequently precipitated by a sudden emotional or physical stress. The exact physiopathology is still debated and may involve catecholamine-induced myocardial stunning. Alcohol withdrawal is associated with an hyperadrenergic state and may be a period at risk of cardiac events. We report a 56-year-old man with Takotsubo cardiomyopathy triggered by alcohol withdrawal.

  17. Biventricular Takotsubo cardiomyopathy in Graves hyperthyroidism.

    Science.gov (United States)

    Perkins, Matthew J; Schachter, David T

    2014-03-01

    Graves hyperthyroidism is commonly seen in clinical practice and Takotsubo stress cardiomyopathy is an increasingly recognized cardiac complication of physical or emotional stress. We report the rare case of a patient with Graves hyperthyroidism that was complicated by severe biventricular takotsubo cardiomyopathy, which was demonstrated on heart catheterization. After appropriate pharmacologic treatment of her hyperthyroidism, she had complete resolution of her cardiomyopathy.

  18. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

    Science.gov (United States)

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

    2015-11-01

    Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

  19. Peripartum cardiomyopathy and dilated cardiomyopathy: different at heart

    Directory of Open Access Journals (Sweden)

    Ilse Anne Elise Bollen

    2015-01-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a severe cardiac disease occurring in the last month of pregnancy or in the first 5 months after delivery and shows many similar clinical characteristics as dilated cardiomyopathy (DCM such as ventricle dilation and systolic dysfunction. While PPCM was believed to be DCM triggered by pregnancy, more and more studies show important differences between these diseases. While it is likely they share part of their pathogenesis such as increased oxidative stress and an impaired microvasculature, discrepancies seen in disease progression and outcome indicate there must be differences in pathogenesis as well. In this review, we compared studies in DCM and PPCM to search for overlapping and deviating disease etiology, pathogenesis and outcome in order to understand why these cardiomyopathies share similar clinical features but have different underlying pathologies.

  20. Mitochondrial Mechanisms in Septic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    María Cecilia Cimolai

    2015-08-01

    Full Text Available Sepsis is the manifestation of the immune and inflammatory response to infection that may ultimately result in multi organ failure. Despite the therapeutic strategies that have been used up to now, sepsis and septic shock remain a leading cause of death in critically ill patients. Myocardial dysfunction is a well-described complication of severe sepsis, also referred to as septic cardiomyopathy, which may progress to right and left ventricular pump failure. Many substances and mechanisms seem to be involved in myocardial dysfunction in sepsis, including toxins, cytokines, nitric oxide, complement activation, apoptosis and energy metabolic derangements. Nevertheless, the precise underlying molecular mechanisms as well as their significance in the pathogenesis of septic cardiomyopathy remain incompletely understood. A well-investigated abnormality in septic cardiomyopathy is mitochondrial dysfunction, which likely contributes to cardiac dysfunction by causing myocardial energy depletion. A number of mechanisms have been proposed to cause mitochondrial dysfunction in septic cardiomyopathy, although it remains controversially discussed whether some mechanisms impair mitochondrial function or serve to restore mitochondrial function. The purpose of this review is to discuss mitochondrial mechanisms that may causally contribute to mitochondrial dysfunction and/or may represent adaptive responses to mitochondrial dysfunction in septic cardiomyopathy.

  1. Discoveries in peripartum cardiomyopathy.

    Science.gov (United States)

    Fett, James D; Markham, David W

    2015-07-01

    The past decade has seen remarkable gains for outcomes in peripartum cardiomyopathy (PPCM), one of the leading causes of maternal mortality and morbidity in the USA and many other countries, including the high-incidence areas of Haiti and South Africa. This review article emphasizes the importance of continuing the process of increasing awareness of PPCM and presents details of this evolving picture, including important discoveries that point the way to full recovery for almost all PPCM subjects. In addition, new interventions will be highlighted, which may facilitate recovery. Numerous studies have demonstrated that when the diagnosis of PPCM is made with LVEF > 0.30, the probability is that recovery to LVEF ≥ 0.50 will occur in the overwhelming majority of subjects. PPCM patients diagnosed with severely depressed systolic function (LVEF < 0.30) and a remodeled left ventricle with greater dilatation (LVEDd ≥ 60mm) are least likely to reach the outcome recovery goals. These are the patients with the greatest need for newer interventional strategies.

  2. TAKOTSUBO CARDIOMYOPATHY: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Krishna M

    2014-08-01

    Full Text Available Takotsubo cardiomyopathy is a condition caused by intense emotional or physical stress leading to rapid and severe reversible cardiac dysfunction. A 44 year old labourer presented with three days old bilateral traumatic fracture of femur and severe respiratory distress; he was ventilated for one day. Echocardiography ruled out pulmonary embolism. Patient remained stable for the next three days. On the fifth day, he appeared fearful, presented with sudden chest pain, tachycardia and hypotension. Echocardiography revealed ejection fraction of 34%, global hypokinesia of left ventricle with apical ballooning and no regional wall motion abnormalities. Coronary angiography was done which revealed no vascular abnormalities. Diagnosis of Takotsubo cardiomyopathy was made and vasopressors were started. Psychiatric treatment of physical and emotional stress was done. Patient gradually improved with ongoing treatment and on eighth day his cardiac function reverted back to normal. Takotsubo cardiomyopathy can be efficiently managed by early recognition, proper supportive treatment and meticulous management of physical and emotional stress.

  3. An update on peripartum cardiomyopathy.

    Science.gov (United States)

    Dalzell, Jonathan R; Jackson, Colette E; Gardner, Roy S

    2011-09-01

    Peripartum cardiomyopathy is a rare but potentially devastating complication of pregnancy. Although the definition of this condition has recently been revised by the Heart Failure Association of the European Society of Cardiology, the pathogenesis of peripartum cardiomyopathy is not well understood and relatively little is known about its incidence and prevalence. Hence, peripartum cardiomyopathy is often under-recognized in the clinical setting. A heightened awareness of this condition and its current management options is therefore warranted throughout primary and secondary care. The identification of the putative role of prolactin in the development and progression of this condition has been recently discovered, with preclinical work suggesting beneficial effects of prolactin antagonism. In this article, we review the literature regarding this condition including these recent advances.

  4. Male sex aggravates the phenotype in mouse models of hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    Maass, AH; Maier, SKG

    2005-01-01

    The authors have created transgenic mouse models of hypertrophic cardiomyopathy with mutations in either cardiac troponin T or myosin heavy chain. Mice mutant in myosin heavy chain develop significant cardiac hypertrophy at young adult age. Female mice keep that hypertrophic state, whereas male mice

  5. Cell therapy in dilated cardiomyopathy: from animal models to clinical trials

    Directory of Open Access Journals (Sweden)

    C. del Corsso

    2011-05-01

    Full Text Available Dilated cardiomyopathy can be the end-stage form and common denominator of several cardiac disorders of known cause, such as hypertensive, ischemic, diabetic and Chagasic diseases. However, some individuals have clinical findings, such as an increase in ventricular chamber size and impaired contractility (classical manifestations of dilated cardiomyopathy even in the absence of a diagnosed primary disease. In these patients, dilated cardiomyopathy is classified as idiopathic since its etiology is obscure. Nevertheless, regardless of all of the advances in medical, pharmacological and surgical procedures, the fate of patients with dilated cardiomyopathy (of idiopathic or of any other known cause is linked to arrhythmic episodes, severe congestive heart failure and an increased risk of sudden cardiac death. In this review, we will summarize present data on the use of cell therapies in animal models of dilated cardiomyopathies and will discuss the few clinical trials that have been published so far involving patients affected by this disease. The animal models discussed here include those in which the cardiomyopathy is produced by genetic manipulation and those in which disease is induced by chemical or infectious agents. The specific model used clearly creates restrictions to translation of the proposed cell therapy to clinical practice, insofar as most of the clinical trials performed to date with cell therapy have used autologous cells. Thus, translation of genetic models of dilated cardiomyopathy may have to wait until the use of allogeneic cells becomes more widespread in clinical trials of cell therapies for cardiac diseases.

  6. Cell therapy in dilated cardiomyopathy: from animal models to clinical trials.

    Science.gov (United States)

    Del Corsso, C; Campos de Carvalho, A C

    2011-05-01

    Dilated cardiomyopathy can be the end-stage form and common denominator of several cardiac disorders of known cause, such as hypertensive, ischemic, diabetic and Chagasic diseases. However, some individuals have clinical findings, such as an increase in ventricular chamber size and impaired contractility (classical manifestations of dilated cardiomyopathy) even in the absence of a diagnosed primary disease. In these patients, dilated cardiomyopathy is classified as idiopathic since its etiology is obscure. Nevertheless, regardless of all of the advances in medical, pharmacological and surgical procedures, the fate of patients with dilated cardiomyopathy (of idiopathic or of any other known cause) is linked to arrhythmic episodes, severe congestive heart failure and an increased risk of sudden cardiac death. In this review, we will summarize present data on the use of cell therapies in animal models of dilated cardiomyopathies and will discuss the few clinical trials that have been published so far involving patients affected by this disease. The animal models discussed here include those in which the cardiomyopathy is produced by genetic manipulation and those in which disease is induced by chemical or infectious agents. The specific model used clearly creates restrictions to translation of the proposed cell therapy to clinical practice, insofar as most of the clinical trials performed to date with cell therapy have used autologous cells. Thus, translation of genetic models of dilated cardiomyopathy may have to wait until the use of allogeneic cells becomes more widespread in clinical trials of cell therapies for cardiac diseases.

  7. Pleiotropic Mutations at the TUP1 Locus That Affect the Expression of Mating-Type-Dependent Functions in SACCHAROMYCES CEREVISIAE.

    Science.gov (United States)

    Lemontt, J F; Fugit, D R; Mackay, V L

    1980-04-01

    The umr7-1 mutation, previously identified in a set of mutants that had been selected for defective UV-induced mutagenesis at CAN1, affects other cellular functions, including many of those regulated by the mating-type locus (MAT) in heterothallic Saccharomyces cerevisiae. The recessive umr7-1 allele, mapping approximately 20 cM distal to thr4 on chromosome III, causes clumpy growth in both a and alpha cells and has no apparent effect on a mating functions. However, alpha umr7 meiotic segregants fail to express several alpha-specific functions (e.g., high-frequency conjugation with a strains, secretion of the hormone alpha-factor and response to the hormone a-factor). In addition, alpha umr7 cells exhibit some a-specific characteristics, such as the barrier phenotype (Bar(+)) that prevents diffusion of alpha-factor and an increased mating frequency with alpha strains. The most striking property of alpha umr7 strains is their altered morphology, in which mitotic cells develop an asymmetric pear shape, like that of normal a cells induced to form "shmoos" by interaction with alpha-factor. Some a/alpha-specific diploid functions are also affected by umr7; instead of polar budding patterns, a/alpha umr7/umr7 diploids have medial budding like a/a, alpha/alpha and haploid strains. Moreover, a/alpha umr7/umr7 diploids have lost the ability to sporulate and are Bar(+) like a or a/a strains. Revertant studies indicate that umr7-1 is a single point mutation. The umr7 mutant fails to complement mutants of both tup1 (selected for deoxythymidine monophosphate utilization) and cyc9 (selected for high iso-2-cytochrome c levels), and all three isolates have similar genetic and phenotypic properties. It is suggested that the product of this gene plays some common central role in the complex regulation of the expression of both MAT-dependent and MAT-independent functions.

  8. Use of advanced recombinant lines to study the impact and potential of mutations affecting starch synthesis in barley.

    Science.gov (United States)

    Howard, Thomas P; Fahy, Brendan; Leigh, Fiona; Howell, Phil; Powell, Wayne; Greenland, Andy; Trafford, Kay; Smith, Alison M

    2014-03-01

    The effects on barley starch and grain properties of four starch synthesis mutations were studied during the introgression of the mutations from diverse backgrounds into an elite variety. The lys5f (ADPglucose transporter), wax (granule-bound starch synthase), isa1 (debranching enzyme isoamylase 1) and sex6 (starch synthase IIa) mutations were introgressed into NFC Tipple to give mutant and wild-type BC2F4 families with different genomic contributions of the donor parent. Comparison of starch and grain properties between the donor parents, the BC2F4 families and NFC Tipple allowed the effects of the mutations to be distinguished from genetic background effects. The wax and sex6 mutations had marked effects on starch properties regardless of genetic background. The sex6 mutation conditioned low grain weight and starch content, but the wax mutation did not. The lys5 mutation conditioned low grain weight and starch content, but exceptionally high β-glucan contents. The isa1 mutation promotes synthesis of soluble α-glucan (phytoglycogen). Its introgression into NFC Tipple increased grain weight and total α-glucan content relative to the donor parent, but reduced the ratio of phytoglycogen to starch. This study shows that introgression of mutations into a common, commercial background provides new insights that could not be gained from the donor parent.

  9. Use of advanced recombinant lines to study the impact and potential of mutations affecting starch synthesis in barley☆

    Science.gov (United States)

    Howard, Thomas P.; Fahy, Brendan; Leigh, Fiona; Howell, Phil; Powell, Wayne; Greenland, Andy; Trafford, Kay; Smith, Alison M.

    2014-01-01

    The effects on barley starch and grain properties of four starch synthesis mutations were studied during the introgression of the mutations from diverse backgrounds into an elite variety. The lys5f (ADPglucose transporter), wax (granule-bound starch synthase), isa1 (debranching enzyme isoamylase 1) and sex6 (starch synthase IIa) mutations were introgressed into NFC Tipple to give mutant and wild-type BC2F4 families with different genomic contributions of the donor parent. Comparison of starch and grain properties between the donor parents, the BC2F4 families and NFC Tipple allowed the effects of the mutations to be distinguished from genetic background effects. The wax and sex6 mutations had marked effects on starch properties regardless of genetic background. The sex6 mutation conditioned low grain weight and starch content, but the wax mutation did not. The lys5 mutation conditioned low grain weight and starch content, but exceptionally high β-glucan contents. The isa1 mutation promotes synthesis of soluble α-glucan (phytoglycogen). Its introgression into NFC Tipple increased grain weight and total α-glucan content relative to the donor parent, but reduced the ratio of phytoglycogen to starch. This study shows that introgression of mutations into a common, commercial background provides new insights that could not be gained from the donor parent. PMID:24748716

  10. Silent diabetic cardiomyopathy in everyday practice: a clinical and echocardiographic study

    OpenAIRE

    Loncarevic, Brane; Trifunovic, Danijela; Soldatovic, Ivan; Vujisic-Tesic, Bosiljka

    2016-01-01

    Background Whether type 2 diabetes mellitus (DM) in the absence of hypertension (HTA) and coronary artery disease (CAD) affects left ventricular (LV) phenotype and function among asymptomatic DM patients that can be easily discovered in everyday practice, what is the clinical risk profile for diabetic cardiomyopathy and how HTA and CAD modulate LV structure and function above diabetic cardiomyopathy, are still incompletely answered questions. Methods In 210 DM patients (group I: 70 asymptomat...

  11. Peripartum cardiomyopathy: a contemporary review.

    Science.gov (United States)

    Shah, Tina; Ather, Sameer; Bavishi, Chirag; Bambhroliya, Arvind; Ma, Tony; Bozkurt, Biykem

    2013-01-01

    Peripartum cardiomyopathy is a rare and potentially fatal disease. Though approximately half of the patients recover, the clinical course is highly variable and some patients develop refractory heart failure and persistent left ventricular systolic dysfunction. It is diagnosed when women present with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. Etiology remains unclear, and treatment is similar to other cardiomyopathies and includes evidence-based standard heart failure management strategies. Experimental strategies such as intravenous immunoglobulin and bromocriptine await further clinical validation.

  12. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C.

    Science.gov (United States)

    Speckman, R A; Garg, A; Du, F; Bennett, L; Veile, R; Arioglu, E; Taylor, S I; Lovett, M; Bowcock, A M

    2000-04-01

    Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.

  13. Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy

    DEFF Research Database (Denmark)

    Ranthe, Mattis F; Carstensen, Lisbeth; Øyen, Nina;

    2015-01-01

    at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (... ascertained family history of premature (death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at ... incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged

  14. Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

    Science.gov (United States)

    Brown, C A; Lanning, R W; McKinney, K Q; Salvino, A R; Cherniske, E; Crowe, C A; Darras, B T; Gominak, S; Greenberg, C R; Grosmann, C; Heydemann, P; Mendell, J R; Pober, B R; Sasaki, T; Shapiro, F; Simpson, D A; Suchowersky, O; Spence, J E

    2001-09-01

    Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function.

  15. Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation.

    Science.gov (United States)

    Asselta, Rosanna; Robusto, Michela; Platé, Manuela; Santoro, Cristina; Peyvandi, Flora; Duga, Stefano

    2015-07-01

    Fibrinogen is a hexameric glycoprotein consisting of two sets of three polypeptides (the Aα, Bβ, and γ chains, encoded by the three genes FGA, FGB, and FGG). It is involved in the final phase of the coagulation process, being the precursor of the fibrin monomers necessary for the formation of the hemostatic plug. Rare inherited fibrinogen disorders can manifest as quantitative deficiencies, qualitative defects, or both. In particular, dysfibrinogenemia and hypo-dysfibrinogenemia are characterized by reduced functional activity associated with normal or reduced antigen levels, and are usually determined by heterozygous mutations affecting any of the three fibrinogen genes. In this study, we investigated the genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients. Mutational screening disclosed six different variants, two of which novel (FGB-p.Asp185Asn and FGG-p.Asn230Lys). The molecular characterization of the FGG-p.Asn230Lys mutation, performed by transient expression experiments of the recombinant mutant protein, demonstrated that it induces an almost complete impairment in fibrinogen secretion, according to a molecular mechanism often associated with quantitative fibrinogen disorders. Conversely, the FGB-p.Asp185Asn variant was demonstrated to be a gain-of-glycosylation mutation leading to a hyperglycosylation of the Bβ chain, not affecting fibrinogen assembly and secretion. To our knowledge, this is the second gain-of-glycosylation mutation involving the FGB gene.

  16. Peripartum Cardiomyopathy: A Case Report

    Directory of Open Access Journals (Sweden)

    Z Basirat

    2006-04-01

    Full Text Available ABSTRACT: Introduction & Objective: Peripartum cardiomyopathy is a rare but sometimes fatal form of heart failure during the period of 1 month antepartum to 5 months postpartum. The aim of this report is to assess the clinical presentation, management and crucial role of echocardiography in women with peripartum cardiomyopathy. Case: A 22 year-old woman, with previously healthy primipara, was admitted to the emergency ward with sever dyspnea, cough, and bloody hemoptesis and a preliminary diagnosis of pulmonary embolism (PE two weeks after cesarean section. Neither perfusion scintigaphy nor Doppler sonography test of lower extremities and pelvis showed any evidence of PE or deep venous thrombosis. Echocardiography revealed features of left ventricular failure. A diagnosis of peripartum cardiomyopathy was made, appropriate treatment was administered and the patient improved. Conclusion: It is possible to misdiagnose peripartum cardiomyopathy with PE. Echocardiography is a valuable tool in the differential diagnosis. As a noninvasive procedure, it should be performed at the bedside as soon as possible to introduce proper treatment and to avoid potentially fatal errors.

  17. Genetic basis of hypertrophic cardiomyopathy

    NARCIS (Netherlands)

    Bos, J.M.

    2010-01-01

    The understanding of hypertrophic cardiomyopathy (HCM) has matured from its cornerstone as a disease of the sarcomere to a compendium of diseases with various clinical, genetic and morphologic substrates. Research has provided us more insights into i) the pathogenetic development of HCM, ii) the pos

  18. Improving Outcomes in Hypertrophic Cardiomyopathy

    NARCIS (Netherlands)

    P.A. Vriesendorp (Pieter)

    2016-01-01

    markdownabstractImproving outcomes in hypertrophic cardiomyopathy (HCM) is focused on the improvement of the therapeutic strategies for patients with HCM. First it demonstrates that individual patient selection in patients with obstructive and symptomatic HCM can lead to near normal life-expectancy;

  19. Variable Autosomal and X Divergence Near and Far from Genes Affects Estimates of Male Mutation Bias in Great Apes.

    Science.gov (United States)

    Narang, Pooja; Wilson Sayres, Melissa A

    2016-12-31

    Male mutation bias, when more mutations are passed on via the male germline than via the female germline, is observed across mammals. One common way to infer the magnitude of male mutation bias, α, is to compare levels of neutral sequence divergence between genomic regions that spend different amounts of time in the male and female germline. For great apes, including human, we show that estimates of divergence are reduced in putatively unconstrained regions near genes relative to unconstrained regions far from genes. Divergence increases with increasing distance from genes on both the X chromosome and autosomes, but increases faster on the X chromosome than autosomes. As a result, ratios of X/A divergence increase with increasing distance from genes and corresponding estimates of male mutation bias are significantly higher in intergenic regions near genes versus far from genes. Future studies in other species will need to carefully consider the effect that genomic location will have on estimates of male mutation bias.

  20. Cardiac MRI in a Patient with Coincident Left Ventricular Non-Compaction and Hypertrophic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Zahra Alizadeh-Sani

    2011-12-01

    Full Text Available Left ventricular non-compaction cardiomyopathy is a rare congenital cardiomyopathy that affects both children and adults. Since the clinical manifestations are not sufficient to establish diagnosis, echocardiography is the diagnostic tool that makes it possible to document ventricular non-compaction and establish prognostic factors. We report a 47-year-old woman with a history of dilated cardiomyopathy with unknown etiology. Echocardiography showed mild left ventricular enlargement with severe systolic dysfunction (EF = 20-25%. According to cardiac magnetic resonance imaging findings non-compaction left ventricle with hypertrophic cardiomyopathy was considered, and right ventricular septal biopsy was recommended. Right ventricular endomyocardial biopsy showed moderate hypertrophy of cardiac myocytes with foci of myocytolysis and moderate interstitial fibrosis. No evidence of infiltrative deposition was seen.

  1. Characterization and Long-Term Prognosis of Postmyocarditic Dilated Cardiomyopathy Compared With Idiopathic Dilated Cardiomyopathy.

    Science.gov (United States)

    Merlo, Marco; Anzini, Marco; Bussani, Rossana; Artico, Jessica; Barbati, Giulia; Stolfo, Davide; Gigli, Marta; Muça, Matilda; Naso, Paola; Ramani, Federica; Di Lenarda, Andrea; Pinamonti, Bruno; Sinagra, Gianfranco

    2016-09-15

    Dilated cardiomyopathy (DC) is the final common pathway of different pathogenetic processes and presents a significant prognostic heterogeneity, possibly related to its etiologic variety. The characterization and long-term prognosis of postmyocarditic dilated cardiomyopathy (PM-DC) remain unknown. This study assesses the clinical-instrumental evolution and long-term prognosis of a large cohort of patients with PM-DC. We analyzed 175 patients affected with DC consecutively enrolled from 1993 to 2008 with endomyocardial biopsy (EMB) data available. PM-DC was defined in the presence of borderline myocarditis at EMB or persistent left ventricular dysfunction 1 year after diagnosis of active myocarditis at EMB. Other patients were defined as affected by idiopathic dilated cardiomyopathy (IDC). Analysis of follow-up evaluations was performed at 24, 60, and 120 months. We found 72 PM-DC of 175 enrolled patients (41%). Compared with IDC, patients with PM-DC were more frequently females and less frequently presented a familial history of DC. No other baseline significant differences were found. During the long-term follow-up (median 154, first to third interquartile range 78 to 220 months), patients with PM-DC showed a trend toward slower disease progression. Globally, 18 patients with PM-DC (25%) versus 49 with IDC (48%) experienced death/heart transplantation (p = 0.045). The prognostic advantage for patients with PM-DC became significant beyond 40 months of follow-up. At multivariable time-dependent Cox analysis, PM-DC was confirmed to have a global independent protective role (hazard ratio 0.53, 95% confidence interval 0.28 to 0.97, p = 0.04). In conclusion, PM-DC is characterized by better long-term prognosis compared with IDC. An exhaustive etiologic characterization appears relevant in the prognostic assessment of DC.

