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Sample records for monogenic disease mutations

  1. Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic mendelian diseases by exome sequencing.

    Directory of Open Access Journals (Sweden)

    Degui Zhi

    Full Text Available Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work.

  2. Monogenic Autoinflammatory Diseases: Concept And Clinical Manifestations

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    De Jesus, Adriana Almeida; Goldbach-Mansky, Raphaela

    2013-01-01

    The objectives of this review are to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary “periodic fever syndromes”, familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) 6. very rare conditions presenting with autoinflammation and immunodeficiency. PMID:23711932

  3. Monogenic autoinflammatory diseases: concept and clinical manifestations.

    Science.gov (United States)

    Almeida de Jesus, Adriana; Goldbach-Mansky, Raphaela

    2013-06-01

    The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.

  4. Clinical, Biological, and Imaging Features of Monogenic Alzheimer’s Disease

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    Andrea Pilotto

    2013-01-01

    Full Text Available The discovery of monogenic forms of Alzheimer’s Disease (AD associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/Aβ ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.

  5. Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

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    Bersano, Anna; Markus, Hugh Stephen; Quaglini, Silvana; Arbustini, Eloisa; Lanfranconi, Silvia; Micieli, Giuseppe; Boncoraglio, Giorgio B; Taroni, Franco; Gellera, Cinzia; Baratta, Silvia; Penco, Silvana; Mosca, Lorena; Grasso, Maurizia; Carrera, Paola; Ferrari, Maurizio; Cereda, Cristina; Grieco, Gaetano; Corti, Stefania; Ronchi, Dario; Bassi, Maria Teresa; Obici, Laura; Parati, Eugenio A; Pezzini, Alessando; De Lodovici, Maria Luisa; Verrengia, Elena P; Bono, Giorgio; Mazucchelli, Francesca; Zarcone, Davide; Calloni, Maria Vittoria; Perrone, Patrizia; Bordo, Bianca Maria; Colombo, Antonio; Padovani, Alessandro; Cavallini, Anna; Beretta, Simone; Ferrarese, Carlo; Motto, Cristina; Agostoni, Elio; Molini, Graziella; Sasanelli, Francesco; Corato, Manuel; Marcheselli, Simona; Sessa, Maria; Comi, Giancarlo; Checcarelli, Nicoletta; Guidotti, Mario; Uccellini, Davide; Capitani, Erminio; Tancredi, Lucia; Arnaboldi, Marco; Incorvaia, Barbara; Tadeo, Carlo Sebastiano; Fusi, Laura; Grampa, Giampiero; Merlini, Giampaolo; Trobia, Nadia; Comi, Giacomo Pietro; Braga, Massimiliano; Vitali, Paolo; Baron, Pierluigi; Grond-Ginsbach, Caspar; Candelise, Livia

    2016-07-01

    Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of genetic analysis. In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series. © 2016 American Heart Association, Inc.

  6. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

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    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects.

  7. Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

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    Elisa Grillo

    Full Text Available Rett syndrome (OMIM#312750 is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005 mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome, while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant. In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

  8. Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

    Science.gov (United States)

    Grillo, Elisa; Lo Rizzo, Caterina; Bianciardi, Laura; Bizzarri, Veronica; Baldassarri, Margherita; Spiga, Ottavia; Furini, Simone; De Felice, Claudio; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Ciccoli, Lucia; Mencarelli, Maria Antonietta; Hayek, Joussef; Meloni, Ilaria; Ariani, Francesca; Mari, Francesca; Renieri, Alessandra

    2013-01-01

    Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

  9. Cost-effectiveness of DNA-diagnosis for four monogenic diseases

    NARCIS (Netherlands)

    A.A.P.M. van der Riet; B.A. van Hout (Ben); F.F.H. Rutten (Frans)

    1994-01-01

    textabstractIn this paper the costs and benefits associated with DNA-diagnosis of individuals who are at risk of a child with a monogenic disease and who seek genetic counselling because of their reproductive plans are predicted under various assumptions using a mathematical model. Four monogenic

  10. Cost-effectiveness of DNA-diagnosis for four monogenic diseases

    NARCIS (Netherlands)