  2. Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish

    Directory of Open Access Journals (Sweden)

    Jingchun Yang

    2016-01-01

    Full Text Available Animal models have played a critical role in validating human dilated cardiomyopathy (DCM genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents. Specifically, we studied the zebrafish homologue of GATAD1, a recently identified gene for adult-onset autosomal recessive DCM. We showed cardiac expression of gatad1 transcripts, by whole mount in situ hybridization in zebrafish embryos, and demonstrated nuclear and sarcomeric I-band subcellular localization of Gatad1 protein in cardiomyocytes, by injecting a Tol2 plasmid encoding fluorescently-tagged Gatad1. We next generated gatad1 knock-out fish lines by TALEN technology and a transgenic fish line that expresses the human DCM GATAD1-S102P mutation in cardiomyocytes. Under stress conditions, longitudinal studies uncovered heart failure (HF-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines. Based on these efforts of studying a gene-based inherited cardiomyopathy model, we discuss the strengths and bottlenecks of adult zebrafish as a new vertebrate model for assessing candidate cardiomyopathy genes.

  3. Neonatal cardiomyopathies and metabolic crises due to oxidative phosphorylation defects.

    Science.gov (United States)

    Schiff, Manuel; Ogier de Baulny, Hélène; Lombès, Anne

    2011-08-01

    Neonatal cardiomyopathies due to mitochondrial oxidative phosphorylation (OXPHOS) defects are extremely severe conditions which can be either isolated or included in a multi-organ disease, with or without metabolic crises, of which profound lactic acidosis is the prominent feature. Cardiomyopathy is more often hypertrophic than dilated. Antenatal manifestations such as fetal cardiomyopathy, arrhythmia and/or hydrops have been reported. Pathophysiological mechanisms are complex, going beyond ATP deficiency of the high-energy-consuming neonatal myocardium. Birth is a key metabolic period when the myocardium switches ATP production from anaerobic glycolysis to mitochondrial fatty acid oxidation and OXPHOS. Heart-specificity of the defect may be related to the specific localization of the defect, to the high myocardium dependency on OXPHOS, and/or to interaction between the primary genetic alteration and other factors such as modifier genes. Therapeutic options are limited but standardized diagnostic procedures are mandatory to confirm the OXPHOS defect and to identify its causal mutation, allowing genetic counseling and potential prenatal diagnosis.

  4. Molecular profiling of dilated cardiomyopathy that progresses to heart failure

    Science.gov (United States)

    Burke, Michael A.; Chang, Stephen; Wakimoto, Hiroko; Gorham, Joshua M.; Conner, David A.; Christodoulou, Danos C.; Parfenov, Michael G.; DePalma, Steve R.; Eminaga, Seda; Konno, Tetsuo; Seidman, Jonathan G.; Seidman, Christine E.

    2016-01-01

    Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10–4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10–33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM. PMID:27239561

  5. A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation

    Science.gov (United States)

    Sana, Maria Elena; Quilliam, Lawrence A.; Spitaleri, Andrea; Pezzoli, Laura; Marchetti, Daniela; Lodrini, Chiara; Candiago, Elisabetta; Lincesso, Anna Rita; Ferrazzi, Paolo; Iascone, Maria

    2016-01-01

    Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband’s daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed. PMID:28002430

  6. Ventricular fibrillation following autologous intramyocardial cell therapy for inherited cardiomyopathy.

    Science.gov (United States)

    Pytel, Peter; Husain, Aliya; Moskowitz, Ivan; Raman, Jai; MacLeod, Heather; Anderson, Allen S; Burke, Martin; McNally, Elizabeth M

    2010-01-01

    A 41-year-old male with cardiomyopathy from an inherited beta myosin heavy-chain mutation underwent treatment for heart failure with intramyocardial cell transplantation. He received direct injections into his heart of autologous precursor cells isolated from his blood. He immediately suffered ventricular fibrillation. Although he was resuscitated, he experienced a prolonged downward course that prohibited his undergoing transplantation. His autopsy revealed marked fibrosis throughout the myocardium with areas of mononuclear cell infiltrate. This case highlights the potential adverse effects associated with intramyocardial therapy in the cardiomyopathic heart.

  7. Ventricular fibrillation following autologous intramyocardial cell therapy for inherited cardiomyopathy

    Science.gov (United States)

    Pytel, Peter; Husain, Aliya; Moskowitz, Ivan; Raman, Jai; MacLeod, Heather; Anderson, Allen S.; Burke, Martin; McNally, Elizabeth M.

    2010-01-01

    A 41 year old male with cardiomyopathy from an inherited β myosin heavy chain mutation underwent treatment for heart failure with intramyocardial cell transplantation. He received direct injections into his heart of autologous precursor cells isolated from his blood. He immediately suffered ventricular fibrillation. Although he was resuscitated, he experienced a prolonged downward course that prohibited his undergoing transplantation. His autopsy revealed marked fibrosis throughout the myocardium with areas of mononuclear cell infiltrate. This case highlights the potential adverse effects associated with intramyocardial therapy in the cardiomyopathic heart. PMID:19026577

  8. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    DEFF Research Database (Denmark)

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S

    2011-01-01

    The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere...... as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic...

  9. Location of glycine mutations within a bacterial collagen protein affects degree of disruption of triple-helix folding and conformation.

    Science.gov (United States)

    Cheng, Haiming; Rashid, Shayan; Yu, Zhuoxin; Yoshizumi, Ayumi; Hwang, Eileen; Brodsky, Barbara

    2011-01-21

    The hereditary bone disorder osteogenesis imperfecta is often caused by missense mutations in type I collagen that change one Gly residue to a larger residue and that break the typical (Gly-Xaa-Yaa)(n) sequence pattern. Site-directed mutagenesis in a recombinant bacterial collagen system was used to explore the effects of the Gly mutation position and of the identity of the residue replacing Gly in a homogeneous collagen molecular population. Homotrimeric bacterial collagen proteins with a Gly-to-Arg or Gly-to-Ser replacement formed stable triple-helix molecules with a reproducible 2 °C decrease in stability. All Gly replacements led to a significant delay in triple-helix folding, but a more dramatic delay was observed when the mutation was located near the N terminus of the triple-helix domain. This highly disruptive mutation, close to the globular N-terminal trimerization domain where folding is initiated, is likely to interfere with triple-helix nucleation. A positional effect of mutations was also suggested by trypsin sensitivity for a Gly-to-Arg replacement close to the triple-helix N terminus but not for the same replacement near the center of the molecule. The significant impact of the location of a mutation on triple-helix folding and conformation could relate to the severe consequences of mutations located near the C terminus of type I and type III collagens, where trimerization occurs and triple-helix folding is initiated.

  10. Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy

    Directory of Open Access Journals (Sweden)

    Nardone Anna

    2004-04-01

    Full Text Available Abstract Background Cystic fibrosis (CF is a multisystem disorder characterised by mutations of the CFTR gene, which encodes for an important component in the coordination of electrolyte movement across of epithelial cell membranes. Symptoms are pulmonary disease, pancreatic exocrine insufficiency, male infertility and elevated sweat concentrations. The CFTR gene has numerous mutations (>1000 and functionally important polymorphisms (>200. Early identification is important to provide appropriate therapeutic interventions, prognostic and genetic counselling and to ensure access to specialised medical services. However, molecular diagnosis by direct mutation screening has proved difficult in certain ethnic groups due to allelic heterogeneity and variable frequency of causative mutations. Methods We applied a gene scanning approach using DHPLC system for analysing specifically all CFTR exons and characterise sequence variations in a subgroup of CF Italian patients from the Lazio region (Central Italy characterised by an extensive allelic heterogeneity. Results We have identified a total of 36 different mutations representing 88% of the CF chromosomes. Among these are two novel CFTR mutations, including one missense (H199R and one microdeletion (4167delCTAAGCC. Conclusion Using this approach, we were able to increase our standard power rate of mutation detection of about 11% (77% vs. 88%.

  11. Mutations in exons of the CYP17-II gene affect sex steroid concentration in male Japanese flounder ( Paralichthys olivaceus)

    Science.gov (United States)

    Ma, Ruiqin; He, Feng; Wen, Haishen; Li, Jifang; Shi, Bao; Shi, Dan; Liu, Miao; Mu, Weijie; Zhang, Yuanqing; Hu, Jian; Han, Weiguo; Zhang, Jianan; Wang, Qingqing; Yuan, Yuren; Liu, Qun

    2012-03-01

    As a specific gene of fish, cytochrome P450c17-II ( CYP17-II) gene plays a key role in the growth, development an reproduction level of fish. In this study, the single-stranded conformational polymorphism (SSCP) technique was used to characterize polymorphisms within the coding region of CYP17-II gene in a population of 75 male Japanese flounder ( Paralichthys olivaceus). Three single nucleotide polymorphisms (SNPs) were identified in CYP17-II gene of Japanese flounder. They were c.G594A (p.G188R), c.G939A and c.G1502A (p.G490D). SNP1 (c.G594A), located in exon 4 of CYP17-II gene, was significantly associated with gonadosomatic index (GSI). Individuals with genotype GG of SNP1 had significantly lower GSI ( P < 0.05) than those with genotype AA or AG. SNP2 (c.G939A) located at the CpG island of CYP17-II gene. The mutation changed the methylation of exon 6. Individuals with genotype AA of SNP2 had significantly lower serum testosterone (T) level and hepatosomatic index (HSI) compared to those with genotype GG. The results suggested that SNP2 could influence the reproductive endocrine of male Japanese flounder. However, the SNP3 (c.G1502A) located in exon 9 did not affect the four measured reproductive traits. This study showed that CYP17-II gene could be a potentially useful candidate gene for the research of genetic breeding and physiological aspects of Japanese flounder.

  12. Mutations in Exons of the CYP17- Ⅱ Gene Affect Sex Steroid Concentration in Male Japanese Flounder (Paralichthys olivaceus)

    Institute of Scientific and Technical Information of China (English)

    MA Ruiqin; HU Jian; HAN Weiguo; ZHANG Jianan; WANG Qingqing; YUAN Yuren; LIU Qun; HE Feng; WEN Haishen; LI Jifang; SHI Bao; SHI Dan; LIU Miao; MU Weijie; ZHANG Yuanqing

    2012-01-01

    As a specific gene of fish,cytochrome P450c 17-Ⅱ (CYP17-Ⅱ) gene plays a key role in the growth,development and reproduction level of fish.In this study,the single-stranded conformational polymorphism (SSCP) technique was used to characterize polymorphisms within the coding region of CYP17- Ⅱ gene in a population of 75 male Japanese flounder (Paralichthys olivaceus).Three single nucleotide polymorphisms (SNPs) were identified in CYP17-Ⅱ gene of Japanese flounder.They were c.G594A (p.G188R),c.G939A and c.G1502A (p.G490D).SNP1 (c.G594A),located in exon 4 of CYP17-Ⅱ gene,was significantly associated with gonadosomatic index (GSI).Individuals with genotype GG of SNP1 had significantly lower GSI (P<0.05) than those with genotype AA or AG.SNP2 (c.G939A) located at the CpG island of CYP17-Ⅱ gene.The mutation changed the methylation of exon 6.Individuals with genotype AA of SNP2 had significantly lower serum testosterone (T) level and hepatosomatic index (HSI) compared to those with genotype GG.The results suggested that SNP2 could influence the reproductive endocrine of male Japanese flounder.However,the SNP3 (c.G 1502A) located in exon 9 did not affect the four measured reproductive traits.This study showed that CYP17-Ⅱgene could be a potentially useful candidate gene for the research of genetic breeding and physiological aspects of Japanese flounder.

  13. Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy.

    Science.gov (United States)

    Sysi-Aho, Marko; Koikkalainen, Juha; Seppänen-Laakso, Tuulikki; Kaartinen, Maija; Kuusisto, Johanna; Peuhkurinen, Keijo; Kärkkäinen, Satu; Antila, Margareta; Lauerma, Kirsi; Reissell, Eeva; Jurkko, Raija; Lötjönen, Jyrki; Heliö, Tiina; Orešič, Matej

    2011-01-20

    Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA) on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI) to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance.

  14. Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Marko Sysi-Aho

    Full Text Available Dilated cardiomyopathy (DCM, characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance.

  15. MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients.

    Science.gov (United States)

    Mouton, J M; van der Merwe, L; Goosen, A; Revera, M; Brink, P A; Moolman-Smook, J C; Kinnear, C

    2016-05-01

    Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in β-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM.

  16. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy.

    Science.gov (United States)

    Riisager, M; Duno, M; Hansen, F Juul; Krag, T O; Vissing, C R; Vissing, J

    2013-07-01

    Defects in glycosylations of α-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of α-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far.

  17. A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members

    DEFF Research Database (Denmark)

    Milman, N; Ursin, K; Rødevand, E

    2009-01-01

    BACKGROUND: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. OBJECTIVE: To report a novel mutation in the NOD2 gene...... associated with Blau syndrome. METHODS AND RESULTS: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has...... not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal...

  18. Cushing's Disease Presented by Reversible Dilated Cardiomyopathy

    OpenAIRE

    Berna İmge Aydoğan; Demet Menekşe Gerede; Asena Gökçay Canpolat; Murat Faik Erdoğan

    2015-01-01

    Introduction. Dilated cardiomyopathy is rarely reported among CS patients especially without hypertension and left ventricular hypertrophy. Materials and Methods. We hereby report a Cushing’s syndrome case presenting with dilated cardiomyopathy. Results. A 48-year-old female patient was admitted to our clinic with severe proximal myopathy and dilated cardiomyopathy without ventricular hypertrophy. Cushing’s disease was diagnosed and magnetic-resonance imaging of the pituitary gland revealed a...

  19. Outcome in Patients Treated with Isolated Liver Transplantation for Familial Transthyretin Amyloidosis to Prevent Cardiomyopathy

    DEFF Research Database (Denmark)

    Nelson, Laerke Marie; Penninga, Luit; Villadsen, Gerda Elisabeth;

    2015-01-01

    with echocardiographic manifestations of early cardiac amyloid involvement and in five endomyocardial biopsy was positive for TTR amyloid. RESULTS: Median age at LTx was 45.5 yr (range 39-54), and four were male (67%). All patients were alive at a median follow-up of 56.6 months (range 18-104). No surgical complications......BACKGROUND: Familial transthyretin (TTR) amyloidosis is caused by different TTR mutations resulting in different clinical phenotypes of the disease. The Leu111Met mutation causes severe restrictive cardiomyopathy. Liver transplantation (LTx) is an established treatment option for patients with TTR...... for patients with familial TTR amyloidosis due to Leu111Met mutation. Appropriate timing of LTx is of utmost importance to avoid development of severe amyloid cardiomyopathy and the need for combined heart and liver transplantation....

  20. Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes.

    Science.gov (United States)

    Ercolino, Tonino; Lai, Roberta; Giachè, Valentino; Melchionda, Salvatore; Carella, Massimo; Delitala, Alessandro; Mannelli, Massimo; Fanciulli, Giuseppe

    2014-02-25

    Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with an estimated incidence of 1 in 3000/3500 live births. NF1 is caused by a mutation in a gene which encodes a protein known as neurofibromin. In up to 5% of cases, NF1 is associated with pheochromocytomas. RET proto-oncogene encodes a member of the receptor tyrosine kinase family involved in the normal development or the neoplastic growth of neural crest cell lineages. Germ-line RET mutations account for cases of Multiple Endocrine Neoplasia type 2 (MEN2), an autosomal dominant genetic syndrome where medullary thyroid carcinoma (MTC) is the major and more clinically severe feature, with nearly complete penetrance. C-cell hyperplasia (CCH) is described in MEN2 patients, and it has been implicated as the precursor of in situ MTC. Patients with RET mutations develop pheochromocytomas in 50% of cases. Rarely, patients with NF1 have been found to present, in addition to the NF1 clinical picture, other lesions, such as parathyroid hyperplasia/adenoma and/or medullary thyroid carcinoma. In spite of the presence of these MEN2 lesions, in none of these patients mutations of gene RET have been found so far. In this report, we describe the first case of a patient affected by a germ-line mutation in both NF1 and RET genes.

  1. A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia

    Directory of Open Access Journals (Sweden)

    Pariset Lorraine

    2011-07-01

    Full Text Available Abstract Background X-linked anhidrotic ectodermal dysplasia is a disorder characterized by abnormal development of tissues and organs of ectodermal origin caused by mutations in the EDA gene. The bovine EDA gene encodes the ectodysplasin A, a membrane protein expressed in keratinocytes, hair follicles and sweat glands, which is involved in the interactions between cell and cell and/or cell and matrix. Four mutations causing ectodermal dysplasia in cattle have been described so far. Results We identified a new single nucleotide polymorphism (SNP at the 9th base of exon 8 in the EDA gene in two calves of Holstein Friesian cattle breed affected by ectodermal dysplasia. This SNP is located in the exonic splicing enhancer (ESEs recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp in the RNA processing, causing a severe alteration of the protein structure and thus the disease. Conclusion We identified a mutation, never described before, that changes the regulation of alternative splicing in the EDA gene and causes ectodermal dysplasia in cattle. The analysis of the SNP allows the identification of carriers that can transmit the disease to the offspring. This mutation can thus be exploited for a rational and efficient selection of unequivocally healthy cows for breeding.

  2. Peripartum cardiomyopathy (A literature review

    Directory of Open Access Journals (Sweden)

    Farveh Vakilian

    2014-07-01

    Full Text Available Heart failure (HF is a serious and growing public health concern, which has many causes. Pregnancy is a critical condition with significant hemodynamic and immunologic changes. Peripartum cardiomyopathy (PPCM is a disease of unknown cause in which left ventricular (LV dysfunction occurs during the last trimester of pregnancy or the early puerperium. PPCM is known to be the most common cardiovascular cause of severe complications in pregnancy.  Risk factors for peripartum cardiomyopathy include advanced maternal age, twin pregnancy, smoking, pregnancy-related hypertension and preeclampsia, multiparity, African descent, and long-term tocolysis. Oxidative stress and some inflammatory markers have been diagnosed in PPCM pathophysiology. Recent observations have suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. Patients developed peripartum cardiomiopathy treated with bromocriptine showed significantly improved LV ejection fraction and heart failure symptoms. This article tries to have a short review on this clinical scenario.

  3. Takotsubo cardiomyopathy: a historical note

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ To the Editor: I read with interest the case report of Takotsubo cardiomyopathy in a Chinese woman.1 Unfortunately, the authors mistakenly attributed the original description of this syndrome to Tsuchihashi et al in 2001.2Actually Dote et al3 first described this syndrome in 1991, ten years before Tsuchihashi et al did.2 Incidentally, the authors did make a reference in their case report to the article by Dote et al3 which was cited as reference 1.

  4. Determinants of Thyrotoxic Cardiomyopathy Recovery

    Directory of Open Access Journals (Sweden)

    Lucia Oliveros-Ruiz

    2013-01-01

    Full Text Available The purpose was to evaluate the effect of the disease duration prior to treatment, thyroid hormones level, or both on the reversibility of dilated cardiomyopathy. Between January 2006 and December 2010, a longitudinal study with a 6 months follow-up was carried on. One hundred and seventy patients with hyperthyroidism were referred to the cardiologist, and 127 had a 6 months followup after antithyroid treatment and were evaluated by echocardiography. Dilated cardiomyopathy reversibility criteria were established according to echocardiographic parameters. Complete reversibility existed when all parameters were met, partial reversibility when LVEF was ≥55% plus two or three other parameters, and no reversibility when LVEF was ≤55% regardless of other parameters. The results showed that echocardiography parameters related to the regression of myocardial mass were associated with a disease duration shorter than 10.38 months. This was the main predictive variable for reversal of dilated cardiomyopathy, followed by β-blocker treatment, and the last predictive variable was the serum level of free triiodothyronine. This study showed that the effect on the myocardium related to thyrotoxicosis was associated with the disease duration before treatment.

  5. Genetic mapping of ada and adc mutations affecting the adaptive response of Escherichia coli to alkylating agents.

    Science.gov (United States)

    Sedgwick, B

    1982-05-01

    The adaptive response to alkylating agents is an inducible repair system which protects Escherichia coli against the mutagenicity and toxicity of these agents. Four mutations, ada-3, ada-5, ada-6, and adc-1, which confer differing phenotypes as regards this response, were shown to be cotransducible with gyrA, and were located at 47 min on the E. coli genetic map. A mutation already shown on the map at 47 min as tag (B. J. Bachmann and K. B. Low, Microbiol. Rev. 44:1--56, 1980; Karran et al., J. Mol. Biol. 140:101--127, 1980) is now known to be an ada mutation (G. Evensen and E. Seeberg, personal communication).

  6. LHON/MELAS overlap mutation in ND1 subunit of mitochondrial complex I affects ubiquinone binding as revealed by modeling in Escherichia coli NDH-1.

    Science.gov (United States)

    Pätsi, Jukka; Maliniemi, Pilvi; Pakanen, Salla; Hinttala, Reetta; Uusimaa, Johanna; Majamaa, Kari; Nyström, Thomas; Kervinen, Marko; Hassinen, Ilmo E

    2012-02-01

    Defects in complex I due to mutations in mitochondrial DNA are associated with clinical features ranging from single organ manifestation like Leber hereditary optic neuropathy (LHON) to multiorgan disorders like mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Specific mutations cause overlap syndromes combining several phenotypes, but the mechanisms of their biochemical effects are largely unknown. The m.3376G>A transition leading to p.E24K substitution in ND1 with LHON/MELAS phenotype was modeled here in a homologous position (NuoH-E36K) in the Escherichia coli enzyme and it almost totally abolished complex I activity. The more conservative mutation NuoH-E36Q resulted in higher apparent K(m) for ubiquinone and diminished inhibitor sensitivity. A NuoH homolog of the m.3865A>G transition, which has been found concomitantly in the overlap syndrome patient with the m.3376G>A, had only a minor effect. Consequences of a primary LHON-mutation m.3460G>A affecting the same extramembrane loop as the m.3376G>A substitution were also studied in the E. coli model and were found to be mild. The results indicate that the overlap syndrome-associated m.3376G>A transition in MTND1 is the pathogenic mutation and m.3865A>G transition has minor, if any, effect on presentation of the disease. The kinetic effects of the NuoH-E36Q mutation suggest its proximity to the putative ubiquinone binding domain in 49kD/PSST subunits. In all, m.3376G>A perturbs ubiquinone binding, a phenomenon found in LHON, and decreases the activity of fully assembled complex I as in MELAS.

  7. Transient stress cardiomyopathies in the elderly: Clinical & Pathophysiologic considerations

    Institute of Scientific and Technical Information of China (English)

    Michael A Chen

    2012-01-01

    Transient stress-induced cardiomyopathies have been increasingly recognized and while rare,they tend to affect elderly women more than other demographic groups.One type,often called tako-tsubo cardiomyopathy (TTC),is typically triggered by significant emotional or physical stress and is associated with chest pain,electrocardiogram (ECG) changes and abnormal cardiac enzymes.Significant left ventricular regional wall motion abnormalities usually include an akinetic "ballooning" apex with normal or hyperdynamic function of the base.A second type,often called neurogenic stunned myocardium,typically associated with subarachnoid hemorrhage,also usually presents with ECG changes and positive enzymes,but the typical wall motion abnormalities seen include normal basal and apical left ventricular contraction with akinesis of the mid-cavity in a circumferential fashion.The pathophysiology,clinical care and typical courses,are reviewed.

  8. Mutation Analysis of Mitochondrial tRNA Gene in Patients with Primary Dilated Cardiomyopathy%原发性扩张型心肌病的线粒体tRNA基因突变分析

    Institute of Scientific and Technical Information of China (English)

    李红超; 舒红英; 李晓杰; 倪斌; 谢海龙; 周海燕; 倪崖

    2015-01-01

    To identify the potential pathogenic mutations of mitochondrial tRNA in patients with primary dilated cardio-myopathy(DCM) and the possible association of the mutations with DCM.Paraffin-embedded myocardial tissues from two patients with DCM and 10 healthy controls,which were discarded after forensic examination,were used for the study.PCR amplification wasperformed for the mitochondrial tRNA genes and direct sequencing was conducted.Sequencing re-sults showed no variation for mitochondrial tRNA genes in the normal myocardial tissues.The tRNAVal G1664A variation and tRNAMet T4454C variation were identified in patients with DCM.These two variations were previously reported as polymorphism in MitoMap.There was no pathogenic mutation detected in mitochondrial tRNA genes of the two patients with DCM.A patient pool of large sample size is expected for analysis of the pathogenic mutations,polymorphism loci and haplogroup that might be associated with DCM.%为寻找原发性扩张型心肌病病例是否存在已知以及未知的线粒体tRNA致病性突变,以探讨扩张型心肌病可能的发病原因.收集2例原发性扩张型心肌病患者和10例正常对照尸检心肌组织石蜡标本,针对22种线粒体tRNA基因分别设计一对引物,PCR扩增后并测序分析线粒体tRNA基因突变情况.结果在对照样本中未检测到线粒体tRNA变异位点,在1例患者中检测到了tRNAVal基因G1664A变异,Mitomap已有报道为多态性位点;于另1例患者中检测到tRNAMetT4454C变异,有文章报道该位点与线粒体功能障碍有关,Mitomap报道为多态性位点.本研究中2例病例中未检测到线粒体tRNA致病性突变位点,可能与病例个体的心衰程度有关,有必要扩大样本量深入研究线粒体tRNA以及mtDNA其他基因突变与原发性扩张型心肌病之间的关系,以寻找可能的致病突变位点、易感的多态性位点或者单倍体群,为认识原发性扩张型心肌病的发病机制进一步提供理论基础和依据.

  9. Perturbation of NCOA6 Leads to Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Jae-il Roh

    2014-08-01

    Full Text Available Dilated cardiomyopathy (DCM is a progressive heart disease characterized by left ventricular dilation and contractile dysfunction. Although many candidate genes have been identified with mouse models, few of them have been shown to be associated with DCM in humans. Germline depletion of Ncoa6, a nuclear hormone receptor coactivator, leads to embryonic lethality and heart defects. However, it is unclear whether Ncoa6 mutations cause heart diseases in adults. Here, we report that two independent mouse models of NCOA6 dysfunction develop severe DCM with impaired mitochondrial function and reduced activity of peroxisome proliferator-activated receptor δ (PPARδ, an NCOA6 target critical for normal heart function. Sequencing of NCOA6-coding regions revealed three independent nonsynonymous mutations present in 5 of 50 (10% patients with idiopathic DCM (iDCM. These data suggest that malfunction of NCOA6 can cause DCM in humans.

  10. Recurrent takotsubo cardiomyopathy in a child.

    Science.gov (United States)

    Srivastava, Nayan T; Parent, John J; Hurwitz, Roger A

    2016-02-01

    Takotsubo cardiomyopathy or transient apical ballooning syndrome very rarely presents in children. In all patients with takotsubo, it is estimated that only 3.5% will have recurrence. In this study, we describe a case of recurrent takotsubo cardiomyopathy in a child, likely triggered by status epilepticus.

  11. The hunt for a functional mutation affecting conformation and calving traits on chromosome 18 in Holstein cattle

    Science.gov (United States)

    Sequence data from 11 US Holstein bulls were analyzed to identify putative causal mutations associated with calving and conformation traits. The SNP ARS-BFGL-NGS-109285 at 57,589,121 bp (UMD 3.1 assembly) on BTA18 has large effects on 4 measures of body shape and size, 2 measures of dystocia, longev...

  12. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary.

    Science.gov (United States)

    Lin, H; Spradling, A C

    1997-06-01

    Germline stem cells play a pivotal role in gametogenesis; yet little is known about how they are formed, how they divide to self-renew, and how these processes are genetically controlled. Here we describe the self-renewing asymmetric division of germline stem cells in the Drosophila ovarian germline, as marked by the spectrosome, a cytoplasmic structure rich in membrane skeletal proteins. The ontogeny of the spectrosome marks the lineage of germline stem cells. We identified two new groups of mutations in which the divisional asymmetry is disrupted. The first, which we refer to as ovarette (ovt) mutations, was shown to correspond to a novel class of mutations in the pumilio locus. Since pumilio is known to posttranscriptionally repress the expression of target genes at earlier stages of germ cell development, our results suggest that a similar activity is needed to maintain germ line stem cells. We have also identified a second and novel gene, piwi, whose mutations abolish germline stem cell division.

  13. COL1A2 gene analysis in a Czech osteogenesis imperfecta patient: a candidate novel mutation in a patient affected by osteogenesis imperfecta type 3

    Directory of Open Access Journals (Sweden)

    Hrušková L

    2015-08-01

    Full Text Available Lucie Hrušková,1 Ivo Mařík,2,3 Stella Mazurová,1 Pavel Martásek,1 Ivan Mazura1 1Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; 2Ambulant Centre for Defects of Locomotor Apparatus 1.1.c., Prague, Czech Republic; 3Faculty of Medical Studies, West Bohemia University, Pilsen, Czech RepublicAbstract: Osteogenesis imperfecta is a heritable bone fragility disease with a heterogenic genetic origin. Most cases result from mutations of either the COL1A1 gene or the COL1A2 gene. We identified a novel COL1A2 gene mutation in a Czech patient, born to unaffected parents, who was diagnosed according to clinical and anthropometric findings and radiographic features as having type 3 osteogenesis imperfecta, which is a severe form of this disease. The identified Gly814Trp mutation was predicted by a number of complementary bioinformatic programs to result in functional alteration of the protein. This case report provides both evidence of a novel COL1A2 mutation resulting in type 3 osteogenesis imperfecta and a genotype:phenotype correlation in this affected individual. Keywords: osteogenesis imperfecta type 3, collagen, alpha-2 (I chain, substitution, sequencing 

  14. Variable pathogenic potentials of mutations located in the desmin alpha-helical domain

    NARCIS (Netherlands)

    B. Goudeau; F. Rodrigues-Lima; D. Fischer; M. Casteras-Simon; N. Sambuughin; M. de Visser; P. Laforet; X. Ferrer; F. Chapon; G. Sjoberg; A. Kostareva; T. Sejersen; M.C. Dalakas; L.G. Goldfarb; P. Vicart

    2006-01-01

    Mutations in the desmin gene have been recognized as a cause of desminopathy, a familial or sporadic disorder characterized by skeletal muscle weakness, often associated with cardiomyopathy or respiratory insufficiency. Distinctive histopathologic features include aberrant intracytoplasmic accumulat

  15. PERIPARTUM CARDIOMYOPATHY--REPORT OF 16 CASES

    Institute of Scientific and Technical Information of China (English)

    杨佳欣; 刘俊涛; 边旭明

    2002-01-01

    Objective.To analyze the clinical characteristics of peripartum cardiomyopathy and to evaluate the different factors that influence the prognosis of the peripartum cardiomyopathy.Method.A retrospective review was undertaken on records of women who were diagnosed with peripartum cardiomyopathy at Peking Union Medical College Hospital between Jan.1983 and May 1999.Results.During the research period,only 16 pregnant women were documented as peripartum cardiomyopathy.Some of the women undertook ultrasonic cardiographic (UCG) examination that showed decreased systolic function.Seven women were complicated with pregnancy induced hypertension.Three died of disseminated intravascular coagulation,embolism and cardiogenic shock respectively.Conclusion.Early diagnosis of the peripartum cardiomyopathy is extremely important.The UCG can provide helpful information on disease progression or regression.

  16. Cardiac effects of the c.1583 C→G LMNA mutation in two families with Emery-Dreifuss muscular dystrophy.

    Science.gov (United States)

    Zhang, Li; Shen, Hongrui; Zhao, Zhe; Bing, Qi; Hu, Jing

    2015-10-01

    The present study aimed to examine and analyze cardiac involvement in two Emery‑Dreifuss muscular dystrophy (EDMD) pedigrees caused by the c.1583 C→G mutation of the lamin A/C gene (LMNA). The clinical and genetic characteristics of members of two families with EDMD were evaluated by performing neurological examinations, skeletal muscle biopsies, cardiac evaluations, including electrocardiography, 24 h Holter, ultrasound cardiography and 99TcM‑MIBI‑gated myocardiac perfusion imaging, and genomic DNA sequencing. Family history investigations revealed an autosomal dominant transmission pattern of the disease in Family 1 and a sporadic case in Family 2. The three affected patients exhibited typical clinical features of EDMD, including joint contractures, muscle weakness and cardiac involvement. Muscle histopathological investigation revealed dystrophic features. In addition, each affected individual exhibited either cardiac arrhythmia, which was evident as sinus tachycardia, atrial flutter or complete atrioventricular inhibition. Cardiac imaging revealed dilated cardiomyopathy in two of the individuals, one of whom was presented with heart failure. The second patient presented with no significant abnormalities in cardiac structure or function. The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C→G), which caused a T528R amino acid change in the LMNA protein. In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure. As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis.

  17. MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.

    Science.gov (United States)

    Djuric, Ugljesa; Cheung, Aaron Y L; Zhang, Wenbo; Mok, Rebecca S; Lai, Wesley; Piekna, Alina; Hendry, Jason A; Ross, P Joel; Pasceri, Peter; Kim, Dae-Sung; Salter, Michael W; Ellis, James

    2015-04-01

    MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele. Single-cell mRNA analysis demonstrated they have a molecular signature of cortical neurons. Mutant neurons exhibited a decrease in soma size, reduced dendritic complexity and decreased cell capacitance, consistent with impaired neuronal maturation. The soma size phenotype was rescued cell-autonomously by MECP2e1 transduction in a level-dependent manner but not by MECP2e2 gene transfer. Importantly, MECP2e1 mutant neurons showed a dysfunction in action potential generation, voltage-gated Na(+) currents, and miniature excitatory synaptic current frequency and amplitude. We conclude that MECP2e1 mutation affects soma size, information encoding properties and synaptic connectivity in human neurons that are defective in RTT.

  18. Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface.

    Science.gov (United States)

    Zhao, Jian; Zhu, Jing; Thornhill, William B

    2013-09-01

    The voltage-gated potassium channel Kv3.3 is the causative gene of SCA13 (spinocerebellar ataxia type 13), an autosomal dominant neurological disorder. The four dominant mutations identified to date cause Kv3.3 channels to be non-functional or have altered gating properties in Xenopus oocytes. In the present paper, we report that SCA13 mutations affect functional as well as protein expression of Kv3.3 channels in a mammalian cell line. The reduced protein level of SCA13 mutants is caused by a shorter protein half-life, and blocking the ubiquitin-proteasome pathway increases the total protein of SCA13 mutants more than wild-type. SCA13 mutated amino acids are highly conserved, and the side chains of these residues play a critical role in the stable expression of Kv3.3 proteins. In addition, we show that mutant Kv3.3 protein levels could be partially rescued by treatment with the chemical chaperone TMAO (trimethylamine N-oxide) and to a lesser extent with co-expression of Kv3.1b. Thus our results suggest that amino acid side chains of SCA13 positions affect the protein half-life and/or function of Kv3.3, and the adverse effect on protein expression cannot be fully rescued.

  19. Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase.

    Science.gov (United States)

    Akman, Hasan O; Sampayo, James N; Ross, Fiona A; Scott, John W; Wilson, Gregory; Benson, Lee; Bruno, Claudio; Shanske, Sara; Hardie, D Grahame; Dimauro, Salvatore

    2007-10-01

    A 10-wk-old infant girl with severe hypertrophy of the septal and atrial walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the gamma2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMP-binding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency.

  20. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.

    Science.gov (United States)

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna; Rehnman, Anna-Carin; Lodahl, Marianne; Wedén, Ulla; Dahl, Niklas; Tranebjærg, Lisbeth; Rendtorff, Nanna D

    2015-05-25

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  1. Characterization of a spontaneous novel mutation in the NPC2 gene in a cat affected by Niemann Pick type C disease.

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    Stefania Zampieri

    Full Text Available Niemann-Pick C disease (NPC is an autosomal recessive lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids within the lysosomes due to mutation in NPC1 or NPC2 genes. A feline model of NPC carrying a mutation in NPC1 gene has been previously described. We have identified two kittens affected by NPC disease due to a mutation in NPC2 gene. They manifested with tremors at the age of 3 months, which progressed to dystonia and severe ataxia. At 6 months of age cat 2 was unable to stand without assistance and had bilaterally reduced menace response. It died at the age of 10 months. Post-mortem histological analysis of the brain showed the presence of neurons with cytoplasmic swelling and vacuoles, gliosis of the substantia nigra and degeneration of the white matter. Spheroids with accumulation of ubiquitinated aggregates were prominent in the cerebellar cortex. Purkinje cells were markedly reduced in number and they showed prominent intracytoplasmic storage. Scattered perivascular aggregates of lymphocytes and microglial cells proliferation were present in the thalamus and midbrain. Proliferation of Bergmann glia was also observed. In the liver, hepatocytes were swollen because of accumulation of small vacuoles and foamy Kupffer cells were also detected. Foamy macrophages were observed within the pulmonary interstitium and alveoli as well. At 9 months cat 1 was unable to walk, developed seizures and it was euthanized at 21 months. Filipin staining of cultured fibroblasts showed massive storage of unesterified cholesterol. Molecular analysis of NPC1 and NPC2 genes showed the presence of a homozygous intronic mutation (c.82+5G>A in the NPC2 gene. The subsequent analysis of the mRNA showed that the mutation causes the retention of 105 bp in the mature mRNA, which leads to the in frame insertion of 35 amino acids between residues 28 and 29 of NPC2 protein (p.G28_S29ins35.

  2. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

    Science.gov (United States)

    Twigg, Stephen R.F.; Babbs, Christian; van den Elzen, Marijke E.P.; Goriely, Anne; Taylor, Stephen; McGowan, Simon J.; Giannoulatou, Eleni; Lonie, Lorne; Ragoussis, Jiannis; Akha, Elham Sadighi; Knight, Samantha J.L.; Zechi-Ceide, Roseli M.; Hoogeboom, Jeannette A.M.; Pober, Barbara R.; Toriello, Helga V.; Wall, Steven A.; Rita Passos-Bueno, M.; Brunner, Han G.; Mathijssen, Irene M.J.; Wilkie, Andrew O.M.

    2013-01-01

    Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries—a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5′ untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5′ UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females. PMID:23335590

  3. Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

    Science.gov (United States)

    Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S; Srivas, Rohith; Rivera, Janell; Stone, Nicole R; Pratt, Karishma; Mohamed, Tamer M A; Fu, Ji-Dong; Spencer, C Ian; Tippens, Nathaniel D; Li, Molong; Narasimha, Anil; Radzinsky, Ethan; Moon-Grady, Anita J; Yu, Haiyuan; Pruitt, Beth L; Snyder, Michael P; Srivastava, Deepak

    2016-12-15

    Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.

  4. The Brugada syndrome mutation A39V does not affect surface expression of neuronal rat Cav1.2 channels

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    Simms Brett A

    2012-03-01

    Full Text Available Abstract Background A loss of function of the L-type calcium channel, Cav1.2, results in a cardiac specific disease known as Brugada syndrome. Although many Brugada syndrome channelopathies reduce channel function, one point mutation in the N-terminus of Cav1.2 (A39V has been shown to elicit disease a phenotype because of a loss of surface trafficking of the channel. This lack of cell membrane expression could not be rescued by the trafficking chaperone Cavβ. Findings We report that despite the striking loss of trafficking described previously in the cardiac Cav1.2 channel, the A39V mutation while in the background of the brain isoform traffics and functions normally. We detected no differences in biophysical properties between wild type Cav1.2 and A39V-Cav1.2 in the presence of either a cardiac (Cavβ2b, or a neuronal beta subunit (Cavβ1b. In addition, the A39V-Cav1.2 mutant showed a normal Cavβ2b mediated increase in surface expression in tsA-201 cells. Conclusions The Brugada syndrome mutation A39V when introduced into rat brain Cav1.2 does not trigger the loss-of-trafficking phenotype seen in a previous study on the human heart isoform of the channel.

  5. Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).

    Science.gov (United States)

    Fernandez-Vizarra, Erika; Berardinelli, Angela; Valente, Lucia; Tiranti, Valeria; Zeviani, Massimo

    2009-01-01

    Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a rare condition that combines early-onset myopathy with lactic acidosis and sideroblastic anaemia. MLASA has been associated with a missense mutation in pseudouridylate synthase 1 (PUS1), an enzyme located in both nucleus and mitochondria, which converts uridine into pseudouridine in several cytosolic and mitochondrial tRNA positions and increases the efficiency of protein synthesis in both compartments. We examined two Italian brothers with MLSA and sequenced the PUS1 gene. We found combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria. A novel, homozygous stop mutation was present in PUS1 (E220X). The stop mutation in PUS1 is likely to determine the loss of function of the protein, since it predicts the synthesis of a protein missing 208/427 amino acid residues on the C terminus, and was associated with low mtDNA translation.

  6. Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection.

    Science.gov (United States)

    Sommers, Connie L; Lee, Jan; Steiner, Kevin L; Gurson, Jordan M; Depersis, Corinne L; El-Khoury, Dalal; Fuller, Claudette L; Shores, Elizabeth W; Love, Paul E; Samelson, Lawrence E

    2005-04-01

    Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-gamma1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y136F knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8(hi) HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus.

  7. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.

    Science.gov (United States)

    Garcia Segarra, Nuria; Mittaz, Laureane; Campos-Xavier, Ana Belinda; Bartels, Cynthia F; Tuysuz, Beyhan; Alanay, Yasemin; Cimaz, Rolando; Cormier-Daire, Valerie; Di Rocco, Maja; Duba, Hans-Christoph; Elcioglu, Nursel H; Forzano, Francesca; Hospach, Toni; Kilic, Esra; Kuemmerle-Deschner, Jasmin B; Mortier, Geert; Mrusek, Sonja; Nampoothiri, Sheela; Obersztyn, Ewa; Pauli, Richard M; Selicorni, Angelo; Tenconi, Romano; Unger, Sheila; Utine, G Eda; Wright, Michael; Zabel, Bernhard; Warman, Matthew L; Superti-Furga, Andrea; Bonafé, Luisa

    2012-08-15

    Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected

  8. Hypertrophic cardiomyopathy: an autopsy analysis of 14 cases.

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    Phadke R

    2001-07-01

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM is one of the less common forms of primary cardiomyopathies. There is little data available on HCM in Indian literature. AIMS: To assess the incidence and analyse the clinicopathological features of HCM. SETTINGS: Analysis of data of 15 years from a tertiary care centre. METHODS AND MATERIAL: The clinical and pathological data in fourteen cases of HCM with respect to their gross and microscopic features and clinical presentation were reviewed. RESULTS: Incidence of HCM amongst the autopsied primary cardiomyopathies (N = 101 was 13.9% (n=14. Males were affected more. Common presenting symptoms were exertional dyspnoea, angina and palpitations. Concentric and asymmetric hypertrophy was equally seen. Obliterative small vessel disease was noted in 50% of the cases. Although significant myofibre disarray (>5% was seen in all fourteen cases, it could be demonstrated in only 40- 50% of an average of twenty sections studied. Type IA myofibre disarray was the commonest. Six of the fourteen patients died suddenly. Cardiac failure was the commonest cause of death. CONCLUSIONS: Myofibre disarray is a highly sensitive and specific marker for HCM only when considered in a quantitative rather than a qualitative fashion. In this context, the rationale for performing endomyocardial biopsy is to rule out mimics of HCM.

  9. Improving outcomes in peripartum cardiomyopathy.

    Science.gov (United States)

    Dalzell, Jonathan R; Cannon, Jane A; Simpson, Joanne; Gardner, Roy S; Petrie, Mark C

    2015-06-01

    Peripartum cardiomyopathy (PPCM) is a rare condition with a diverse spectrum of potential outcomes, ranging from frequent complete recovery to fulminant heart failure and death. The pathogenesis of PPCM is not well understood, and relatively little is known about its incidence and prevalence. PPCM is often under-recognised in the clinical setting. Early investigation and diagnosis with subsequent expert management may improve outcomes. The development of registries will allow this condition to be better characterised and may help answer crucial questions regarding its optimal medical and surgical management. This paper reviews the potential approaches to improve outcomes in patients with PPCM.

  10. PERIPARTUM CARDIOMYOPATHY: A CASE REPORT

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    Sowjanya

    2015-04-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a rare form of heart failure with a reported Incidence of 1 per3000 to 1 per 4000 live births and a fatality rate of 20 – 50%.Onset is usually between the last month of pregnancy and up to 5 months postpartum in previously healthy women. Although viral autoimmune and idiopathic factors may be contributory , its eti ology remains unknown. PPCM is usually presents with signs and symptoms of congestive heart failure. Early diagnosis is important and effective treatment reduces mortality rates and increases the chance of complete recovery of ventricular systolic functio n.

  11. Peripartum Cardiomyopathy: A Current Review

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    Katie M. Twomley

    2010-01-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a rare but potentially lethal complication of pregnancy occurring in approximately 1 : 3,000 live births in the United States although some series report a much higher incidence. African-American women are particularly at risk. Diagnosis requires symptoms of heart failure in the last month of pregnancy or within five months of delivery in the absence of recognized cardiac disease prior to pregnancy as well as objective evidence of left ventricular systolic dysfunction. This paper provides an updated, comprehensive review of PPCM, including emerging insights into the etiology of this disorder as well as current treatment options.

  12. Takotsubo cardiomyopathy associated with Miller-Fisher syndrome.

    Science.gov (United States)

    Gill, Dalvir; Liu, Kan

    2016-12-22

    51-year-old female who presented with progressive paresthesia, numbness of the lower extremities, double vision, and trouble walking. Physical exam was remarkable for areflexia, and ptosis. Her initial EKG showed nonspecific ST segment changes and her Troponin T was elevated to 0.41ng/mL which peaked at 0.66ng/mL. Echocardiogram showed a depressed left ventricular ejection fraction to 35% with severely hypokinetic anterior wall and left ventricular apex was severely hypokinetic. EMG nerve conduction study showed severely decreased conduction velocity and prolonged distal latency in all nerves consistent with demyelinating disease. She was treated with 5days of intravenous immunoglobulin therapy to which she showed significant improvement in strength in her lower extremities. Echocardiogram repeated 4days later showing an improved left ventricular ejection fraction of 55% and no left ventricular wall motion abnormalities. Takotsubo cardiomyopathy is a rare complication of Miller-Fisher syndrome and literature review did not reveal any cases. Miller-Fisher syndrome is an autoimmune process that affects the peripheral nervous system causing autonomic dysfunction which may involve the heart. Due to significant autonomic dysfunction in Miller-Fisher syndrome, it could lead to arrhythmias, blood pressure changes, acute coronary syndrome and myocarditis, Takotsubo cardiomyopathy can be difficult to distinguish. The treatment of Takotsubo cardiomyopathy is supportive with beta-blockers and angiotensin-converting enzyme inhibitors are recommended until left ventricle ejection fraction improvement. Takotsubo cardiomyopathy is a rare complication during the acute phase of Miller-Fisher syndrome and must be distinguished from autonomic dysfunction as both diagnoses have different approaches to treatment.

  13. The erratic mitochondrial clock: variations of mutation rate, not population size, affect mtDNA diversity across birds and mammals

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    Galtier Nicolas

    2009-03-01

    Full Text Available Abstract Background During the last ten years, major advances have been made in characterizing and understanding the evolution of mitochondrial DNA, the most popular marker of molecular biodiversity. Several important results were recently reported using mammals as model organisms, including (i the absence of relationship between mitochondrial DNA diversity and life-history or ecological variables, (ii the absence of prominent adaptive selection, contrary to what was found in invertebrates, and (iii the unexpectedly large variation in neutral substitution rate among lineages, revealing a possible link with species maximal longevity. We propose to challenge these results thanks to the bird/mammal comparison. Direct estimates of population size are available in birds, and this group presents striking life-history trait differences with mammals (higher mass-specific metabolic rate and longevity. These properties make birds the ideal model to directly test for population size effects, and to discriminate between competing hypotheses about the causes of substitution rate variation. Results A phylogenetic analysis of cytochrome b third-codon position confirms that the mitochondrial DNA mutation rate is quite variable in birds, passerines being the fastest evolving order. On average, mitochondrial DNA evolves slower in birds than in mammals of similar body size. This result is in agreement with the longevity hypothesis, and contradicts the hypothesis of a metabolic rate-dependent mutation rate. Birds show no footprint of adaptive selection on cytochrome b evolutionary patterns, but no link between direct estimates of population size and cytochrome b diversity. The mutation rate is the best predictor we have of within-species mitochondrial diversity in birds. It partly explains the differences in mitochondrial DNA diversity patterns observed between mammals and birds, previously interpreted as reflecting Hill-Robertson interferences with the W

  14. Contribution of Post-translational Phosphorylation to Sarcomere-linked Cardiomyopathy Phenotypes

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    Margaret V Westfall

    2016-09-01

    Full Text Available Secondary shifts develop in post-translational phosphorylation of sarcomeric proteins in multi¬ple animal models of inherited cardiomyopathy. These signaling alterations together with the primary mutation are predicted to contribute to the overall cardiac phenotype. As a result, identification and integration of post-translational myofilament signaling responses are identified as priorities for gaining insights into sarcomeric cardiomyopathies. However, significant questions remain about the nature and contribution of post-translational phosphorylation to structural remodeling and cardiac dysfunction in animal models and human patients. This perspective essay discusses specific goals for filling critical gaps about post-translational signaling in response to these inherited mutations, especially within sarcomeric proteins. The discussion focuses primarily on pre-clinical analysis of animal models and defines challenges and future directions in this field.