    A.A.P.M. van der Riet; B.A. van Hout (Ben); F.F.H. Rutten (Frans)

    1994-01-01

    textabstractIn this paper the costs and benefits associated with DNA-diagnosis of individuals who are at risk of a child with a monogenic disease and who seek genetic counselling because of their reproductive plans are predicted under various assumptions using a mathematical model. Four monogenic

  11. Clinical genetics in 2014: New monogenic diseases span the immunological disease continuum.

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    Savic, Sinisa; McDermott, Michael F

    2015-02-01

    Three monogenic diseases, with features of both autoinflammation and autoimmunity, were described for the first time in 2014. As well as providing insights into the molecular basis of several rare immunological disorders, the discoveries have implications for their diagnosis and treatment.

  12. Depression and quality of life in monogenic compared to idiopathic, early-onset Parkinson's disease.

    NARCIS (Netherlands)

    Kasten, M.; Kertelge, L.; Tadic, V.; Bruggemann, N.; Schmidt, A.; Vegt, J.P.M. van der; Siebner, H.; Buhmann, C.; Lencer, R.; Kumar, K.R.; Lohmann, K.; Hagenah, J.; Klein, C.

    2012-01-01

    Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comp

  13. Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease

    DEFF Research Database (Denmark)

    Kertelge, Lena; Brüggemann, Norbert; Schmidt, Alexander

    2010-01-01

    Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both def...

  14. Gene-specific function prediction for non-synonymous mutations in monogenic diabetes genes.

    Directory of Open Access Journals (Sweden)

    Quan Li

    Full Text Available The rapid progress of genomic technologies has been providing new opportunities to address the need of maturity-onset diabetes of the young (MODY molecular diagnosis. However, whether a new mutation causes MODY can be questionable. A number of in silico methods have been developed to predict functional effects of rare human mutations. The purpose of this study is to compare the performance of different bioinformatics methods in the functional prediction of nonsynonymous mutations in each MODY gene, and provides reference matrices to assist the molecular diagnosis of MODY. Our study showed that the prediction scores by different methods of the diabetes mutations were highly correlated, but were more complimentary than replacement to each other. The available in silico methods for the prediction of diabetes mutations had varied performances across different genes. Applying gene-specific thresholds defined by this study may be able to increase the performance of in silico prediction of disease-causing mutations.

  15. [Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary].

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    Jermendy, György; Balogh, István; Gaál, Zsolt

    2016-03-20

    The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.

  16. Human induced pluripotent stem cells for monogenic disease modelling and therapy

    Institute of Scientific and Technical Information of China (English)

    Paola; Spitalieri; Valentina; Rosa; Talarico; Michela; Murdocca; Giuseppe; Novelli; Federica; Sangiuolo

    2016-01-01

    Recent and advanced protocols are now available toderive human induced pluripotent stem cells(hi PSCs)from patients affected by genetic diseases.No curative treatments are available for many of these diseases;thus,hiP SCs represent a major impact on patient’health.hiP SCs represent a valid model for the in vitro study of monogenic diseases,together with a better comprehension of the pathogenic mechanisms of the pathology,for both cell and gene therapy protocol applications.Moreover,these pluripotent cells represent a good opportunity to test innovative pharmacological treatments focused on evaluating the efficacy and toxicity of novel drugs.Today,innovative gene therapy protocols,especially gene editingbased,are being developed,allowing the use of these cells not only as in vitro disease models but also as an unlimited source of cells useful for tissue regeneration and regenerative medicine,eluding ethical and immune rejection problems.In this review,we will provide an upto-date of modelling monogenic disease by using hiP SCs and the ultimate applications of these in vitro models for cell therapy.We consider and summarize some peculiar aspects such as the type of parental cells used for reprogramming,the methods currently used to induce the transcription of the reprogramming factors,and the type of iP SC-derived differentiated cells,relating them to the genetic basis of diseases and to their inheritance model.