  15. Advandances in the related gene of hypertrophic cardiomyopathy%肥厚性心肌病相关基因的研究进展

    Institute of Scientific and Technical Information of China (English)

    曹瑞雪; 徐让

    2013-01-01

    肥厚性心肌病(hypertrophic cardiomyopathy,HCM)是以左心室或室间隔不对称性肥厚为基本特征的原发性心肌病,其发病率约为0.2%,是青少年和运动员心源性猝死的首要原因,目前被普遍认为是一种基因突变所致的常染色体显性遗传性疾病.至今为止,至少有20种基因的450余种突变被报道与HCM相关,主要定位于心脏肌节蛋白基因.此外越来越多的线粒体基因、修饰基因突变也被发现与HCM的发生发展有关.该文将对HCM的相关基因的研究进展作一个综述.%Hypertrophic Cardiomyopathy (HCM) is one of primary cardiac disorders characterized by asymmetric thickening of the septum and left ventricular wall.HCM affects 1 in 500 individuals in the general population,and it is the most common cause of sudden death in the young and athletes.HCM is generally considered as anautosomal dominant inherited disease and caused by gene mutations.To date,about 450 mutations have been reported to be related HCM,which were mainly located in genes encoding cardiac sarcomere protein.In addition,more and more mitochondrial DNA mutations and modifier genes were reported to be associated with the pathogenesis of HCM.This review will focuses on the research in the genes related to HCM and their recent advances.

  16. Cardiac and skeletal muscle expression of mutant β-myosin heavy chains, degree of functional impairment and phenotypic heterogeneity in hypertrophic cardiomyopathy.

    Science.gov (United States)

    Di Domenico, Marina; Casadonte, Rita; Ricci, Pietroantonio; Santini, Mario; Frati, Giacomo; Rizzo, Antonietta; Carratelli, Caterina Romano; Lamberti, Monica; Parrotta, Elvira; Quaresima, Barbara; Faniello, Concetta M; Costanzo, Francesco; Cuda, Giovanni

    2012-10-01

    Several mutations in distinct genes, all coding for sarcomeric proteins, have been reported in unrelated kindreds with familial hypertrophic cardiomyopathy (FHC). We have identified nine individuals from three families harboring two distinct mutations in one copy of the β-myosin heavy chain (β-MHC) gene. In this study, the expression of the mutant β-myosin protein isoform, isolated from slow-twitch fibers of skeletal muscle, was demonstrated by Northern and Western blot analysis; this myosin showed a decreased in vitro motility activity and produced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed a significant decrease. The degree of impairment of β-myosin function, as well as the loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strong correlation was also demonstrated between mutant β-myosin content and clinical features of FHC. On the other hand, we were unable to detect any correlation between mutant β-myosin expression and degree of cardiac hypertrophy, thereby strengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, might not necessarily be related to the clinical evolution of this disease. These findings lend support to the notion that additional factors rather than the mutated gene may play a pathogenetic role in cardiac wall thickening, whereas the prognosis appears to be strongly related to the amount of mutant protein.

  17. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.

    Science.gov (United States)

    Mahoney, My G; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku

    2010-04-01

    Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

  18. [Peripartum cardiomyopathy--a case report].

    Science.gov (United States)

    Banaczek, Zbigniew; Rak, Grzegorz; Gołyska-Rączkiewicz, Danuta

    2015-01-01

    Peripartum cardiomyopathy, a type of dilated cardiomyopathy of unknown origin, occurs in previously healthy women in the final month of pregnancy and up to 5 months after delivery. Although the incidence is low--less than 0.1% of pregnancies--morbidity and mortality rates are high at 5% to 32%. The etiology of left ventricular dysfunction is unknown. Diagnosis of peripartum cardiomyopathy requires heightened awareness among multidisciplinary patient care teams and a high degree of suspicion. Confirmation involves the echocardiography reveals severe left ventricular failure. The outcome of peripartum cardiomyopathy is also highly variable. For some women, the clinical and echocardiographic status improves and sometimes returns to normal, whereas for others, the disease progresses to severe cardiac failure and even sudden cardiac death. Management of peripartum cardiomyopathy should aim first at improving heart-failure symptoms through conventional therapies, and then at administering targeted therapies.The prognosis is best when peripartum cardiomyopathy is diagnosed and treated early. Fortunately, despite a high risk of recurrence in subsequent pregnancies, many patients with peripartum cardiomyopathy recover within 3 to 6 months of disease onset. Future pregnancy is not recommended especially in patients with persistent left ventricular dysfunction because of the risk of dangerous complications.

  19. Genetic variation in exon 5 of troponin - I gene in hypertrophic cardiomyopathy cases

    Directory of Open Access Journals (Sweden)

    Annapurna S

    2007-01-01

    Full Text Available Background: Cardiomyopathies are a heterogeneous group of heart muscle disorders and are classified as 1 Hypertrophic Cardiomyopathy (HCM 2 Dilated cardiomyopathy (DCM 3 Restrictive cardiomyopathy (RCM and 4 Arrhythmogenic right ventricular dysplasia (ARVD as per WHO classification, of which HCM and DCM are common. HCM is a complex but relatively common form of inherited heart muscle disease with prevalence of 1 in 500 individuals and is commonly associated with sarcomeric gene mutations. Cardiac muscle troponin I (TNNI-3 is one such sarcomeric protein and is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. Mutations in this gene were found to be associated with a history of sudden cardiac death in HCM patients. Aim: Therefore the present study aims to identify for mutations associated with troponin I gene in a set of HCM patients from Indian population. Materials and Methods: Mutational analyses of 92 HCM cases were carried out following PCR based SSCP analysis. Results: The study revealed band pattern variation in 3 cases from a group of 92 HCM patients. This band pattern variation, on sequencing revealed base changes, one at nt 2560 with G>T transversion in exon-5 region with a wobble and others at nt 2479 and nt 2478 with G>C and C>G transversions in the intronic region upstream of the exon 5 on sequencing. Further analysis showed that one of the probands showed apical form of hypertrophy, two others showing asymmetric septal hypertrophy. Two of these probands showed family history of the condition. Conclusions: Hence, the study supports earlier reports of involvement of TNNI-3 in the causation of apical and asymmetrical forms of hypertrophy.

  20. Smooth muscle cell–extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy

    OpenAIRE

    Wheeler, Matthew T.; Allikian, Michael J.; Heydemann, Ahlke; Hadhazy, Michele; Zarnegar, Sara; McNally, Elizabeth M.

    2004-01-01

    Vascular spasm is a poorly understood but critical biomedical process because it can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice lacking γ-sarcoglycan or δ-sarcoglycan is characterized by focal damage. In the heart, sarcoglycan gene mutations produce regional defects in membrane permeability and focal degeneration, and it was hypothesized that vascular spasm was responsible for this focal necrosis. Supporting this notion, vascular spasm was noted in coronary art...

  1. High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort

    OpenAIRE

    Santos, Susana; Marques, Vanda; Pires, Marina; Silveira, Leonor; Oliveira, Helena; Lança, Vasco; Brito, Dulce; Madeira, Hugo; Esteves, J Fonseca; Freitas, António; Carreira, Isabel M; Gaspar, Isabel M; Monteiro, Carolino; Alexandra R. Fernandes

    2012-01-01

    Background Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. Methodology In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associa...

  2. Depressed Frank-Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210.

    Science.gov (United States)

    Inoue, Takahiro; Kobirumaki-Shimozawa, Fuyu; Kagemoto, Tatsuya; Fujii, Teruyuki; Terui, Takako; Kusakari, Yoichiro; Hongo, Kenichi; Morimoto, Sachio; Ohtsuki, Iwao; Hashimoto, Kazuhiro; Fukuda, Norio

    2013-10-01

    It has been reported that the Frank-Starling mechanism is coordinately regulated in cardiac muscle via thin filament "on-off" equilibrium and titin-based lattice spacing changes. In the present study, we tested the hypothesis that the deletion mutation ΔK210 in the cardiac troponin T gene shifts the equilibrium toward the "off" state and accordingly attenuate the sarcomere length (SL) dependence of active force production, via reduced cross-bridge formation. Confocal imaging in isolated hearts revealed that the cardiomyocytes were enlarged, especially in the longitudinal direction, in ΔK210 hearts, with striation patterns similar to those in wild type (WT) hearts, suggesting that the number of sarcomeres is increased in cardiomyocytes but the sarcomere length remains unaltered. For analysis of the SL dependence of active force, skinned muscle preparations were obtained from the left ventricle of WT and knock-in (ΔK210) mice. An increase in SL from 1.90 to 2.20μm shifted the mid-point (pCa50) of the force-pCa curve leftward by ~0.21pCa units in WT preparations. In ΔK210 muscles, Ca(2+) sensitivity was lower by ~0.37pCa units, and the SL-dependent shift of pCa50, i.e., ΔpCa50, was less pronounced (~0.11pCa units), with and without protein kinase A treatment. The rate of active force redevelopment was lower in ΔK210 preparations than in WT preparations, showing blunted thin filament cooperative activation. An increase in thin filament cooperative activation upon an increase in the fraction of strongly bound cross-bridges by MgADP increased ΔpCa50 to ~0.21pCa units. The depressed Frank-Starling mechanism in ΔK210 hearts is the result of a reduction in thin filament cooperative activation.

  3. Stress cardiomyopathy in a patient with hypertrophic cardiomyopathy and myocardial bridging

    Science.gov (United States)

    Benavides, Miguel; Vinardell, Juan M; Arenas, Ivan; Santana, Orlando

    2017-01-01

    Stress cardiomyopathy is an acquired cardiomyopathy of unknown aetiology. It usually occurs in women over the age of 70 who have experienced physical or emotional stress. It is most commonly characterised by a transient, left ventricular systolic dysfunction in the apical portion and hyperkinesia in the basal segments, without obstructive coronary artery disease. Its association with obstructive hypertrophic cardiomyopathy and myocardial bridging is rare. Herein, we present such a case. PMID:28228389

  4. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis.

    Science.gov (United States)

    Castellani, Carlo; Tridello, Gloria; Tamanini, Anna; Assael, Baroukh M

    2016-01-11

    Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007).

  5. A new era in clinical genetic testing for hypertrophic cardiomyopathy.

    Science.gov (United States)

    Wheeler, Matthew; Pavlovic, Aleksandra; DeGoma, Emil; Salisbury, Heidi; Brown, Colleen; Ashley, Euan A

    2009-12-01

    Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

  6. Evolutionary change mimicking apical hypertrophic cardiomyopathy in a patient with takotsubo cardiomyopathy.

    Science.gov (United States)

    Hwang, Hui-Jeong; Lee, Hyae-Min; Yang, In-Ho; Kim, Dong-Hee; Byun, Jong-Kyu; Sohn, Il Suk

    2014-11-01

    In this report, we introduce a case of thickening of the involved left ventricular apical segment on echocardiography and deep T-wave inversions in precordial leads on electrocardiography transiently seen in the course of recovery from biventricular takotsubo cardiomyopathy, mimicking apical hypertrophic cardiomyopathy. This result suggests that the echocardiographic finding of transient myocardial edema can be identified by cardiac magnetic resonance imaging in takotsubo cardiomyopathy. Additionally, it persisted a few weeks after full functional recovery. We believe that this case will contribute in part toward clarifying the pathophysiology of takotsubo cardiomyopathy.

  7. DNA Microarray and Gene Ontology Enrichment Analysis Reveals That a Mutation in opsX Affects Virulence and Chemotaxis in Xanthomonas oryzae pv. oryzae

    Directory of Open Access Journals (Sweden)

    Hong-Il Kim

    2016-06-01

    Full Text Available Xanthomonas oryzae pv. oryzae (Xoo causes bacterial leaf blight (BLB in rice (Oryza sativa L.. In this study, we investigated the effect of a mutation in opsX (XOO1056, which encodes a saccharide biosynthesis regulatory protein, on the virulence and bacterial chemotaxis of Xoo. We performed DNA microarray analysis, which showed that 63 of 2,678 genes, including genes related to bacterial motility (flagellar and chemotaxis proteins were significantly downregulated (<−2 log₂ fold changes by the mutation in opsX. Indeed, motility assays showed that the mutant strain was nonmotile on semisolid agar swarm plates. In addition, a mutant strain (opsX::Tn5 showed decreased virulence against the susceptible rice cultivar, IR24. Quantitative real-time RT-PCR reaction was performed to confirm the expression levels of these genes, including those related to flagella and chemotaxis, in the opsX mutant. Our findings revealed that mutation of opsX affects both virulence and bacterial motility. These results will help to improve our understanding of Xoo and provide insight into Xoo-rice interactions.

  8. Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions.

    Science.gov (United States)

    Sohn, Mira; Ivanova, Pavlina; Brown, H Alex; Toth, Daniel J; Varnai, Peter; Kim, Yeun Ju; Balla, Tamas

    2016-04-19

    Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in thePTDSS1gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein-related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.

  9. Mutations in Arabidopsis thaliana genes involved in the tryptophan biosynthesis pathway affect root waving on tilted agar surfaces

    Science.gov (United States)

    Rutherford, R.; Gallois, P.; Masson, P. H.

    1998-01-01

    Arabidopsis thaliana roots grow in a wavy pattern upon a slanted surface. A novel mutation in the anthranilate synthase alpha 1 (ASA1) gene, named trp5-2wvc1, and mutations in the tryptophan synthase alpha and beta 1 genes (trp3-1 and trp2-1, respectively) confer a compressed root wave phenotype on tilted agar surfaces. When trp5-2wvc1 seedlings are grown on media supplemented with anthranilate metabolites, their roots wave like wild type. Genetic and pharmacological experiments argue that the compressed root wave phenotypes of trp5-2wvc1, trp2-1 and trp3-1 seedlings are not due to reduced IAA biosynthetic potential, but rather to a deficiency in L-tryptophan (L-Trp), or in a L-Trp derivative. Although the roots of 7-day-old seedlings possess higher concentrations of free L-Trp than the shoot as a whole, trp5-2wvc1 mutants show no detectable alteration in L-Trp levels in either tissue type, suggesting that a very localized shortage of L-Trp, or of a L-Trp-derived compound, is responsible for the observed phenotype.

  10. Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

    Science.gov (United States)

    Kuzmanov, Uros; Guo, Hongbo; Buchsbaum, Diana; Cosme, Jake; Abbasi, Cynthia; Isserlin, Ruth; Sharma, Parveen; Gramolini, Anthony O.; Emili, Andrew

    2016-01-01

    Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca2+-ATPase 2A (SERCA2A) Ca2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates. Dysregulated phosphorylation sites were quantified after affinity capture and identification of 3,908 phosphopeptides from fractionated whole-heart homogenates. Global statistical enrichment analysis of the differential phosphoprotein patterns revealed selective perturbation of signaling pathways regulating cardiovascular activity in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was a prominently perturbed pathway. We verified alterations in Notch-1 downstream components in early symptomatic R9C transgenic mouse cardiomyocytes compared with wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between stress-regulated cell signaling networks, specific protein kinases, and downstream effectors essential for proper cardiac function. PMID:27742792

  11. Loss-of-function mutations in Rab escort protein 1 (REP-1 affect intracellular transport in fibroblasts and monocytes of choroideremia patients.

    Directory of Open Access Journals (Sweden)

    Natalia V Strunnikova

    Full Text Available BACKGROUND: Choroideremia (CHM is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1, an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate this hypothesis, intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in monocytes (CD14+ fraction and primary skin fibroblasts from the nine age-matched controls and thirteen CHM patients carrying 10 different loss-of-function mutations. With the use of pHrodo BioParticles conjugated with E. coli, collagen I coated FluoSpheres beads and fluorescent DQ ovalbumin with BODYPY FL dye, we demonstrated for the first time that lysosomal pH was increased in monocytes of CHM patients and, as a consequence, the rates of proteolytic degradation were slowed. Microarray analysis of gene expression revealed that some genes involved in the immune response, small GTPase regulation, transcription, cell adhesion and the regulation of exocytosis were significantly up and down regulated in cells from CHM patients compared to controls. Finally, CHM fibroblasts secreted significantly lower levels of cytokine/growth factors such as macrophage chemoattractant protein-1 (MCP-1, pigment epithelial derived factor (PEDF, tumor necrosis factor (TNF alpha, fibroblast growth factor (FGF beta and interleukin (lL-8. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time that peripheral cells of CHM patients had increased pH levels in lysosomes, reduced rates of proteolytic degradation and altered secretion of cytokines. Peripheral cells from CHM patients expose characteristics that were not previously recognized and could used as an alternative models to study the effects of different

  12. Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7: corroboration and narrowing of the critical region on 10q22.3.

    Science.gov (United States)

    Kuhl, Angelika; Melberg, Atle; Meinl, Edgar; Nürnberg, Gudrun; Nürnberg, Peter; Kehrer-Sawatzki, Hildegard; Jenne, Dieter E

    2008-03-01

    Several years ago, autosomal dominant myofibrillar myopathy (MFM) in combination with arrhythmogenic right ventricular cardiomyopathy (ARVC7) was tentatively mapped to a 10.6-Mbp (million base pairs) region on chromosome 10q22.3 between D10S605 (78.9 Mbp) and D10S215 (89.5 Mbp) in a Swedish family assuming that ARVC7 was allelic with cardiomyopathy, dilated 1C (CMD1C). To date, neither the genetic defect in ARVC7 nor CMD1C has been reported. In a comprehensive follow-up study we re-examined and confirmed the previous linkage data for ARVC7 using a high-density single nucleotide polymorphism marker panel from Affymetrix (Human Mapping 10K Array). No other regions with significant evidence for linkage were discovered. The critical interval was narrowed down to 4.27 Mbp between D10S1645 and D10S1786. This reduced the total number of candidate genes to 18 of which 17 (RAI17, PPIF, C10ORF56, SFTPA1, SFTPA2, SFTPA1B, SFTPA2B, SFTPD, C10ORF57, PLAC9, ANXA11, MAT1A, DYDC1, DYDC2, C10ORF58, TSPAN14 and SH2D4B) are shared with the CMD1C region. No disease-causing mutation was found in their coding regions. Moreover, metavinculin (VCL) and ZASP/cypher (LDB3) proximal and distal to this linked region were excluded by sequence analysis. To search for submicroscopic and intragenic deletions by PCR, we generated hybrid cell lines carrying only the affected or normal chromosome 10 homolog. All sequence tagged sites and exons were present on both homologs. We speculate that regulatory mutations in 1 of the 18 genes from 10q22.3 are responsible for a heterogenous spectrum of clinically distinct myodegenerative disorders, affecting both skeletal and cardiac muscles to variable degrees.

  13. MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis.

    Science.gov (United States)

    Hsu, Ying-Han R; Yogasundaram, Haran; Parajuli, Nirmal; Valtuille, Lucas; Sergi, Consolato; Oudit, Gavin Y

    2016-01-01

    Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders.

  14. Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX.

    Directory of Open Access Journals (Sweden)

    Raphael Roduit

    Full Text Available BACKGROUND: NR2E3 (PNR is an orphan nuclear receptor essential for proper photoreceptor determination and differentiation. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S- cone syndrome (ESCS and, more recently, with autosomal dominant retinitis pigmentosa (adRP. NR2E3 acts as a suppressor of the cone generation program in late mitotic retinal progenitor cells. In adult rod photoreceptors, NR2E3 represses cone-specific gene expression and acts in concert with the transcription factors CRX and NRL to activate rod-specific genes. NR2E3 and CRX have been shown to physically interact in vitro through their respective DNA-binding domains (DBD. The DBD also contributes to homo- and heterodimerization of nuclear receptors. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed NR2E3 homodimerization and NR2E3/CRX complex formation in an in vivo situation by Bioluminescence Resonance Energy Transfer (BRET(2. NR2E3 wild-type protein formed homodimers in transiently transfected HEK293T cells. NR2E3 homodimerization was impaired in presence of disease-causing mutations in the DBD, except for the p.R76Q and p.R104W mutant proteins. Strikingly, the adRP-linked p.G56R mutant protein interacted with CRX with a similar efficiency to that of NR2E3 wild-type and p.R311Q proteins. In contrast, all other NR2E3 DBD-mutant proteins did not interact with CRX. The p.G56R mutant protein was also more effective in abolishing the potentiation of rhodospin gene transactivation by the NR2E3 wild-type protein. In addition, the p.G56R mutant enhanced the transrepression of the M- and S-opsin promoter, while all other NR2E3 DBD-mutants did not. CONCLUSIONS/SIGNIFICANCE: These results suggest different disease mechanisms in adRP- and ESCS-patients carrying NR2E3 mutations. Titration of CRX by the p.G56R mutant protein acting as a repressor in trans may account for the severe clinical phenotype in adRP patients.

  15. Non-invasive evaluation of arrhythmic risk in dilated cardiomyopathy:From imaging to electrocardiographic measures

    Institute of Scientific and Technical Information of China (English)

    Massimo; Iacoviello; Francesco; Monitillo

    2014-01-01

    Malignant ventricular arrhythmias are a major adverse event and worsen the prognosis of patients affected by ischemic and non-ischemic dilated cardiomyopathy.The main parameter currently used to stratify arrhythmic risk and guide decision making towards the implantation of a cardioverter defibrillator is the evaluation of the left ventricular ejection fraction.However,this strategy is characterized by several limitations and consequently additional parameters have been suggested in order to improve arrhythmic risk stratification.The aim of this review is to critically revise the prognostic significance of non-invasive diagnostic tools in order to better stratify the arrhythmic risk prognosis of dilated cardiomyopathy patients.

  16. The clinical features, outcomes and genetic characteristics of hypertrophic cardiomyopathy patients with severe right ventricular hypertrophy

    Science.gov (United States)

    Guo, Xiying; Fan, Chaomei; Tian, Lei; Zhang, Xiuling; Zhao, Xing; Wang, Fengqi; Zhu, Hongguang; Lin, Aiqing; Wu, Xia; Li, Yishi

    2017-01-01

    Introduction Severe right ventricular hypertrophy (SRVH) is a rare phenotype in hypertrophic cardiomyopathy (HCM) for which limited information is available. This study was undertaken to investigate the clinical, prognostic and genetic characteristics of HCM patients with SRVH. Methods HCM with SRVH was defined as HCM with a maximum right ventricular wall thickness ≥10 mm. Whole-genome sequencing (WGS) was performed in HCM patients with SRVH. Multivariate Cox proportional hazards regression models were used to identify risk factors for cardiac death and events in HCM with SRVH. Patients with apical hypertrophic cardiomyopathy (ApHCM) were selected as a comparison group. The clinical features and outcomes of 34 HCM patients with SRVH and 273 ApHCM patients were compared. Results Compared with the ApHCM group, the HCM with SRVH group included younger patients and a higher proportion of female patients and also displayed higher cardiovascular morbidity and mortality. The multivariate Cox proportional hazards regression models identified 2 independent predictors of cardiovascular death in HCM patients with SRVH, a New York Heart Association class ≥III (hazard ratio [HR] = 8.7, 95% confidence interval (CI): 1.43-52.87, p = 0.019) and an age at the time of HCM diagnosis ≤18 (HR = 5.5, 95% CI: 1.24-28.36, p = 0.026). Among the 11 HCM patients with SRVH who underwent WGS, 10 (90.9%) were identified as carriers of at least one specific sarcomere gene mutation. MYH7 and TTN mutations were the most common sarcomere mutations noted in this study. Two or more HCM-related gene mutations were observed in 9 (82%) patients, and mutations in either other cardiomyopathy-related genes or ion-channel disease-related genes were found in 8 (73%) patients. Conclusions HCM patients with SRVH were characterized by poor clinical outcomes and the presentation of multiple gene mutations. PMID:28323875

  17. Epidemiology and genetics of dilated cardiomyopathy in the Indian context

    Directory of Open Access Journals (Sweden)

    Ushasree B

    2009-07-01

    Full Text Available Background: Dilated cardiomyopathy (DCM still remains to be a poorly understood and less analyzed group of cardiac-muscle disorders when compared to hypertrophic cardiomyopathy (HCM. Also, the vast clinical heterogeneity among the patients has rendered the small and isolated kindred studies less informative on the genetics and epidemiology of DCM. Aim of the study: The study aimed at understanding the epidemiology and genetics of DCMs in the Indian context. Materials and methods/ Statistical analysis: One hundred seven DCM patients and 105 healthy individuals were included in the study for epidemiological and genetic risk factor identification and to fit the possible mode of inheritance. Single′s ascertainment methodology for segregation analysis and Penrose frequency estimates were followed to evaluate for the role of specific epidemiological factors in the disease etiology. Chi-square analysis was carried out to interpret the results statistically. Results and Conclusion: Our study suggests that epidemiological factors like gender, age at onset and vegetarian diet in conjunction with sarcomere gene mutations may play a role in the disease expression. Similarly, segregation analysis for the possible mode of inheritance showed a deviation from the autosomal dominant mode of inheritance, strengthening the underlying genetic heterogeneity of DCM.

  18. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.

    Science.gov (United States)

    Clop, Alex; Marcq, Fabienne; Takeda, Haruko; Pirottin, Dimitri; Tordoir, Xavier; Bibé, Bernard; Bouix, Jacques; Caiment, Florian; Elsen, Jean-Michel; Eychenne, Francis; Larzul, Catherine; Laville, Elisabeth; Meish, Françoise; Milenkovic, Dragan; Tobin, James; Charlier, Carole; Georges, Michel

    2006-07-01

    Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.

  19. [Ventricular tachyarrhythmias in patients with cardiomyopathy

    DEFF Research Database (Denmark)

    Henningsen, K.; Christensen, A.H.; Svendsen, Jesper Hastrup

    2008-01-01

    of patients discharged with the diagnostic codes ventricular tachycardia, ventricular fibrillation or premature ventricular contractions with cardiomyopathy as the presumed aetiology. Patients discharged during a period of 6 years and 5 months were included in the study. The patients were characterized......INTRODUCTION: The purpose of this study was to determine the number and distribution of cardiomyopathies as the aetiology of ventricular tachyarrhythmias among patients discharged from the Department of Cardiology, Rigshospitalet. MATERIALS AND METHODS: The study was a retrospective review......), 57 (45%) patients had arrhythmogenic right ventricular cardiomyopathy (ARVC) and 13 (10%) had hypertrophic cardiomyopathy (HCM). The average age was 44 years for HCM, 41 years for ARVC and 58 years for DCM. The majority of the patients were male. ICD treatment was used in 95% of the patients...

  20. Genetics Home Reference: arrhythmogenic right ventricular cardiomyopathy

    Science.gov (United States)

    ... with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007 Apr ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  1. Genetics Home Reference: familial hypertrophic cardiomyopathy

    Science.gov (United States)

    ... PubMed Ho CY. New Paradigms in Hypertrophic Cardiomyopathy: Insights from Genetics. Prog Pediatr Cardiol. 2011 May;31( ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links USA.gov Copyright ...

  2. Echocardiographic differences between preeclampsia and peripartum cardiomyopathy.

    Science.gov (United States)

    Dennis, A T; Castro, J M

    2014-08-01

    Peripartum heart failure due to preeclampsia or peripartum cardiomyopathy represents a significant global health issue. Transthoracic echocardiography enables differentiation of heart failure with preserved ejection fraction, commonly observed in women with preeclampsia, from that with peripartum cardiomyopathy in which a reduced ejection fraction is more common. An understanding of the different definitions and diagnostic features of these two diseases, as well as accurate characterisation of the haemodynamics in preeclampsia and peripartum cardiomyopathy, allows clinicians to manage these conditions appropriately. This article outlines the echocardiographic differences between preeclampsia and peripartum cardiomyopathy, the likely mechanisms for heart failure in preeclampsia and the relevance of these differences to clinicians in relation to prevention and treatment. It also emphasises the importance of disease definitions as a key framework for the more consistent classification of the two diseases.

  3. Hypertrophic cardiomyopathy screening in young athletes

    Energy Technology Data Exchange (ETDEWEB)

    Rappoport, W.J. [Arizona Heart Inst., Phoenix, AZ (United States); Steingard, P.M. [Phoenix Suns, Phoenix, AZ (United States)

    2006-07-01

    Hypertrophic cardiomyopathy is the leading cause of sudden death during vigorous exercise. Early identification of this abnormality by ECG screening of high-school athletes before they participate in competitive sports helps save lives. (orig.)

  4. Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

    Directory of Open Access Journals (Sweden)

    Irene Papatheodorou

    Full Text Available A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

  5. Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

    Science.gov (United States)

    Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M

    2012-01-01

    A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

  6. In Azospirillum brasilense, mutations in flmA or flmB genes affect polar flagellum assembly, surface polysaccharides, and attachment to maize roots.

    Science.gov (United States)

    Rossi, Fernando Ariel; Medeot, Daniela Beatriz; Liaudat, Juan Pablo; Pistorio, Mariano; Jofré, Edgardo

    2016-09-01

    Azospirillum brasilense is a soil bacterium capable of promoting plant growth. Several surface components were previously reported to be involved in the attachment of A. brasilense to root plants. Among these components are the exopolysaccharide (EPS), lipopolysaccharide (LPS) and the polar flagellum. Flagellin from polar flagellum is glycosylated and it was suggested that genes involved in such a posttranslational modification are the same ones involved in the biosynthesis of sugars present in the O-antigen of the LPS. In this work, we report on the characterization of two homologs present in A. brasilense Cd, to the well characterized flagellin modification genes, flmA and flmB, from Aeromonas caviae. We show that mutations in either flmA or flmB genes of A. brasilense resulted in non-motile cells due to alterations in the polar flagellum assembly. Moreover, these mutations also affected the capability of A. brasilense cells to adsorb to maize roots and to produce LPS and EPS. By generating a mutant containing the polar flagellum affected in their rotation, we show the importance of the bacterial motility for the early colonization of maize roots.

  7. A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype.

    Directory of Open Access Journals (Sweden)

    Pascal Gosselin-Badaroudine

    Full Text Available Cardiac Na(+ channels encoded by the SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated with atrial fibrillation, ventricular arrhythmias, conduction disorders, and dilated cardiomyopathy (DCM.We investigated a young male patient with a mixed phenotype composed of documented conduction disorder, atrial flutter, and ventricular tachycardia associated with DCM. Further family screening revealed DCM in the patient's mother and sister and in three of the mother's sisters. Because of the complex clinical phenotypes, we screened SCN5A and identified a novel mutation, R219H, which is located on a highly conserved region on the fourth helix of the voltage sensor domain of Na(v1.5. Three family members with DCM carried the R219H mutation.The wild-type (WT and mutant Na(+ channels were expressed in a heterologous expression system, and intracellular pH (pHi was measured using a pH-sensitive electrode. The biophysical characterization of the mutant channel revealed an unexpected selective proton leak with no effect on its biophysical properties. The H(+ leak through the mutated Na(v1.5 channel was not related to the Na(+ permeation pathway but occurred through an alternative pore, most probably a proton wire on the voltage sensor domain.We propose that acidification of cardiac myocytes and/or downstream events may cause the DCM phenotype and other electrical problems in affected family members. The identification of this clinically significant H(+ leak may lead to the development of more targeted treatments.

  8. Acute and reversible cardiomyopathy provoked by stress in a Chinese woman

    Institute of Scientific and Technical Information of China (English)

    KANG Lian-ming; ZHANG Jian; DOU Ke-fei; XU Zhi-min; GAO Xiao-jin; YANG Yue-jin

    2008-01-01

    @@ Areversible cardiomyopathy triggered by psychologically stressful events occurs in older women and may mimic evolving acute myocardial infarction or coronary syndrome.This condition is characterized by a distinctive form of systolic dysfunction that predominantly affects the distal left ventricle chamber and a favourable outcome with appropriate medical therapy.

  9. Pregnancy course and outcomes in women with arrhythmogenic right ventricular cardiomyopathy

    NARCIS (Netherlands)

    Hodes, Anke R; Tichnell, Crystal; Te Riele, Anneline S J M; Murray, Brittney; Groeneweg, Judith A; Sawant, Abhishek C; Russell, Stuart D; van Spaendonck-Zwarts, Karin Y; van den Berg, Maarten P; Wilde, Arthur A; Tandri, Harikrishna; Judge, Daniel P; Hauer, Richard N W; Calkins, Hugh; van Tintelen, J Peter; James, Cynthia A

    2016-01-01

    OBJECTIVES: To characterise pregnancy course and outcomes in women with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). METHODS: From a combined Johns Hopkins/Dutch ARVD/C registry, we identified 26 women affected with ARVD/C (by 2010 Task Force Criteria) during 39 singleton preg

  10. Takotsubo Cardiomyopathy: A New Perspective in Asthma

    Directory of Open Access Journals (Sweden)

    Fady Y. Marmoush

    2015-01-01

    Full Text Available Takotsubo cardiomyopathy (TCM is an entity of reversible cardiomyopathy known for its association with physical or emotional stress and may mimic myocardial infarction. We report an exceedingly rare case of albuterol-induced TCM with moderate asthma exacerbation. An interesting association that may help in understanding the etiology of TCM in the asthmatic population. Although the prognosis of TCM is excellent, it is crucial to recognize beta agonists as a potential stressor.

  11. Mechanical aberrations in hypetrophic cardiomyopathy: emerging concepts.

    Directory of Open Access Journals (Sweden)

    Dimitrios eNtelios

    2015-08-01

    Full Text Available Hypertrophic cardiomyopathy is the most common monogenic disorder in cardiology. Despite important advances in understanding disease pathogenesis, it is not clear how flaws in individual sarcomere components are responsible for the observed phenotype. The aim of this article is to provide a brief interpretative analysis of some currently proposed pathophysiological mechanisms of hypertrophic cardiomyopathy, with a special emphasis on alterations in the cardiac mechanical properties.

  12. Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice

    OpenAIRE

    1999-01-01

    To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles expre...

  13. Takotsubo Cardiomyopathy Occurring in the Postoperative Period.

    Science.gov (United States)

    Deniz, Süleyman; Bakal, Ömer; İnangil, Gökhan; Şen, Hüseyin; Özkan, Sezai

    2015-02-01

    Takotsubo cardiomyopathy simulates acute myocardial infarction, and it is characterised by reversible left ventricular failure. A case of Takotsubo cardiomyopathy diagnosed after emergency angiography performed in a patient with evidence of acute myocardial infarction in the postoperative period will be described in this report. Transurethral resection of a bladder tumour (TUR-BT) was performed in a 92-year-old male patient by the urology clinic. The patient was transferred to the post-anaesthesia care unit after the operation. An echocardiography was performed because of the sudden onset of dyspnoea, tachycardia (140-150 beats per minute, rhythm-atrial fibrillation) and ST-segment elevation on electrocardiography (ECG) at the first postoperative hour, and midapical dyskinesia was detected at the patient. An immediate angiography was performed due to suspicion of acute coronary syndrome. Patent coronary arteries and temporary aneurysmatic dilatation of the apex of the heart were revealed by angiography. As a result of these findings, the patient was diagnosed with Takotsubo cardiomyopathy by the cardiology service. The patient was discharged uneventfully following 10 days in the intensive care unit. Aneurysm of the apex of the left ventricle and normal anatomy of the coronary arteries in the angiography have diagnostic value for Takotsubo cardiomyopathy. Diuretics (furosemide) and beta-blockers (metoprolol) are commonly used for the treatment of Takotsubo cardiomyopathy. Even though Takotsubo cardiomyopathy is a rare and benign disease, it should be kept in mind in patients suspected for acute myocardial infarction in the postoperative period.

  14. RATIONAL PHARMACOTHERAPY IN TAKOTSUBO CARDIOMYOPATHY

    Directory of Open Access Journals (Sweden)

    S. Marchev

    2012-01-01

    Full Text Available Rational pharmacotherapy in Takotsubo cardiomyopathy is based on clinical picture and data of functional and laboratory investigations of concrete patient. In patients with hypotension and moderate-to-severe left ventricle outflow tract obstruction inotropic agents must not to be used because they can worsen the degree of obstruction. In these patients beta blockers can improve hemodynamics by causing resolution of the obstruction. If intraventricular thrombus is detected, anticoagulation for at least 3 months is recommended. The duration of anticoagulant therapy may be modified depending on the extent of cardiac function recovery and thrombus resolution. For patients without thrombus but with severe left ventricular dysfunction, anticoagulation is recommended until the akinesis or dyskinesis has resolved but not more than 3 months.

  15. [Peripartum cardiomyopathy: A multiple entity].

    Science.gov (United States)

    Vanzetto, Gérald; Martin, Alix; Bouvaist, Hélène; Marlière, Stéphanie; Durand, Michel; Chavanon, Olivier

    2012-06-01

    Peripartum cardiomyopathy (PPCMP) is a dilated and hypokinetic cardiomyopathy occurring during pregnancy or after delivery, with an estimated incidence between 1/1000 and 1/4000 births. It has been defined as a new onset of heart failure in the month preceding or following delivery, without demonstrated aetiology nor previously known heart disease, and with echocardiographic evidences of left ventricular (LV) dysfunction (LV ejection fraction<0.45). It's a multifactorial disease, immunologic, hormonal, and possibly viral mechanisms playing a determinant pathophysiological role. The classical clinical presentation is a rapid and unexpected onset of heart failure in a previously healthy woman, echocardiography being the key examination for positive and differential diagnosis, prognostication, therapeutic decision-making, and follow-up. The potential severity of PPCMP, and its unpredictable evolution in the first days following diagnosis, require that patients be referred to a tertiary care centre with a high skill in intensive cardiology care. Therapeutic management of PPCMP does not offer any specificity when compared to other causes of acute or chronic heart failure (from diuretics to extracorporeal life support), except for ACE-inhibitors, that are contraindicated before delivery. The high incidence of thrombo-embolic complications observed in the disease requires however rapid and curative anticoagulation, and immuno-suppressive treatment has been proposed in fulminant and highly inflammatory presentation, but its efficacy remains controversial. Very recently, promising results have been reported with bromocriptin-a prolactin secretion inhibitor-for reducing 6-month morbidity and mortality, but these findings have to be confirmed in larger scale randomised trials. As for the long-term evolution, approximately half of the patients will heal, while half of the women will keep some degree of LV dysfunction, 25% of them developing moderate to severe chronic heart

  16. Epidemiology and genetics of hypertrophic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Tanjore Reena

    2006-01-01

    Full Text Available Background: Hypertrophic cardiomyopathy (HCM is a heart muscle disorder and is known to be inherited as an autosomal dominant trait. Mutations in several sarcomeric, cytoskeletal and mitochondrial genes have been reported in HCM. Though many cases of HCM are being identified, there is limited data regarding the epidemiology and genetics of HCM in India. Aim: Therefore the present study is envisaged at identifying the epidemiological variables in HCM and fitting a probability model assuming dominant mode of inheritance in HCM, which may in turn shed light on the heterogeneity of this complex disorder. Materials AND Methods: The 127 HCM cases were divided into subtypes based on pattern of hypertrophy. Chi square analysis, odds ratio, probability, relative frequency, penetrance and heritability estimates were calculated apart from epidemiological variables. Results: The HCM subtypes revealed the heterogeneous nature of the condition suggesting that the genes/mutations involved in their pathogenesis are different and this is supported by distinctive differences observed in their probability, heritability and penetrance estimates apart from epidemiological variables. An increased male preponderance was observed with the sex ratio being 3.7:1. The age at onset was found to be more than a decade early in familial cases (30 ± 10 yrs compared to non familial cases (44 ± 14 yrs. Chi square analysis revealed obstructive HCM to be following autosomal dominant mode of inheritance where as non-obstructive HCM was significantly deviating. The level of deviation was significantly high for the middle onset group compared to early and late onset groups, therefore this group may be considered as an admixture wherein genes/gene modifiers and environmental variables may be contributing to the heterogeneity and this is further supported by odds ratio. Conclusions: The study thus brings out the complexity of HCM and suggests that modes of inheritance other than

  17. A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome.

    Science.gov (United States)

    Lee, Eunice E; Ma, Jing; Sacharidou, Anastasia; Mi, Wentao; Salato, Valerie K; Nguyen, Nam; Jiang, Youxing; Pascual, Juan M; North, Paula E; Shaul, Philip W; Mettlen, Marcel; Wang, Richard C

    2015-06-04

    Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 in vitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport.

  18. Novel and recurrent mutations in the TAT gene in Tunisian families affected with Richner-Hanhart syndrome.

    Science.gov (United States)

    Bouyacoub, Yosra; Zribi, Hela; Azzouz, Hatem; Nasrallah, Fehmi; Abdelaziz, Rim Ben; Kacem, Monia; Rekaya, Ben; Messaoud, Olfa; Romdhane, Lilia; Charfeddine, Cherine; Bouziri, Mustapha; Bouziri, Sonia; Tebib, Neji; Mokni, Mourad; Kaabachi, Naziha; Boubaker, Samir; Abdelhak, Sonia

    2013-10-15

    Tyrosinemia type II, also designated as oculocutaneous tyrosinemia or Richner-Hanhart syndrome (RHS), is a very rare autosomal recessive disorder. In the present study, we report clinical features and molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in two young patients, both born to consanguineous unions between first-degree cousins. These two unrelated families originated from Northern and Southern Tunisia. The clinical diagnosis was based on the observation of several complications related to Richner-Hanhart syndrome: recurrent eye redness, tearing and burning pain, photophobia, bilateral pseudodendritic keratitis, an erythematous and painful focal palmo-plantar hyperkeratosis and a mild delay of mental development. The diagnosis was confirmed by biochemical analysis. Sequencing of the TAT gene revealed the presence of a previously reported missense mutation (c.452G>A, p.Cys151Tyr) in a Tunisian family, and a novel G duplication (c.869dupG, p.Trp291Leufs 6). Early diagnosis of RHS and protein-restricted diet are crucial to reduce the risk and the severity of long-term complications of hypertyrosinemia such as intellectual disability.

  19. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix.

    Science.gov (United States)

    Haji-Seyed-Javadi, Ramona; Jelodari-Mamaghani, Sahar; Paylakhi, Seyed Hassan; Yazdani, Shahin; Nilforushan, Naveed; Fan, Jian-Bing; Klotzle, Brandy; Mahmoudi, Mohammad Jafar; Ebrahimian, Mohammad Jafar; Chelich, Noori; Taghiabadi, Ehsan; Kamyab, Kambiz; Boileau, Catherine; Paisan-Ruiz, Coro; Ronaghi, Mostafa; Elahi, Elahe

    2012-08-01

    Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils. Various factors prompted considering LTBP2 in the etiology of isolated ectopia lentis and associated conditions such as Weill-Marchesani syndrome (WMS) and Marfan syndrome (MFS). LTBP2 was screened in 30 unrelated Iranian patients. Mutations were found only in one WMS proband and one MFS proband. Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping. Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin. In conjunction with recent findings regarding other ECM proteins, the results presented strongly support the contention that anomalies in WMS patients are due to disruptions in the ECM. Heterozygous c.1642C >T (p.Arg548*) possibly contributed to MFS-related phenotypes, including ocular manifestations, mitral valve prolapse, and pectus excavatum, but was not cause of MFS.

  20. Defining the molecular genetic basis of idiopathic dilated cardiomyopathy.

    Science.gov (United States)

    Olson, T M; Keating, M T

    1997-02-01

    Dilated cardiomyopathy (DCM) is a significant health care problem. The etiology is idiopathic in approximately half of the patients. Recognition that 20%-25% of idiopathic DCM cases are familial has advanced the hypothesis that single gene defects are important in the disease's pathogenesis. General linkage analyses in rare, large DCM families have determined the chromosome location of five idiopathic DCM genes. Candidate-gene mutational analyses in more typical, small pedigrees represent an alternative strategy for DCM gene identification. Human molecular genetics will play a fundamental role in defining pathogenic mechanisms for DCM with the prospect of new, molecular-based diagnostic and therapeutic approaches. (Trends Cardiovasc Med 1997;7:60-63). © 1997, Elsevier Science Inc.

  1. Cardiomyopathy

    Science.gov (United States)

    ... Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 65. McKenna WJ, Elliott P. ... eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 60. McMurray JJV, Pfeffer MA. ...

  2. Cardiomyopathy

    Science.gov (United States)

    ... Kawasaki Disease Long Q-T Syndrome Marfan Syndrome Metabolic Syndrome Mitral Valve Prolapse Myocardial Bridge Myocarditis Obstructive Sleep Apnea Pericarditis Peripheral Vascular Disease Rheumatic Fever Sick Sinus Syndrome Silent Ischemia Stroke Sudden ...

  3. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

    Science.gov (United States)

    Kuster, Diederik W. D.

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. HCM is caused by mutations in genes encoding contractile proteins. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament contractile protein that regulates sarcomere organization and cardiac contractility. About 200 different mutations in the cMyBP-C gene (MYBPC3) have thus far been reported as causing HCM. Among them, a 25 base pair deletion in the branch point of intron 32 of MYBPC3 is widespread, particularly in South Asia, where it affects ≈4% of South Asian descendants worldwide. This polymorphic mutation results in skipping of exon 33 and a reading frame shift, which, in turn, replaces the last 65 amino acids of the C-terminal C10 domain of cMyBP-C (cMyBP-CC10mut) with a novel sequence of 58 residues. Carriers of the 25 base pair deletion mutation are at increased risk of developing cardiomyopathy and heart failure. Because of the high prevalence of this mutation in certain populations, genetic screening of at-risk groups might be beneficial. Scientifically, the functional consequences of C-terminal mutations and the precise mechanisms leading to HCM should be defined using induced pluripotent stem cells and engineered heart tissue in vitro, or mouse models in vivo. Most importantly, therapeutic strategies that include pharmacology, gene repair and gene therapy should be developed to prevent the adverse clinical effects of cMyBP-CC10mut. This review article aims to examine the effects of cMyBP-CC10mut on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies. PMID:24327208

  4. Arrhythmogenic cardiomyopathy : diagnosis, genetic background, and risk management

    NARCIS (Netherlands)

    Groeneweg, J. A.; van der Heijden, J. F.; Dooijes, D.; van Veen, T. A. B.; van Tintelen, J. P.; Hauer, R. N.

    2014-01-01

    Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with A

  5. Glycerol hypersensitivity in a Drosophila model for glycerol kinase deficiency is affected by mutations in eye pigmentation genes.

    Directory of Open Access Journals (Sweden)

    Patrick J Wightman

    Full Text Available Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374 and dGK (CG7995. As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency.

  6. A Novel Alpha Cardiac Actin (ACTC1) Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects

    Science.gov (United States)

    Augière, Céline; Mégy, Simon; El Malti, Rajae; Boland, Anne; El Zein, Loubna; Verrier, Bernard; Mégarbané, André; Deleuze, Jean-François; Bouvagnet, Patrice

    2015-01-01

    Background A Lebanese Maronite family presented with 13 relatives affected by various congenital heart defects (mainly atrial septal defects), conduction tissue anomalies and midline defects. No mutations were found in GATA4 and NKX2-5. Methods and Results A set of 399 poly(AC) markers was used to perform a linkage analysis which peaked at a 2.98 lod score on the long arm of chromosome 15. The haplotype analysis delineated a 7.7 meganucleotides genomic interval which included the alpha-cardiac actin gene (ACTC1) among 36 other protein coding genes. A heterozygous missense mutation was found (c.251T>C, p.(Met84Thr)) in the ACTC1 gene which changed a methionine residue conserved up to yeast. This mutation was absent from 1000 genomes and exome variant server database but segregated perfectly in this family with the affection status. This mutation and 2 other ACTC1 mutations (p.(Glu101Lys) and p.(Met125Val)) which result also in congenital heart defects are located in a region in close apposition to a myosin heavy chain head region by contrast to 3 other alpha-cardiac actin mutations (p.(Ala297Ser),p.(Asp313His) and p.(Arg314His)) which result in diverse cardiomyopathies and are located in a totally different interaction surface. Conclusions Alpha-cardiac actin mutations lead to congenital heart defects, cardiomyopathies and eventually midline defects. The consequence of an ACTC1 mutation may in part be dependent on the interaction surface between actin and myosin. PMID:26061005

  7. Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G > A mitochondrial DNA mutation: a case report

    Directory of Open Access Journals (Sweden)

    Moggio Maurizio

    2011-07-01

    Full Text Available Abstract Background Leigh Syndrome (LS is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors. Case presentation Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C > G and the already known m.14459G > A resulting in p.His16Asp change in cytochrome b (MT-CYB and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G > A was heteroplasmic in the mother's blood-derived DNA. Conclusions The m.14459G > A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G > A-mutated patients does not explain this large clinical heterogeneity.

  8. Novel ETHE1 mutation in a carrier couple having prior offspring affected with ethylmalonic encephalopathy: Genetic analysis, clinical management and reproductive outcome.

    LENUS (Irish Health Repository)

    Walsh, David J

    2010-03-01

    Ethylmalonic encephalopathy (EE) is an autosomally recessive inherited disorder with a relentlessly progressive decline in neurological function, usually fatal by the age of ten. It is characterised by generalised hypotonia, psychomotor regression, spastic tetraparesis, dystonia, seizures and, eventually, global neurological failure. Approximately 50 reports have been published worldwide describing this devastating disease, most involving patients of Mediterranean or Arab origin. The fundamental defect in EE likely involves the impairment of a mitochondrial sulphur dioxygenase coded by the ETHE1 gene responsible for the catabolism of sulphide, which subsequently accumulates to toxic levels. A diagnosis of EE should initiate careful genetic evaluation and counselling, particularly if the parents intend to have additional offspring. The present report describes the diagnosis of EE in a reproductive endocrinology context, where both members of a non-consanguineous couple were confirmed to be carriers of an identical A↷G mutation. This previously unknown mutation at nucleotide position c.494 resulted in an amino acid substitution, p.Asp165Gly. Although consideration was given to in vitro fertilisation, embryo biopsy and single gene pre-implantation genetic diagnosis, the couple decided to first utilise a less aggressive therapeutic approach with donor sperm insemination. Pregnancy with a low risk of EE was indeed achieved; however, the infant was affected with a different anomaly (hypoplastic left heart). As this case demonstrates, prior to the initiation of fertility therapy, genetic analysis may be used to provide a confirmatory diagnosis when EE is suspected.

  9. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    Directory of Open Access Journals (Sweden)

    Moolman-Smook Johanna C

    2011-10-01

    Full Text Available Abstract Background The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM, a genetic disease associated with an improper hypertrophic response. Results The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmia

  10. Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy.

    Science.gov (United States)

    Chelko, Stephen P; Asimaki, Angeliki; Andersen, Peter; Bedja, Djahida; Amat-Alarcon, Nuria; DeMazumder, Deeptankar; Jasti, Ravirasmi; MacRae, Calum A; Leber, Remo; Kleber, Andre G; Saffitz, Jeffrey E; Judge, Daniel P

    2016-04-21

    Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3β inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3β inhibition improved left ventricle function and survival in sedentary and exercised Dsg2(mut/mut) mice compared with Veh-treated Dsg2(mut/mut) mice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3β showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3β redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3β protein levels but not phosphorylated Ser 9-GSK3β in ACM mice. Constitutively active GSK3β worsens ACM in mutant mice, while GSK3β shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSKβ in the complex phenotype of ACM and provide further evidence that pharmacologic GSKβ inhibition improves cardiomyopathies due to desmosome mutations.

  11. A new 4D trajectory-based approach unveils abnormal LV revolution dynamics in hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Andrea Madeo

    Full Text Available The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers explained by first Principal Component scores. Trajectories' shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by

  12. [Effects of monorecessive and double recessive mutations affecting coat color on the monoamine content of the brain of the American mink (Mustela vison Schreber, 1777)].

    Science.gov (United States)

    Trapezov, O V; Trapezova, L I; alekhina, T A; Klochkov, D V; Ivanov, Iu N

    2009-12-01

    The effects of mutations affecting the coat color on the dopamine, noradrenaline, and serotonin contents of the hypothalamus and brainstem of the American mink have been studied. The sample comprised standard (+/+) and mutant minks, including the monorecessive pastel (b/b), silver-blue (p/p), and white hedlund (h/h) and the combination double recessive sapphire (a/a p/p) and pearl (k/k p/p) ones. The dopamine content of the brainstem of the monorecessive pastel (b/b) and silver-blue (p/p) minks has been found to be higher than in standard (+/+) minks. Conversely, the homozigosity for two coat color loci in double recessive pearl minks (k/k p/p) significantly decreases the noradrenaline and serotonin contents of the hypothalamus. In addition, monorecessive and double recessive minks differ from each other in the serotonin contents of the midbrain and medulla.

  13. Apical Hypertrophic Cardiomyopathy in Association with PulmonaryArtery Hypertension

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    Mehdi Peighambari

    2012-09-01

    Full Text Available Apical Hypertrophic Cardiomyopathy is an uncommon condition constituting 1% -2% of the cases with Hypertrophic Cardiomyopathy (HCM diagnosis. We interestingly report two patients with apical hypertrophic cardiomyopathy in association with significant pulmonary artery hypertension without any other underlying reason for pulmonary hypertension. The patients were assessed by echocardiography, cardiac catheterization and pulmonary function parameters study.

  14. MR imaging in cardiomyopathies; MR-tomographische Diagnostik von Kardiomyopathien

    Energy Technology Data Exchange (ETDEWEB)

    Miller, S. [Radiologische Universitaetsklinik Tuebingen (Germany); Riessen, R. [Tuebingen Univ. (Germany). Medizinische Klinik

    2005-11-15

    According to the WHO classification, cardiomyopathies are a group of diseases which are associated with myocardial dysfunction and can be classified either as primary or secondary cardiomyopathies. Genetic disorders have been identified in certain primary cardiomyopathies, however often the etiology remains unknown. The term ''secondary cardiomyopathy'' is used to specify diseases with the clinical indications of a cardiomyopathy, but can be attributed to a certain pathophysiological mechanism such as exposure to toxic substances, metabolic syndromes or systemic diseases. Based on morphological and functional criteria, primary cardiomyopathies are divided into dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and restrictive cardiomyopathy (RCM). During the last two decades MR imaging has emerged to a well established diagnostic tool for the understanding and treatment of cardiomyopathies. Morphological and functional information can be achieved with a high level of accuracy and reproducibility. Tissue alteration of the myocardium can be detected assessing regional contrast enhancement, T1- and T2-signal intensities and chemical shift phenomena. This article describes characteristic aspects of MR imaging for the diagnosis of primary and secondary cardiomyopathies. (orig.)

  15. Mutations affecting the high affinity ATPase center of gpA, the large subunit of bacteriophage lambda terminase, inactivate the endonuclease activity of terminase.

    Science.gov (United States)

    Hwang, Y; Feiss, M

    1996-08-30

    Phage lambda terminase carries out the cos cleavage reaction that generates mature chromosomes from immature concatemeric DNA. The ATP-stimulated endonuclease activity of terminase is located in gpA, the large terminase subunit. There is a high affinity ATPase center in gpA, and a match to the conserved P-loop of known ATPases is found starting near residue 490. Changing the conserved P-loop lysine at residue 497 of gpA affects the high affinity ATPase activity of terminase. In the present work, mutations causing the gpA changes K497A and K497D were found to be lethal, and phages carrying these mutations were defective in cos cleavage, in vivo. Purified K497A and K497D enzymes cleaved cos in vitro at rates reduced from the wild-type rate by factors of 1000 and 2000, respectively. The strong defects in cos cleavage are sufficient to explain the lethality of the K497A and K497D defects. In in vitro packaging studies using mature (cleaved) phage DNA, the K497A enzyme was indistinguishable from the wild-type enzyme, and the K497D enzyme showed a mild packaging defect under limiting terminase conditions. In a purified DNA packaging system, the wild-type and K497D enzymes showed similar packaging activities that were stimulated to half-maximal levels at about 3 microM ATP, indicating that the K497D change does not affect DNA translocation. In sum, the work indicates that the high affinity ATPase center of gpA is involved in stimulation of the endonuclease activity of terminase.

  16. Becker Muscular Dystrophy (BMD) caused by duplication of exons 3-6 of the dystrophin gene presenting as dilated cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, A.C.; Allingham-Hawkins, D.J.; Becker, L. [Univ. of Toronto, Ontario (Canada)] [and others

    1994-09-01

    X-linked dilated cardiomyopathy (XLCM) is a progressive myocardial disease presenting with congestive heart failure in teenage males without clinical signs of skeletal myopathy. Tight linkage of XLCM to the DMD locus has been demonstrated; it has been suggested that, at least in some families, XLCM is a {open_quotes}dystrophinopathy.{close_quotes} We report a 14-year-old boy who presented with acute heart failure due to dilated cardiomyopathy. He had no history of muscle weakness, but physical examination revealed pseudohypertrophy of the calf muscles. He subsequently received a heart transplantation. Family history was negative. Serum CK level at the time of diagnosis was 10,416. Myocardial biopsy showed no evidence of carditis. Dystrophin staining of cardiac and skeletal muscle with anti-sera to COOH and NH{sub 2}termini showed a patchy distribution of positivity suggestive of Becker muscular dystrophy. Analysis of 18 of the 79 dystrophin exons detected a duplication that included exons 3-6. The proband`s mother has an elevated serum CK and was confirmed to be a carrier of the same duplication. A mutation in the muscle promotor region of the dystrophin gene has been implicated in the etiology of SLCM. However, Towbin et al. (1991) argued that other 5{prime} mutations in the dystrophin gene could cause selective cardiomyopathy. The findings in our patient support the latter hypothesis. This suggests that there are multiple regions in the dystrophin gene which, when disrupted, can cause isolated dilated cardiomyopathy.

  17. MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Lore Becker

    Full Text Available Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1 were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.

  18. Electrocardiographic predictors of peripartum cardiomyopathy

    Science.gov (United States)

    Karaye, Kamilu M; Karaye, Kamilu M; Lindmark, Krister; Henein, Michael Y; Lindmark, Krister; Henein, Michael Y

    2016-01-01

    Summary Objective To identify potential electrocardiographic predictors of peripartum cardiomyopathy (PPCM). Methods: This was a case–control study carried out in three hospitals in Kano, Nigeria. Logistic regression models and a risk score were developed to determine electrocardiographic predictors of PPCM. Results: A total of 54 PPCM and 77 controls were consecutively recruited after satisfying the inclusion criteria. After controlling for confounding variables, a rise in heart rate of one beat/minute increased the risk of PPCM by 6.4% (p = 0.001), while the presence of ST–T-wave changes increased the odds of PPCM 12.06-fold (p < 0.001). In the patients, QRS duration modestly correlated (r = 0.4; p < 0.003) with left ventricular dimensions and end-systolic volume index, and was responsible for 19.9% of the variability of the latter (R2 = 0.199; p = 0.003). A risk score of ≥ 2, developed by scoring 1 for each of the three ECG disturbances (tachycardia, ST–T-wave abnormalities and QRS duration), had a sensitivity of 85.2%, specificity of 64.9%, negative predictive value of 86.2% and area under the curve of 83.8% (p < 0.0001) for potentially predicting PPCM. Conclusion In postpartum women, using the risk score could help to streamline the diagnosis of PPCM with significant accuracy, prior to confirmatory investigations PMID:27213852

  19. Peripartum cardiomyopathy – case series

    Science.gov (United States)

    Prasad, Gowri Sayi; Bhupali, Ashok; Prasad, Sayi; Patil, Ajit N.; Deka, Yashodhan

    2014-01-01

    Objectives To study the pattern of presentation, course of disease and outcome of pregnancy in Peripartum Cardiomyopathy. Methods A prospective study of sixteen cases of PPCM was conducted at Apple Saraswati Multispecialty Hospital and Dr. D.Y. Patil Medical College and Hospital, Kolhapur, Maharashtra, India from January 2006 to December 2012. Data included age distribution, parity, gestational age, symptoms and risk factors. Medical management and pregnancy outcome were documented. Serial echocardiography data was compiled for a period of one year. Results In our study 9/16 (56%) were primigravidae, 4/16 (25%) had pre-eclamsia and 6/16 (35%) had co-existing hypertension. The difference in Echocardiography parameters observed between recovered and non-recovered patients was significant: Left Ventricular End diastolic dimension (5.6 cm vs 6.06 cm), Left Ventricular Ejection Fraction (28.7% vs 22.4%) and Left Ventricular fractional shortening (17.5% vs 13.4%). Thirteen out of sixteen patients were followed up for a period of one year out of which 61% (8/13) patients recovered completely. There was one mortality. Conclusion PPCM is a diagnosis of exclusion. Majority were young primigravidae presenting postnatally. Pre-eclampsia and hypertension were risk factors. ECHO parameters were reliable predictors of recovery. Future pregnancies are better avoided. PMID:24814122

  20. Cardiac sarcoid: a chameleon masquerading as hypertrophic cardiomyopathy and dilated cardiomyopathy in the same patient.

    Science.gov (United States)

    Agarwal, Anushree; Sulemanjee, Nasir Z; Cheema, Omar; Downey, Francis X; Tajik, A Jamil

    2014-05-01

    Sarcoidosis is a multisystem, granulomatous disease of unknown etiology often seen in young adults, with cardiac involvement in more than one-quarter of sarcoid patients. The clinical presentation of cardiac sarcoid depends upon the location and extent of myocardium involved. Although cardiac sarcoid may produce asymmetrical septal hypertrophy, it is most commonly considered in the differential diagnosis of dilated cardiomyopathy. The hypertrophic stage of cardiac sarcoid is rarely seen. We describe a case of cardiac sarcoid in a young patient wherein a distinctive appearance of the cardiac sarcoid spectrum from "hypertrophic" stage to thinned/scarred stage, masquerading as hypertrophic cardiomyopathy followed by dilated cardiomyopathy, is demonstrated.

  1. Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart.

    Directory of Open Access Journals (Sweden)

    Xaver Koenig

    Full Text Available Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.

  2. Pyrosequencing-Based Assays for Rapid Detection of HER2 and HER3 Mutations in Clinical Samples Uncover an E332E Mutation Affecting HER3 in Retroperitoneal Leiomyosarcoma.

    Science.gov (United States)

    González-Alonso, Paula; Chamizo, Cristina; Moreno, Víctor; Madoz-Gúrpide, Juan; Carvajal, Nerea; Daoud, Lina; Zazo, Sandra; Martín-Aparicio, Ester; Cristóbal, Ion; Rincón, Raúl; García-Foncillas, Jesús; Rojo, Federico

    2015-08-17

    Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific PCR-based pyrosequencing assays for identification of most prevalent HER2 and HER3 mutations, including S310F/Y, R678Q, L755M/P/S/W, V777A/L/M, 774-776 insertion, and V842I mutations in HER2, as well as M91I, V104M/L, D297N/V/Y, and E332E/K mutations in HER3. We tested 85 Formalin Fixed and Paraffin Embbeded (FFPE) samples and we detected three HER2-V842I mutations in colorectal carcinoma (CRC), ovarian carcinoma, and pancreatic carcinoma patients, respectively, and a HER2-L755M mutation in a CRC specimen. We also determined the presence of a HER3-E332K mutation in an urothelial carcinoma sample, and two HER3-D297Y mutations, in both gastric adenocarcinoma and CRC specimens. The D297Y mutation was previously detected in breast and gastric tumors, but not in CRC. Moreover, we found a not-previously-described HER3-E332E synonymous mutation in a retroperitoneal leiomyosarcoma patient. The pyrosequencing assays presented here allow the detection and characterization of specific HER2 and HER3 mutations. These pyrosequencing assays might be implemented in routine diagnosis for molecular characterization of HER2/HER3 receptors as an alternative to complex NGS approaches.

  3. Sheehan syndrome with reversible dilated cardiomyopathy.

    Science.gov (United States)

    Laway, Bashir A; Alai, Mohammad S; Gojwari, Tariq; Ganie, Mohd A; Zargar, Abdul Hamid

    2010-01-01

    Cardiac abnormalities in patients with Sheehan syndrome are uncommon. A case of Sheehan syndrome with dilated cardiomyopathy is presented in whom hormone replacement with levothyroxine and prednisolone resulted in complete recovery of cardiomyopathy. A 25-year-old woman presented with lactation failure, secondary amenorrhea, features of hypothyroidism and a hypocortisol state following severe postpartum hemorrhage after her last child birth. She also had smear positive pulmonary tuberculosis. After starting antitubercular treatment, she developed shock, suggestive of hypocortisol crisis. Hormonal investigations revealed evidence of panhypopitutarism and magnetic resonance imaging revealed partial empty sella. Meanwhile echocardiography revealed evidence of dilated cardiomyopathy (DCM). The patient was given replacement therapy in the form of glucocorticoids and levothyroxine in addition to antitubercular treatment. She improved and on follow-up over a period of 7 months, the DCM completely reversed. To our knowledge this is the first report of reversible DCM in a patient with Sheehan syndrome.

  4. Cardiomyopathie hypertrophique neonatale de diagnostic etiologique difficile

    Directory of Open Access Journals (Sweden)

    Rania Hammami

    2011-12-01

    Full Text Available La cardiomyopathie hypertrophique neonatale est une entite rare, heterogene regroupant plusieurs formes cliniques et donc de diagnostic etiologique difficile. Nous rapportons l�observation d�un nouveau ne issu d�une grossesse gemellaire, ayant presente a la naissance un tableau d�insuffisance cardiaque, l�echocardiographie avait conclut a une cardiomyopathie hypertrophique obstructive. Le bilan etiologique etait negatif notamment une mere non diabetique. L�evolution etait favorable avec regression de l�hypertrophie 2 semaines apres la naissance. L�etiologie finalement suggeree etait une cardiomyopathie secondaire a l�injection antenatale de corticoides dans le but d�accelerer la maturation pulmonaire. L�etablissement par les societes savantes d�un consensus de bilan etiologique minimal standard selon une chronologie bien determinee serait d�un grand apport dans la prise en charge de cette anomalie.

  5. A family with a complex clinical presentation characterized by arrhythmogenic right ventricular dysplasia/cardiomyopathy and features of branchio-oculo-facial syndrome.

    Science.gov (United States)

    Murray, Brittney; Wagle, Rohan; Amat-Alarcon, Nuria; Wilkens, Alisha; Stephens, Paul; Zackai, Elaine H; Goldmuntz, Elizabeth; Calkins, Hugh; Deardorff, Matthew A; Judge, Daniel P

    2013-02-01

    Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial form of cardiomyopathy typically caused by mutations in genes that encode an element of the cardiac desmosome. Branchio-oculo-facial syndrome (BOFS) is a craniofacial disorder caused by TFAP2A mutations. In a family segregating ARVD/C, some members also had features of BOFS. Genetic testing for ARVD/C identified a mutation in PKP2, encoding plakophilin-2, a component of the cardiac desmosome. Evaluation of dysmorphology by chromosome microarray (CMA) identified a 4.4 Mb deletion at chromosome 6p24 that included both TFAP2A and DSP, encoding desmoplakin, an additional component of the cardiac desmosome implicated in ARVD/C. A family member with both the 6p24 deletion and PKP2 mutation had more severe cardiac dysfunction. These findings suggest that this contiguous gene deletion contributes to both ARVD/C and BOFS, and that DSP haploinsufficiency may contribute to cardiomyopathy. This family provides a clinical example that underscores the need for careful evaluation in clinical scenarios where genetic heterogeneity is known to exist. Finally, it suggests that individuals with unexplained cardiomyopathy and dysmorphic facial features may benefit from CMA analysis.

  6. Null mutation of chloride channel 7 (Clcn7) impairs dental root formation but does not affect enamel mineralization.

    Science.gov (United States)

    Guo, Jing; Bervoets, Theodore J M; Henriksen, Kim; Everts, Vincent; Bronckers, Antonius L J J

    2016-02-01

    ClC-7, located in late endosomes and lysosomes, is critical for the function of osteoclasts. Secretion of Cl(-) by the ruffled border of osteoclasts enables H(+) secretion by v-H(+)-ATPases to dissolve bone mineral. Mice lacking ClC-7 show altered lysosomal function that leads to severe lysosomal storage. Maturation ameloblasts are epithelial cells with a ruffled border that secrete Cl(-) as well as endocytose and digest large quantities of enamel matrix proteins during formation of dental enamel. We tested the hypothesis that ClC-7 in maturation ameloblasts is required for intracellular digestion of matrix fragments to complete enamel mineralization. Craniofacial bones and developing teeth in Clcn7(-/-) mice were examined by micro-CT, immunohistochemistry, quantified histomorphometry and electron microscopy. Osteoclasts and ameloblasts in wild-type mice stained intensely with anti-ClC-7 antibody but not in Clcn7(-/-) mice. Craniofacial bones in Clcn7(-/-) mice were severely osteopetrotic and contained 1.4- to 1.6-fold more bone volume, which was less mineralized than the wild-type littermates. In Clcn7(-/-) mice maturation ameloblasts and osteoclasts highly expressed Ae2 as in wild-type mice. However, teeth failed to erupt, incisors were much shorter and roots were disfigured. Molars formed a normal dental crown. In compacted teeth, dentin was slightly less mineralized, enamel did not retain a matrix and mineralized fairly normal. We concluded that ClC-7 is essential for osteoclasts to resorb craniofacial bones to enable tooth eruption and root development. Disruption of Clcn7 reduces bone and dentin mineral density but does not affect enamel mineralization.

  7. Cardiomyopathy in Africa: heredity versus environment.

    Science.gov (United States)

    Mayosi, Bongani M; Somers, Krishna

    2007-01-01

    Unlike other parts of the world in which cardiomyopathy is rare, heart muscle disease is endemic in Africa. The major forms of cardiomyopathy in Africa are dilated cardiomyopathy (DCM) and endomyocardial fibrosis (EMF). Whereas DCM is a major cause of heart failure throughout the continent, EMF is restricted to the tropical regions of East, Central, and West Africa. Although epidemiological studies are lacking, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy seem to have characteristics similar to those of other populations elsewhere in the world. Recent advances in the genetic analysis of DCM in other parts of the world indicate that it is a genetically heterogeneous disorder in which some cases have a Mendelian cause and others have a non-genetic or multifactorial cause. This heterogeneous pattern of inheritance has been confirmed in small studies that have been conducted so far in Africa. The advent of human immunodeficiency virus infection and its association with cardiomyopathy has emphasised the role of inflammatory agents in the pathogenesis of DCM. By contrast with DCM in which some cases have major genetic contributions, there is scanty evidence for the role of genetic factors in the aetiology of EMF. Although the pathogenesis of EMF is not fully understood, it appears that the conditioning factor may be geography (in its widest sense, to include climate and socio-economic status), the triggering factor may be an as yet unidentified infective agent, and the perpetuating factor may be eosinophilia. There is a need for renewed effort to identify genetic and non-genetic factors in EMF and other forms of heart muscle disease that are prevalent on the continent of Africa.

  8. Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis

    Directory of Open Access Journals (Sweden)

    J. Travis Hinson

    2016-12-01

    Full Text Available AMP-activated protein kinase (AMPK is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGFβ isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFβ signaling.

  9. Multimodality imaging in apical hypertrophic cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Rosario; Parisi; Francesca; Mirabella; Gioel; Gabrio; Secco; Rossella; Fattori

    2014-01-01

    Apical hypertrophic cardiomyopathy(AHCM) is a relatively rare morphologic variant of HCM in which the hypertrophy of myocardium is localized to the left ventricular apex. Symptoms of AHCM might vary from none to others mimic coronary artery disease including acute coronary syndrome, thus resulting in inappropriate hospitalization. Transthoracic echocardiography is the firstline imaging technique for the diagnosis of hypertrophic cardiomyopathies. However, when the hypertrophy of the myocardium is localized in the ventricular apex might results in missed diagnosis. Aim of this paper is to review the different imaging techniques used for the diagnosis of AHCM and their role in the detection and comprehension of this uncommon disease.

  10. Gallium-67 myocardial scintigraphy in dilated cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Aoki, Toshikazu; Konishi, Tokuji; Koyama, Takao; Morita, Yuriko; Futagami, Yasuo; Hayashi, Takamaro; Hamada, Masayuki; Nakano, Takeshi

    1988-12-01

    Gallium-67 imaging has been employed clinically in the detection of malignant tumor or chronic inflammatory disease. In this study, we evaluated the usefulness of Gallium-67 myocardial imaging as an adjunct to endomyocardial biopsy in the diagnosis of myocarditis. Nine patients who had been diagnosed clinically as dilated cardiomyopathy underwent Gallium-67 myocardial imaging. Left ventricular endomyocardial biopsy was performed on all patients. Two had positive Gallium-67 imaging, but myocarditis was not proven in their tissue specimen. Two others with proven myocarditis had negative Gallium-67 imaging. These results suggest that Gallium-67 imaging is not always a useful tool to detect latent myocarditis in patients with dilated cardiomyopathy.

  11. A point mutation in the EGF-4 domain of β(3) integrin is responsible for the formation of the Sec(a) platelet alloantigen and affects receptor function.

    Science.gov (United States)

    Sachs, Ulrich J; Bakchoul, Tamam; Eva, Olga; Giptner, Astrid; Bein, Gregor; Aster, Richard H; Gitter, Maria; Peterson, Julie; Santoso, Sentot

    2012-01-01

    Neonatal alloimmune thrombocytopenia (NAIT) is caused by fetomaternal platelet incompatibility with maternal antibodies crossing the placenta and destroying fetal platelets. Antibodies against human platelet antigen-1a (HPA-1a) and HPA-5b are responsible for the majority of NAIT cases. We observed a suspected NAIT in a newborn with a platelet count of 25 G/l and petechial haemorrhages. Serological analysis of maternal serum revealed an immunisation against αIIbβ3 on paternal platelets only, indicating the presence of an antibody against a new rare alloantigen (Sec(a)) residing on αIIbβ3. The location of Sec(a) on αIIbβ3 was confirmed by immunoprecipitation. Nucleotide sequence analysis of paternal β3 revealed a single nucleotide exchange (G(1818)T) in exon 11 of the β3 gene (ITGB3), changing Lys(580) (wild-type) to Asn(580) (Sec(a)). Two additional members of the family Sec were typed Sec(a) positive, but none of 300 blood donors. Chinese hamster ovary cells expressing Asn(580), but not Lys(580) αIIbβ3, bound anti-Sec(a), which was corroborated by immunoprecipitation. Adhesion of transfected cells onto immobilised fibrinogen showed reduced binding of the Asn(580) variant compared to wild-type αIIbβ3. Analysis of transfected cells with anti-LIBS and PAC-1 antibody showed reduced binding when compared to the wild-type. No such effects were observed with Sec(a) positive platelets, which, however, are heterozygous for the Lys(580)Asn mutation. In this study, we describe a NAIT case caused by maternal alloimmunisation against a new antigen on αIIbβ3. Analysis with mutant transfected cells showed that the Lys(580)Asn mutation responsible for the formation of the Sec(a) antigenic determinant affects αIIbβ3 receptor function.

  12. Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects

    DEFF Research Database (Denmark)

    Hasselberg, Nina E; Edvardsen, Thor; Petri, Helle;

    2014-01-01

    Mutations in the Lamin A/C gene may cause atrioventricular block, supraventricular arrhythmias, ventricular arrhythmias (VA), and dilated cardiomyopathy. We aimed to explore the predictors and the mechanisms of VA in Lamin A/C mutation-positive subjects.METHODS AND RESULTS: We included 41 Lamin A...

  13. Diabetic cardiomyopathy:Pathophysiology,diagnostic evaluation and management

    Institute of Scientific and Technical Information of China (English)

    Joseph; M; Pappachan; George; I; Varughese; Rajagopalan; Sriraman; Ganesan; Arunagirinathan

    2013-01-01

    Diabetes affects every organ in the body and cardiovascular disease accounts for two-thirds of the mortality in the diabetic population.Diabetes-related heart disease occurs in the form of coronary artery disease(CAD),cardiac autonomic neuropathy or diabetic cardiomyopathy(DbCM).The prevalence of cardiac failure is high in the diabetic population and DbCM is a common but underestimated cause of heart failure in diabetes.The pathogenesis of diabetic cardiomyopathy is yet to be clearly defined.Hyperglycemia,dyslipidemia and inflammation are thought to play key roles in the generation of reactive oxygen or nitrogen species which are in turn implicated.The myocardial interstitium undergoes alterations resulting in abnormal contractile function noted in DbCM.In the early stages of the disease diastolic dysfunction is the only abnormality,but systolic dysfunction supervenes in the later stages with impaired left ventricular ejection fraction.Transmitral Doppler echocardiography is usually used to assess diastolic dysfunction,but tissue Doppler Imaging and Cardiac Magnetic Resonance Imaging are being increasingly used recently for early detection of DbCM.The management of DbCM involves improvement in lifestyle,control of glucose and lipid abnormalities,and treatment of hypertension and CAD,if present.The role of vasoactive drugs and antioxidants is being explored.This review discusses the pathophysiology,diagnostic evaluation and management options of DbCM.

  14. Posterolateral hypertrophic cardiomyopathy: a rare, but clinically significant variant of hypertrophic cardiomyopathy.

    Science.gov (United States)

    Seki, Atsuko; Perens, Gregory; Fishbein, Michael C

    2014-01-01

    Posterolateral hypertrophic cardiomyopathy (HCM) is a rare variant of HCM. Segmental HCM is seen in 12% of cases of HCM. Among the patterns of segmental HCM, posterolateral HCM is the least common type. Our case of an 18-year old male documents this unusual type of cardiomyopathy. In this form of HCM, left ventricular thickness and the extent of hypertrophy might be underestimated by 2-dimensional echocardiography. This case illustrates the echocardiographic and pathologic features of posterolateral HCM.

  15. Patterns of delayed-enhancement in MRI of ischemic and non-ischemic cardiomyopathies; Muster der spaeten Kontrastmittelanreicherung in der MRT bei ischaemischen und nicht-ischaemischen Kardiomyopathien

    Energy Technology Data Exchange (ETDEWEB)

    Stork, A.; Bansmann, P.M.; Koops, A.; Adam, G. [Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie, Universitaetsklinikum Hamburg-Eppendorf (Germany); Muellerleile, K.; Meinertz, T. [Universitaeres Herzzentrum, Universitaetsklinikum Hamburg-Eppendorf (Germany); Lund, G.K. [Kardiovaskulaere Bildgebung, Roentgeninstitut Duesseldorf (Germany)

    2007-01-15

    Contrast-enhanced MRI using the delayed-enhancement technique (DE-MRI) is widely applied in the clinical work-up of myocardial diseases. Myocardial diseases of varying etiology result in myocardial changes, such as necrosis, fibrosis, edema and metabolite deposition, which can be visualized by DE-MRI. Acute and chronic ischemic diseases based on a coronary artery disease as well as non-ischemic cardiomyopathies display DE. Cardiomyopathies often show a characteristic enhancement pattern. While ischemic lesions are localized in the subendocardium, non-ischemic cardiomyopathies often display an intramyocardial or subepicardial pattern. The typical pattern for dilated cardiomyopathies is band-like and intramyocardial with septal involvement. Arrhythmogenic right-ventricular dysplasias/cardiomyopathies are frequently associated with right-ventricular DE. In the case of amyloid cardiomyopathies which are often restrictive cardiomyopathies, subendocardial and circular DE is typically observed. Hypertrophic cardiomyopathies display patchy intramyocardial DE usually in the anteroseptal region. Acute myocarditis is typically accompanied by intramyocardial or subepicardial DE affecting the lateral wall. In the case of chronic myocarditis, intramyocardial or subepicardial DE is observed most frequently. Cardiac sarcoidosis typically entails patchy subepicardial DE with right- and left-ventricular involvement. Since there is an overlap between the enhancement patterns of cardiomyopathies, the diagnostic accuracy of DE-MRI is limited and the diagnosis must be based on additional clinical and MRI findings. The amount of DE often corresponds with cardiac functional parameters as well as with the frequency of cardiac events so that DE-MRI may be useful for risk stratification. Furthermore, DE-MRI can be helpful in the planning and evaluation of myocardial biopsies and electrophysiological examinations. (orig.)

  16. Myocardial late gadolinium enhancement in specific cardiomyopathies by cardiovascular magnetic resonance: a preliminary experience.

    Science.gov (United States)

    Silva, Caterina; Moon, James C; Elkington, Andrew G; John, Anna S; Mohiaddin, Raad H; Pennell, Dudley J

    2007-12-01

    Late gadolinium enhancement cardiovascular magnetic resonance (CMR) can visualize myocardial interstitial abnormalities. The aim of this study was to assess whether regions of abnormal myocardium can also be visualized by late enhancement gadolinium CMR in the specific cardiomyopathies. A retrospective review of all referrals for gadolinium CMR with specific cardiomyopathy over 20 months. Nine patients with different specific cardiomyopathies were identified. Late enhancement was demonstrated in all patients, with a mean signal intensity of 390 +/- 220% compared with normal regions. The distribution pattern of late enhancement was unlike the subendocardial late enhancement related to coronary territories found in myocardial infarction. The affected areas included papillary muscles (sarcoid), the mid-myocardium (Anderson-Fabry disease, glycogen storage disease, myocarditis, Becker muscular dystrophy) and the global sub-endocardium (systemic sclerosis, Loeffler's endocarditis, amyloid, Churg-Strauss). Focal myocardial late gadolinium enhancement is found in the specific cardiomyopathies, and the pattern is distinct from that seen in infarction. Further systematic studies are warranted to assess whether the pattern and extent of late enhancement may aid diagnosis and prognostic assessment.

  17. Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals with Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death

    Science.gov (United States)

    Boczek, Nicole J.; Ye, Dan; Jin, Fang; Tester, David J.; Huseby, April; Bos, J. Martijn; Johnson, Aaron J.; Kanter, Ronald; Ackerman, Michael J.

    2016-01-01

    Background A portion of sudden cardiac deaths (SCD) can be attributed to structural heart diseases such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long QT syndrome (LQTS); however, the underlying molecular mechanisms are quite distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, SCD, and congenital heart defects (CHDs). Methods and Results Whole exome sequencing (WES) in combination with Ingenuity Variant Analysis was completed on three affected individuals and one unaffected individual from a large pedigree with concomitant LQTS, HCM, and CHDs and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes, and identified two additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2, and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions Through WES and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and CHDs annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and co-segregation with disease in these pedigrees provides evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype. PMID:26253506

  18. Restrictive cardiomyopathy. Report of seven cases

    Directory of Open Access Journals (Sweden)

    Fonseca Sánchez Luis Alfonso

    2014-07-01

    Full Text Available Restrictive cardiomyopathy is a disease characterized by ventricular diastolic failure with elevation of end-dyastolic pressure and preserved systolic function. Materials and methods: retrospective study of patients with a diagnosis of restrictive cardiomyopathy. We carry out an analysis of demographic data, clinical presentation, and studies of patients diagnosed in the last 15 years at Instituto Nacional de Pediatría. Results: all included patients had clinical data of heart failure manifested mainly by medium-sized efforts dyspnea on schoolchildren and dyspnea by feeding in infants, as well as polypnea and diaphoresis. The most important signs were hepatomegaly, ascites, and gallop rhythm. Cardiomegaly by right atrial dilatation was the most frequent radiological data. The most frequent electrocardiographic data were dilatation of both atria, ST-segment depression and negative T waves. Echocardiogram showed in all cases binaural dilation and restrictive pattern. Conclusions: our patients were similar to those described in the specialized literature. Echocardiogram is still the best study for the diagnosis and the use of functional measurements as Doppler imaging can help to reveal early diastolic failure. In our country the heart transplant is just feasible; mortality remains 100%. Keywords: Restrictive cardiomyopathy, Heart failure, Cardiomyopathy.

  19. Diagnostic work-up in cardiomyopathies

    DEFF Research Database (Denmark)

    Rapezzi, Claudio; Arbustini, Eloisa; Caforio, Alida L P

    2013-01-01

    In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. In this position statement, we propose...

  20. Clinical and molecular classification of cardiomyopathies

    Directory of Open Access Journals (Sweden)

    Franco Cecchi

    2012-07-01

    Full Text Available The term “cardiomyopathies” was used for the first time 55 years ago, in 1957. Since then awareness and knowledge of this important and complex group of heart muscle diseases have improved substantially. Over these past five decades a large number of definitions, nomenclature and schemes, have been advanced by experts and consensus panel, which reflect the fast and continued advance of the scientific understanding in the field. Cardiomyopathies are a heterogeneous group of inherited myocardial diseases, which represent an important cause of disability and adverse outcome. Although considered rare diseases, the overall estimated prevalence of all cardiomyopathies is at least 3% in the general population worldwide. Furthermore, their recognition is increasing due to advances in imaging techniques and greater awareness in both the public and medical community. Cardiomyopathies represent an ideal translational model of integration between basic and clinical sciences. A multidisciplinary approach is therefore essential in order to ensure their correct diagnosis and management. In the present work, we aim to provide a concise overview of the historical background, genetic and phenotypic spectrum and evolving concepts leading to the various attempts of cardiomyopathy classifications produced over the decades.

  1. Update in cardiomyopathies and congestive heart failure

    Directory of Open Access Journals (Sweden)

    The Heart Hospital, London, UK and Monaldi Hospital, Naples, Italy

    2012-05-01

    Full Text Available This abstract book contains four reports and all abstracts presented to the Joint Meeting: Update in cardiomyopathies and congestive heart failure, 22-23 September 2011 - Naples, Italy, endorsed by the Working Group on Myocardial and Pericardial Diseases (WG 21 of the European Society of Cardiology (ESC.

  2. Contractile Dysfunction in Sarcomeric Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    MacIver, David H; Clark, Andrew L

    2016-09-01

    The pathophysiological mechanisms underlying the clinical phenotype of sarcomeric hypertrophic cardiomyopathy are controversial. The development of cardiac hypertrophy in hypertension and aortic stenosis is usually described as a compensatory mechanism that normalizes wall stress. We suggest that an important abnormality in hypertrophic cardiomyopathy is reduced contractile stress (the force per unit area) generated by myocardial tissue secondary to abnormalities such as cardiomyocyte disarray. In turn, a progressive deterioration in contractile stress provokes worsening hypertrophy and disarray. A maintained or even exaggerated ejection fraction is explained by the increased end-diastolic wall thickness producing augmented thickening. We propose that the nature of the hemodynamic load in an individual with hypertrophic cardiomyopathy could determine its phenotype. Hypertensive patients with hypertrophic cardiomyopathy are more likely to develop exaggerated concentric hypertrophy; athletic individuals an asymmetric pattern; and inactive individuals a more apical hypertrophy. The development of a left ventricular outflow tract gradient and mitral regurgitation may be explained by differential regional strain resulting in mitral annular rotation.

  3. Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia

    Science.gov (United States)

    Bhatnagar, Bhavana; Eisfeld, Ann-Kathrin; Nicolet, Deedra; Mrózek, Krzysztof; Blachly, James S.; Orwick, Shelley; Lucas, David M.; Kohlschmidt, Jessica; Blum, William; Kolitz, Jonathan E.; Stone, Richard M.; Bloomfield, Clara D.; Byrd, John C.

    2016-01-01

    Summary Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of NGS methods, persist in the majority of AML patients in CR. PMID:27476855

  4. Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.

    Science.gov (United States)

    Pacheu-Grau, David; Bareth, Bettina; Dudek, Jan; Juris, Lisa; Vögtle, F-Nora; Wissel, Mirjam; Leary, Scot C; Dennerlein, Sven; Rehling, Peter; Deckers, Markus

    2015-06-02

    Three mitochondria-encoded subunits form the catalytic core of cytochrome c oxidase, the terminal enzyme of the respiratory chain. COX1 and COX2 contain heme and copper redox centers, which are integrated during assembly of the enzyme. Defects in this process lead to an enzyme deficiency and manifest as mitochondrial disorders in humans. Here we demonstrate that COA6 is specifically required for COX2 biogenesis. Absence of COA6 leads to fast turnover of newly synthesized COX2 and a concomitant reduction in cytochrome c oxidase levels. COA6 interacts transiently with the copper-containing catalytic domain of newly synthesized COX2. Interestingly, similar to the copper metallochaperone SCO2, loss of COA6 causes cardiomyopathy in humans. We show that COA6 and SCO2 interact and that corresponding pathogenic mutations in each protein affect complex formation. Our analyses define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency.

  5. D471G Mutation in LCMV-NP Affects Its Ability to Self-associate and Results in a Dominant Negative Effect in Viral RNA Synthesis

    Directory of Open Access Journals (Sweden)

    Luis Martínez-Sobrido

    2012-10-01

    Full Text Available Arenaviruses merit significant interest because several family members are etiological agents of severe hemorrhagic fevers, representing a major burden to public health. Currently, there are no FDA-licensed vaccines against arenaviruses and the only available antiviral therapy is limited to the use of ribavirin that is partially effective. Arenavirus nucleoprotein (NP is found associated with the genomic RNA forming the viral ribonucleoproteins (vRNPs that together with the polymerase (L direct viral replication and transcription. Virion formation requires the recruitment of vRNPs into budding sites, a process in which the arenavirus matrix-like protein (Z plays a major role. Therefore, proper NP-NP and NP-Z interactions are required for the generation of infectious progeny. In this work we demonstrate the role of the amino acid residue D471 in the self-association of lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP. Amino acid substitutions at this position abrogate NP oligomerization, affecting its ability to mediate replication and transcription of a minigenome reporter plasmid. However, its ability to interact with the Z protein, counteract the cellular interferon response and bind to dsRNA analogs was retained. Additionally, we also document the dominant negative effect of D471G mutation on viral infection, suggesting that NP self-association is an excellent target for the development of new antivirals against arenaviruses.

  6. Emergency management of decompensated peripartum cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Lata Indu

    2009-01-01

    Full Text Available Peripartum cardiomyopathy (PPCM is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women. [1] the symptomatic patients should receive standard therapy for heart failure, managed by a multidisciplinary team. The diagnosis of PPCM rests on the echocardiographic identification of new left ventricular systolic dysfunction during a limited period surrounding parturition. Diagnostic criteria include an ejection fraction of less than 45%, fractional shortening of less than 30%, or both, and end-diastolic dimension of greater than 2.7 cm/m 2 body surface-area. This entity presents a diagnostic challenge because many women in the last month of a normal pregnancy experience dyspnea, fatigue, and pedal edema, symptoms identical to early congestive heart failure. There are no specific criteria for differentiating subtle symptoms of heart failure from normal late pregnancy. Therefore, it is important that a high index of suspicion be maintained to identify the rare case of PPCM as general examination showing symptoms of heart failure with pulmonary edema. PPCM remains a diagnosis of exclusion. No additional specific criteria have been identified to allow distinction between a peripartum patient with new onset heart failure and left ventricular systolic dysfunction as PPCM and another form of dilated cardiomyopathy. Therefore, all other causes of dilated cardiomyopathy with heart failure must be systematically excluded before accepting the designation of PPCM. Recent observations from Haiti [2] suggest that a latent form of PPCM without clinical symptoms might exist. The investigators identified four clinically normal postpartum women with asymptomatic systolic dysfunction on echocardiography, who subsequently either developed clinically detectable dilated cardiomyopathy or improved and completely recovered heart function.

  7. Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy

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    Tirsa L. E. van Westering

    2015-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of the main causes of death. The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage. Moreover, it pathologically alters intracellular calcium (Ca2+ concentration, neuronal nitric oxide synthase (nNOS localization and mitochondrial function and leads to inflammation and necrosis, all contributing to the development of cardiomyopathy. Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense. Several preclinical therapies are undergoing development, including utrophin up-regulation, stop codon read-through therapy, viral gene therapy, cell-based therapy and exon skipping. Some of these therapies are undergoing clinical trials, but these have predominantly focused on skeletal muscle correction. However, improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function. This review consolidates what is known regarding molecular pathology of the DMD heart, specifically focusing on intracellular Ca2+, nNOS and mitochondrial dysregulation. It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology, with a focus on the heart.

  8. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus

    NARCIS (Netherlands)

    Milting, Hendrik; Klauke, Baerbel; Christensen, Alex Hoerby; Muesebeck, Joerg; Walhorn, Volker; Grannemann, Soeren; Muennich, Tamara; Saric, Tomo; Rasmussen, Torsten Bloch; Jensen, Henrik Kjaerulf; Mogensen, Jens; Baecker, Carolin; Romaker, Elena; Laser, Kai Thorsten; Knyphausen, Edzard zu; Kassner, Astrid; Gummert, Jan; Judge, Daniel P.; Connors, Sean; Hodgkinson, Kathy; Young, Terry-L.; van der Zwaag, Paul A.; van Tintelen, J. Peter; Anselmetti, Dario

    2015-01-01

    Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM4

  9. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Schlossarek, Saskia; Singh, Sonia R; Geertz, Birgit; Schulz, Herbert; Reischmann, Silke; Hübner, Norbert; Carrier, Lucie

    2014-01-01

    A growing line of evidence indicates a dysfunctional ubiquitin-proteasome system (UPS) in cardiac diseases. Anti-hypertrophic effects and improved cardiac function have been reported after treatment with proteasome inhibitors in experimental models of cardiac hypertrophy. Here we tested whether proteasome inhibition could also reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C. At 7 weeks of age, homozygous mutant mice (KI) have 39% higher left ventricular mass-to-body-weight ratio and 29% lower fractional area shortening (FAS) than wild-type (WT) mice. Both groups were treated with epoxomicin (0.5 mg/kg/day) or vehicle for 1 week via osmotic minipumps. Epoxomicin inhibited the chymotrypsin-like activity by ~50% in both groups. All parameters of cardiac hypertrophy (including the fetal gene program) were not affected by epoxomicin treatment in both groups. In contrast, FAS was 12% and 35% higher in epoxomicin-treated than vehicle-treated WT and KI mice, respectively. To identify which genes or pathways could be involved in this positive effect, we performed a transcriptome analysis in KI and WT neonatal cardiac myocytes, treated or not with the proteasome inhibitor MG132 (1 μM, 24 h). This revealed 103 genes (four-fold difference; 5% FDR) which are commonly regulated in both KI and WT cardiac myocytes. Thus, even in genetically-modified mice with manifest HCM, proteasome inhibition showed beneficial effects, at least with regard to cardiac function. Targeting the UPS in cardiac diseases remains therefore a therapeutic option.

  10. Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants.

    Science.gov (United States)

    Brodehl, Andreas; Hedde, Per Niklas; Dieding, Mareike; Fatima, Azra; Walhorn, Volker; Gayda, Susan; Šarić, Tomo; Klauke, Bärbel; Gummert, Jan; Anselmetti, Dario; Heilemann, Mike; Nienhaus, Gerd Ulrich; Milting, Hendrik

    2012-05-01

    Mutations in the DES gene coding for the intermediate filament protein desmin may cause skeletal and cardiac myopathies, which are frequently characterized by cytoplasmic aggregates of desmin and associated proteins at the cellular level. By atomic force microscopy, we demonstrated filament formation defects of desmin mutants, associated with arrhythmogenic right ventricular cardiomyopathy. To understand the pathogenesis of this disease, it is essential to analyze desmin filament structures under conditions in which both healthy and mutant desmin are expressed at equimolar levels mimicking an in vivo situation. Here, we applied dual color photoactivation localization microscopy using photoactivatable fluorescent proteins genetically fused to desmin and characterized the heterozygous status in living cells lacking endogenous desmin. In addition, we applied fluorescence resonance energy transfer to unravel short distance structural patterns of desmin mutants in filaments. For the first time, we present consistent high resolution data on the structural effects of five heterozygous desmin mutations on filament formation in vitro and in living cells. Our results may contribute to the molecular understanding of the pathological filament formation defects of heterozygous DES mutations in cardiomyopathies.

  11. Dual Color Photoactivation Localization Microscopy of Cardiomyopathy-associated Desmin Mutants*

    Science.gov (United States)

    Brodehl, Andreas; Hedde, Per Niklas; Dieding, Mareike; Fatima, Azra; Walhorn, Volker; Gayda, Susan; Šarić, Tomo; Klauke, Bärbel; Gummert, Jan; Anselmetti, Dario; Heilemann, Mike; Nienhaus, Gerd Ulrich; Milting, Hendrik

    2012-01-01

    Mutations in the DES gene coding for the intermediate filament protein desmin may cause skeletal and cardiac myopathies, which are frequently characterized by cytoplasmic aggregates of desmin and associated proteins at the cellular level. By atomic force microscopy, we demonstrated filament formation defects of desmin mutants, associated with arrhythmogenic right ventricular cardiomyopathy. To understand the pathogenesis of this disease, it is essential to analyze desmin filament structures under conditions in which both healthy and mutant desmin are expressed at equimolar levels mimicking an in vivo situation. Here, we applied dual color photoactivation localization microscopy using photoactivatable fluorescent proteins genetically fused to desmin and characterized the heterozygous status in living cells lacking endogenous desmin. In addition, we applied fluorescence resonance energy transfer to unravel short distance structural patterns of desmin mutants in filaments. For the first time, we present consistent high resolution data on the structural effects of five heterozygous desmin mutations on filament formation in vitro and in living cells. Our results may contribute to the molecular understanding of the pathological filament formation defects of heterozygous DES mutations in cardiomyopathies. PMID:22403400

  12. Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.

    Science.gov (United States)

    Theis, Jeanne L; Bos, J Martijn; Bartleson, Virginia B; Will, Melissa L; Binder, Josepha; Vatta, Matteo; Towbin, Jeffrey A; Gersh, Bernard J; Ommen, Steve R; Ackerman, Michael J

    2006-12-29

    Hypertrophic cardiomyopathy (HCM) can be classified into at least four major anatomic subsets based upon the septal contour, and the location and extent of hypertrophy: reverse curvature-, sigmoidal-, apical-, and neutral contour-HCM. Here, we sought to identify genetic determinants for sigmoidal-HCM and hypothesized that Z-disc-HCM may be associated preferentially with a sigmoidal phenotype. Utilizing PCR, DHPLC, and direct DNA sequencing, we performed mutational analysis of five genes encoding cardiomyopathy-associated Z-disc proteins. The study cohort consisted of 239 unrelated patients with HCM previously determined to be negative for mutations in the eight genes associated with myofilament-HCM. Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography. Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated Z-disc mutations involving residues highly conserved across species and absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1), and VCL (2). For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%). While Z-disc-HCM is uncommon, it is equal in prevalence to thin filament-HCM. In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology.

  13. Lamin A/C truncation in dilated cardiomyopathy with conduction disease

    Directory of Open Access Journals (Sweden)

    Huber Jill M

    2003-07-01

    Full Text Available Abstract Background Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. Methods We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1. Results DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. Conclusions Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.

  14. Related factors of dilated cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    Guangyong Huang; Hang Gao; Xiangang Meng; Zhonghua Yan; Xiangquan Kong; Lexin Wang

    2009-01-01

    Objective To investigate the etiology and relative factors of dilated cardiomyopathy (DCM) in Chinese patients. Methods A case-control study was conducted to compare 233 patients with DCM in high-incidence areas (case group) and 150 patients with stable angina pectoris (control group). Life styles and history of diseases information was collected by questionaire; human anti-myocardial antibody IgG (AMA- IgG), human Coxsackie B virus IgG (CBV- IgG) and human adenovirus antibody IgG (ADV- lgG) were measured with ELISA. General chemical and toxicological indicators in drink water from high and low prevalence areas and serum trace elements also were compared. Results 1 ) Compared with the control group, the case group had more farmers (P < 0.01), with low average incomes (P < 0.01), higher alcohol consumption (P < 0.01) and higher incidence of the history of myocarditis (P < 0.01 ). 2) AMA-IgG, CBV-IgG and ADV-IgG levels were low and the positive rates ofAMA-IgG, CBV-IgG and ADV-IgG of patients with DCM were respectively 7.78%, 6.67% and 6.67%, no statistical significance comparing with those in the control group. 3) The content of iron (1.36±2.18 vs 0.39±0.67 mg/L, P<0.05) and manganese (0.384±0.35 vs 0.15±0.14, P<0.01 ) in drinking water of high-incidence areas was significantly higher than that in low-incidence areas. 4) The content of serum iron (69.14±57.8 vs 20.04±17.5 μ mol/L, P<0.01 ) and copper (25.74±4.2 vs 19.7±4.5 μmol/L, P<0.01) in the case group evidently exceeded the normal range and obviously higher than that in the control group. Conclusions 1) The incidence of some DCM is related with low incomes, high alcohol consumption and myocarditis. 2) These data do not support that DCM is related with persistent virus infection and autoimmunization; 3) Iron and manganese contents exceeding standards in drinking water and the high content of serum iron and copper is comparatively related with the incidence of DCM.

  15. Aortic biomechanics in hypertrophic cardiomyopathy

    Science.gov (United States)

    Badran, Hala Mahfouz; Soltan, Ghada; Faheem, Nagla; Elnoamany, Mohamed Fahmy; Tawfik, Mohamed; Yacoub, Magdi

    2015-01-01

    Background: Ventricular-vascular coupling is an important phenomenon in many cardiovascular diseases. The association between aortic mechanical dysfunction and left ventricular (LV) dysfunction is well characterized in many disease entities, but no data are available on how these changes are related in hypertrophic cardiomyopathy (HCM). Aim of the work: This study examined whether HCM alone is associated with an impaired aortic mechanical function in patients without cardiovascular risk factors and the relation of these changes, if any, to LV deformation and cardiac phenotype. Methods: 141 patients with HCM were recruited and compared to 66 age- and sex-matched healthy subjects as control group. Pulse pressure, aortic strain, stiffness and distensibility were calculated from the aortic diameters measured by M-mode echocardiography and blood pressure obtained by sphygmomanometer. Aortic wall systolic and diastolic velocities were measured using pulsed wave Doppler tissue imaging (DTI). Cardiac assessment included geometric parameters and myocardial deformation (strain and strain rate) and mechanical dyssynchrony. Results: The pulsatile change in the aortic diameter, distensibility and aortic wall systolic velocity (AWS') were significantly decreased and aortic stiffness index was increased in HCM compared to control (P < .001) In HCM AWS' was inversely correlated to age(r = − .32, P < .0001), MWT (r = − .22, P < .008), LVMI (r = − .20, P < .02), E/Ea (r = − .16, P < .03) LVOT gradient (r = − 19, P < .02) and severity of mitral regurg (r = − .18, P < .03) but not to the concealed LV deformation abnormalities or mechanical dyssynchrony. On multivariate analysis, the key determinant of aortic stiffness was LV mass index and LVOT obstruction while the role LV dysfunction in aortic stiffness is not evident in this population. Conclusion: HCM is associated with abnormal aortic mechanical properties. The severity of cardiac

  16. Phenotypic consequences of a novel SCO2 gene mutation.

    Science.gov (United States)

    Verdijk, Rob M; de Krijger, Ronald; Schoonderwoerd, Kees; Tiranti, Valeria; Smeets, Hubert; Govaerts, Lutgarde C P; de Coo, René

    2008-11-01

    SCO2 is a cytochrome c oxidase (COX) assembly gene. Mutations in the SCO2 gene have been associated with fatal infantile cardioencephalomyopathy. We report on the phenotype of a novel SCO2 mutation in two siblings with fatal infantile cardioencephalomyopathy. The index patient died of heart failure at 25 days of age. Muscle biopsy was performed for histology and biochemical study of the oxidative phosphorylation system complexes. The entire coding region of the SCO2 gene was sequenced. Autopsy was performed on the index patient and on a female sibling delivered at 23 weeks of gestation following termination of pregnancy during which amniocentesis and genetic testing had been performed. Muscle biopsy and biochemical analysis of heart and skeletal muscle detected a severe isolated COX-IV deficiency. Pathologic findings in both patients confirmed hypertrophic cardiomyopathy. Sequencing of the SCO2 gene showed compound heterozygous mutation; the common E140K mutation and a novel W36X nonsense mutation. Newborns with a combination of hypotonia and cardiomyopathy should be evaluated for multiple congenital anomaly syndromes, inborn errors of metabolism and mitochondrial derangements, and may require extensive diagnostic testing. Mutations in the SCO2 gene are a cause of prenatal-onset hypertrophic cardiomyopathy.

  17. High resolution melting: improvements in the genetic diagnosis of hypertrophic cardiomyopathy in a Portuguese cohort

    Directory of Open Access Journals (Sweden)

    Santos Susana

    2012-03-01

    Full Text Available Abstract Background Hypertrophic Cardiomyopathy (HCM is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. Methodology In this report, we evaluated High Resolution Melting (HRM robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. Results HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. Conclusions HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations.

  18. Differential radiosensitivity phenotypes of DNA-PKcs mutations affecting NHEJ and HRR systems following irradiation with gamma-rays or very low fluences of alpha particles.

    Science.gov (United States)

    Lin, Yu-Fen; Nagasawa, Hatsumi; Little, John B; Kato, Takamitsu A; Shih, Hung-Ying; Xie, Xian-Jin; Wilson, Paul F; Brogan, John R; Kurimasa, Akihiro; Chen, David J; Bedford, Joel S; Chen, Benjamin P C

    2014-01-01

    We have examined cell-cycle dependence of chromosomal aberration induction and cell killing after high or low dose-rate γ irradiation in cells bearing DNA-PKcs mutations in the S2056 cluster, the T2609 cluster, or the kinase domain. We also compared sister chromatid exchanges (SCE) production by very low fluences of α-particles in DNA-PKcs mutant cells, and in homologous recombination repair (HRR) mutant cells including Rad51C, Rad51D, and Fancg/xrcc9. Generally, chromosomal aberrations and cell killing by γ-rays were similarly affected by mutations in DNA-PKcs, and these mutant cells were more sensitive in G1 than in S/G2 phase. In G1-irradiated DNA-PKcs mutant cells, both chromosome- and chromatid-type breaks and exchanges were in excess than wild-type cells. For cells irradiated in late S/G2 phase, mutant cells showed very high yields of chromatid breaks compared to wild-type cells. Few exchanges were seen in DNA-PKcs-null, Ku80-null, or DNA-PKcs kinase dead mutants, but exchanges in excess were detected in the S2506 or T2609 cluster mutants. SCE induction by very low doses of α-particles is resulted from bystander effects in cells not traversed by α-particles. SCE seen in wild-type cells was completely abolished in Rad51C- or Rad51D-deficient cells, but near normal in Fancg/xrcc9 cells. In marked contrast, very high levels of SCEs were observed in DNA-PKcs-null, DNA-PKcs kinase-dead and Ku80-null mutants. SCE induction was also abolished in T2609 cluster mutant cells, but was only slightly reduced in the S2056 cluster mutant cells. Since both non-homologous end-joining (NHEJ) and HRR systems utilize initial DNA lesions as a substrate, these results suggest the possibility of a competitive interference phenomenon operating between NHEJ and at least the Rad51C/D components of HRR; the level of interaction between damaged DNA and a particular DNA-PK component may determine the level of interaction of such DNA with a relevant HRR component.

  19. Myocardial edema in Takotsubo syndrome mimicking apical hypertrophic cardiomyopathy: An insight into diagnosis by cardiovascular magnetic resonance.

    Science.gov (United States)

    Izgi, Cemil; Ray, Sanjoy; Nyktari, Evangelia; Alpendurada, Francisco; Lyon, Alexander R; Rathore, Sudhir; Baksi, Arun John

    2015-01-01

    Myocardial edema is one of the characteristic features in the pathogenesis of Takotsubo syndrome. We report a middle aged man who presented with typical clinical and echocardiographic features of apical variant of Takotsubo syndrome. However, a cardiovascular magnetic resonance study performed 10 days after presentation did not show any apical 'ballooning' but revealed features of an apical hypertrophic cardiomyopathy on cine images. Tissue characterization with T2 weighted images proved severe edema as the cause of significantly increased apical wall thickness. A follow-up cardiovascular magnetic resonance study was performed 5 months later which showed that edema, wall thickening and the appearance of apical hypertrophic cardiomyopathy all resolved, confirming Takotsubo syndrome as the cause of the initial appearance. As the affected myocardium most commonly involves the apical segments, an edema induced increase in apical wall thickness may lead to appearances of an apical hypertrophic cardiomyopathy rather than apical ballooning in the acute to subacute phase of Takotsubo syndrome.

  20. Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population.

    Directory of Open Access Journals (Sweden)

    Christian M Hagen

    Full Text Available Hypertrophic cardiomyopathy (HCM is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA, defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006 and 41% (p = 0.003, in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017 and 9.1%, (p = 0.06. Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02 and 22.8% (p = 0.04. These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy.

  1. Insights into restrictive cardiomyopathy from clinical and animal studies

    Institute of Scientific and Technical Information of China (English)

    Pierre-Yves Jean-Charles; Yue-Jin Li; Chang-Long Nan; Xu-Pei Huang

    2011-01-01

    Catdiomyopathies are diseases that primarily affect the myocardium,leading to serious cardiac dysfimction and heart failure.Out of the three major categories of candiomyopathies(hypertrophic,dilated and restrictive),restrictive cardiomyopathy(RCM)is less common and also the least studied However,the prognosis for RCM is poor as some patients dying in their childhood The molecular mechanisms behind the disease development and progression are not very clear and the treatment of RCM is very difficult and often ineffective.In this article,we reviewed the recent progress in RCM research from the clinical studies and the translational studies done on diseased transgenic animal models.This will help for a better understanding of tare mechanisms underlying the etiology and development of RCM and for the design of better treatments for the disease.

  2. Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis.

    Science.gov (United States)

    Bello, Natalie A; Arany, Zoltan

    2015-08-01

    Peripartum cardiomyopathy (PPCM) is characterized by the development of systolic heart failure in the last month of pregnancy or within the first 5 months postpartum. The disease affects between 1:300 and 1:3000 births worldwide. Heart failure can resolve spontaneously but often does not. Mortality rates, like incidence, vary widely based on location, ranging from 0% to 25%. The consequences of PPCM are thus often devastating for an otherwise healthy young woman and her newborn. The cause of PPCM remains elusive. Numerous hypotheses have been proposed, with mixed supporting evidence. Recent work has suggested that PPCM is a vascular disease, triggered by the profound hormonal changes of late gestation. We focus here on these new mechanistic findings, and their potential implication for understanding and treating PPCM.

  3. Ultrastructural myocardial changes in seven cats with spontaneous hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Christiansen, Liselotte Bruun; Prats Gavalda, Clara; Hyttel, Poul

    2015-01-01

    OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats and shares clinical and pathological characteristics with human HCM. Little is known about the pathogenic mechanisms underlying development of spontaneous feline HCM. ANIMALS: The study population consisted...... of seven cats diagnosed with HCM and eight age-matched cats with no evidence of cardiac disease. METHODS: Fresh myocardial biopsies taken from the middle of the left ventricular posterior free wall were obtained and examined with transmission electron microscopy. RESULTS: Electron microscopic examination...... showed ultrastructural aberrations of the myocardial cytoarchitecture and of the interstitium in the seven cats with HCM. In the most severely affected cats the myofibrils were disorganized and subsarcolemmal mitochondria were depleted. In control cats, contraction band artifacts were commonly seen...

  4. Stress-induced cardiomyopathy in the absence of complaints

    Directory of Open Access Journals (Sweden)

    N. M. Butkevich

    2012-01-01

    Full Text Available Stress-induced cardiomyopathy or Takotsubo cardiomyopathy that generally runs with the clinical manifestations of acute coronary syndrome and left ventricular asynergy, which are caused by emotional, psychological, or physical stress, is most frequently encountered among the unclassified cardiomyopathies. A clinical case of this myocardial lesion without clinical manifestations, but with transient electrocardiographic changes and evident impairment of left ventricular contraction is described.

  5. [Takotsubo cardiomyopathy: a novel beta-adrenergic blocker withdrawal syndrome].

    Science.gov (United States)

    Tomcsányi, János; Jávor, Kinga; Arabadzisz, Hrisula; Zsoldos, András; Wagner, Vince; Sármán, Balázs

    2013-02-17

    The authors describe two cases of takotsubo cardiomyopathy developing after an abrupt withdrawal of carvedilol and bisoprolol. Takotsubo or stress cardiomyopathy is characterized by acute and reversible cardiac dysfunction without coronary artery disease. It is triggered by acute emotional or physical stress, drugs or drug withdrawal. The immediate discontinuation of the long acting vasodilator beta-blocker, carvedilol has not yet been described to cause takotsubo cardiomyopathy. The authors recommend cautious withdrawal of beta-blockers.

  6. Heart failure in pregnant women: is it peripartum cardiomyopathy?

    Science.gov (United States)

    Dennis, Alicia Therese

    2015-03-01

    Peripartum cardiomyopathy is a rare but important cause of maternal morbidity and mortality. Women with peripartum cardiomyopathy often present with symptoms and signs of heart failure. The diagnosis of peripartum cardiomyopathy is made after all other causes of heart failure are excluded. Emphasis is on the immediate recognition of an unwell pregnant or recently pregnant woman, early diagnosis with the use of echocardiography, and the correct treatment of heart failure.

  7. Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin

    Directory of Open Access Journals (Sweden)

    Audrey N. Chang

    2014-12-01

    Full Text Available The potential alterations to structure and associations with thin filament proteins caused by the dilated cardiomyopathy (DCM associated tropomyosin (Tm mutants E40K and E54K, and the hypertrophic cardiomyopathy (HCM associated Tm mutants E62Q and L185R, were investigated. In order to ascertain what the cause of the known functional effects may be, structural and protein-protein interaction studies were conducted utilizing actomyosin ATPase activity measurements and spectroscopy. In actomyosin ATPase measurements, both HCM mutants and the DCM mutant E54K caused increases in Ca2+-induced maximal activities, while E40K caused a decrease. Investigation of Tm’s ability to inhibit actomyosin ATPase in the absence of troponin showed that HCM-associated mutant Tms did not inhibit as well as wildtype, whereas the DCM associated mutant E40K inhibited better. E54K did not inhibit the actomyosin ATPase activity at any concentration of Tm tested. Thermal denaturation studies by circular dichroism and molecular modeling of the mutations in Tm showed that in general, the DCM mutants caused destabilization within the Tm, while the HCM mutants resulted in increased stability. These findings demonstrate that the structural alterations in Tm observed here may affect the regulatory function of Tm on actin, thereby directly altering the ATPase rates of myosin.

  8. Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos‐like syndrome

    Science.gov (United States)

    Uzumcu, A; Norgett, E E; Dindar, A; Uyguner, O; Nisli, K; Kayserili, H; Sahin, S E; Dupont, E; Severs, N J; Leigh, I M; Yuksel‐Apak, M; Kelsell, D P; Wollnik, B

    2006-01-01

    Background Desmosomes are cellular junctions important for intercellular adhesion and anchoring the intermediate filament (IF) cytoskeleton to the cell membrane. Desmoplakin (DSP) is the most abundant desmosomal protein with 2 isoforms produced by alternative splicing. Methods We describe a patient with a recessively inherited arrhythmogenic dilated cardiomyopathy with left and right ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair. The patient showed a severe heart phenotype with an early onset and rapid progression to heart failure at 4 years of age. Results A homozygous nonsense mutation, R1267X, was found in exon 23 of the desmoplakin gene, which results in an isoform specific truncation of the larger DSPI isoform. The loss of most of the DSPI specific rod domain and C‐terminal area was confirmed by Western blotting and immunofluorescence. We further showed that the truncated DSPI transcript is unstable, leading to a loss of DSPI. DSPI is reported to be an obligate constituent of desmosomes and the only isoform present in cardiac tissue. To address this, we reviewed the expression of DSP isoforms in the heart. Our data suggest that DSPI is the major cardiac isoform but we also show that specific compartments of the heart have detectable DSPII expression. Conclusions This is the first description of a phenotype caused by a mutation affecting only one DSP isoform. Our findings emphasise the importance of desmoplakin and desmosomes in epidermal and cardiac function and additionally highlight the possibility that the different isoforms of desmoplakin may have distinct functional properties within the desmosome. PMID:16467215

  9. Psychological disorders in adults with inherited cardiomyopathies and Takotsubo syndrome.

    Science.gov (United States)

    Suárez Bagnasco, Mariana; Núñez-Gil, Iván J

    2016-06-03

    We performed a narrative review about psychological disorders in adults with Takotsubo syndrome and inherited cardiomyopathies. Through the electronic database PubMed and PsycINFO we searched all relevant related manuscripts published between 2000 and 2015. We found twelve studies that explore psychological disorders in Takotsubo syndrome and eight about inherited cardiomyopathies: five enrolled patients with hypertrophic cardiomyopathy, two dilated cardiomyopathy, and one arrhythmogenic right ventricular cardiomyopathy. All papers reported the presence of psychological disorders. In Takotsubo syndrome, depression fluctuates between 20.5 and 48% and anxiety was present among 26 and 56%. A study reported that anxiety increases the probability of developing Takotsubo syndrome. In dilated cardiomyopathy, anxiety was present in 50% and depression in 22%. In arrhythmogenic right ventricular cardiomyopathy, younger age, poorer functional capacity and having experienced at least one implantable cardioverter defibrillator shock, were significant independent predictors of both device-specific and generalized anxiety. In hypertrophic cardiomyopathy, anxiety and depression were present in 45.2% and 17.9%, respectively. Thirty seven percent met diagnostic criteria for anxiety disorders and 21% for mood disorders. Nearby half hypertrophic cardiomyopathy patients report triggering of chest pain, dyspnea, and dizziness by emotional stress. Due to the small number of studies, conclusions are limited. However, we discuss some results.

  10. Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

    Institute of Scientific and Technical Information of China (English)

    Stephanie; L; Byers; Can; Ficicioglu

    2014-01-01

    Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of “red flags” which should prompt additional evaluation.

  11. Intrathecal baclofen withdrawal: A rare cause of reversible cardiomyopathy.

    Science.gov (United States)

    Awuor, Stephen O; Kitei, Paul M; Nawaz, Yassir; Ahnert, Amy M

    2016-03-01

    Baclofen is commonly used to treat spasticity of central etiology. Unfortunately, a potentially lethal withdrawal syndrome can complicate its use. This is especially true when the drug is administered intrathecally. There are very few cases of baclofen withdrawal leading to reversible cardiomyopathy described in the literature. The authors present a patient with a history of chronic intrathecal baclofen use who, in the setting of acute baclofen withdrawal, develops laboratory, electrocardiogram, and echocardiogram abnormalities consistent with cardiomyopathy. Upon reinstitution of intrathecal baclofen, the cardiomyopathy and associated abnormalities quickly resolve. Although rare, it is crucial to be aware of this reversible cardiomyopathy to ensure its prompt diagnosis and treatment.

  12. Two cases of apical ballooning syndrome masking apical hypertrophic cardiomyopathy.

    Science.gov (United States)

    Roy, Ranjini Raina; Hakim, Fayaz A; Hurst, R Todd; Simper, David; Appleton, Christopher P

    2014-04-01

    Apical akinesis and dilation in the absence of obstructive coronary artery disease is a typical feature of stress-induced (takotsubo) cardiomyopathy, whereas apical hypertrophy is seen in apical-variant hypertrophic cardiomyopathy. We report the cases of 2 patients who presented with takotsubo cardiomyopathy and were subsequently found to have apical-variant hypertrophic cardiomyopathy, after the apical ballooning from the takotsubo cardiomyopathy had resolved. The first patient, a 43-year-old woman with a history of alcohol abuse, presented with shortness of breath, electrocardiographic and echocardiographic features consistent with takotsubo cardiomyopathy, and no significant coronary artery disease. An echocardiogram 2 weeks later revealed a normal left ventricular ejection fraction and newly apparent apical hypertrophy. The 2nd patient, a 70-year-old woman with pancreatitis, presented with chest pain, apical akinesis, and a left ventricular ejection fraction of 0.39, consistent with takotsubo cardiomyopathy. One month later, her left ventricular ejection fraction was normal; however, hypertrophy of the left ventricular apex was newly noted. To our knowledge, these are the first reported cases in which apical-variant hypertrophic cardiomyopathy was masked by apical ballooning from stress-induced cardiomyopathy.

  13. The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

    Science.gov (United States)

    Amornwichet, Napapat; Oike, Takahiro; Shibata, Atsushi; Nirodi, Chaitanya S; Ogiwara, Hideaki; Makino, Haruhiko; Kimura, Yuka; Hirota, Yuka; Isono, Mayu; Yoshida, Yukari; Ohno, Tatsuya; Kohno, Takashi; Nakano, Takashi

    2015-06-11

    Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently mutated in NSCLC, and the relative biological effectiveness (RBE) of carbon-ion beams over X-rays. The assessment of 15 NSCLC lines of different EGFR/KRAS mutational status and that of isogenic NSCLC lines expressing wild-type or mutant EGFR revealed that EGFR-mutant NSCLC cells, but not KRAS-mutant cells, show low RBE. This was attributable to (i) the high X-ray sensitivity of EGFR-mutant cells, since EGFR mutation is associated with a defect in non-homologous end joining, a major pathway for DNA double-strand break (DSB) repair, and (ii) the strong cell-killing effect of carbon-ion beams due to poor repair of carbon-ion beam-induced DSBs regardless of EGFR mutation status. These data highlight the potential of EGFR mutation status as a predictor of response to CIRT, i.e., CIRT may show a high therapeutic index in EGFR mutation-negative NSCLC.

  14. The G1613A mutation in the HBV genome affects HBeAg expression and viral replication through altered core promote