  17. Monogenic Diabetes

    Science.gov (United States)

    ... form of monogenic diabetes? • What type of monogenic diabetes does my child (or do I) have? • What are the treatment options? • What are the advantages and disadvantages of each treatment option? • Should I see a diabetes educator? • Should I see an endocrinologist? Resources • Find- ...

  18. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

    Science.gov (United States)

    Flanagan, Sarah E; Haapaniemi, Emma; Russell, Mark A; Caswell, Richard; Lango Allen, Hana; De Franco, Elisa; McDonald, Timothy J; Rajala, Hanna; Ramelius, Anita; Barton, John; Heiskanen, Kaarina; Heiskanen-Kosma, Tarja; Kajosaari, Merja; Murphy, Nuala P; Milenkovic, Tatjana; Seppänen, Mikko; Lernmark, Åke; Mustjoki, Satu; Otonkoski, Timo; Kere, Juha; Morgan, Noel G; Ellard, Sian; Hattersley, Andrew T

    2014-08-01

    Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

  19. Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies

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    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Katherine; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; Baghdadi, Jamila El; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri G; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; Ikincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2016-01-01

    Background T follicular helper (Tfh) cells underpin T-cell dependent humoral immunity and the success of most vaccines. Tfh cells also contribute to human immune disorders such as autoimmunity, immunodeficiency and malignancy. Understanding the molecular requirements for the generation and function of Tfh cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunological abnormalities. Objective To determine the signaling pathways and cellular interactions required for the development and function of Tfh cells in humans. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating Tfh (cTfh) cell subsets, memory B cells and serum Ig levels were quantified and functionally assessed in healthy controls as well as patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS or BTK. Results Loss-of function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS or BTK reduced cTfh frequencies. STAT3, IL21/R LOF and STAT1 gain-of function mutations skewed cTfh differentiation towards a phenotype characterized by over-expression of IFNγ and programmed death -1 (PD-1). IFNγ inhibited cTfh function in vitro and in vivo, corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1 and IL12RB1 LOF mutations. Conclusion Specific mutations impact the quantity and quality of cTfh cells, highlighting the need to assess Tfh cells in patients by multiple criteria, including phenotype and function. Furthermore, IFNγ functions in vivo to restrain Tfh-induced B cell differentiation. These findings shed new light on Tfh biology and the integrated signaling pathways required for their generation, maintenance and effector function, and explain compromised humoral immunity in some PIDs. PMID:26162572

  20. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

    Science.gov (United States)

    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Kathryn; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri Giang; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; İkincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2015-10-01

    Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised

  1. Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children.

    Science.gov (United States)

    Ozen, Seza; Demirkaya, Erkan; Amaryan, Gayane; Koné-Paut, Isabelle; Polat, Adem; Woo, Pat; Uziel, Yosef; Modesto, Consuelo; Finetti, Martina; Quartier, Pierre; Papadopoulou-Alataki, Efimia; Al-Mayouf, Sulaiman M; Fabio, Giovanna; Gallizzi, Romina; Cantarini, Luca; Frenkel, Joost; Nielsen, Susan; Hofer, Michael; Insalaco, Antonella; Acikel, C; Ozdogan, Huri; Martini, Alberto; Ruperto, Nicolino; Gattorno, Marco

    2014-04-01

    Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (pMediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.

  2. Depression and quality of life in monogenic compared to idiopathic, early-onset Parkinson's disease

    DEFF Research Database (Denmark)

    Kasten, Meike; Kertelge, Lena; Tadic, Vera

    2012-01-01

    , monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further...... optimized....

  3. Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-Onset Diabetes of the Young

    Science.gov (United States)

    ... Diabetes Monogenic Forms of Diabetes Monogenic Forms of Diabetes The most common forms of diabetes, type 1 ... is inherited from each parent. Monogenic Forms of Diabetes Some rare forms of diabetes result from mutations ...

  4. Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study.

    Science.gov (United States)

    Dreesen, Jos; Destouni, Aspasia; Kourlaba, Georgia; Degn, Birte; Mette, Wulf Christensen; Carvalho, Filipa; Moutou, Celine; Sengupta, Sioban; Dhanjal, Seema; Renwick, Pamela; Davies, Steven; Kanavakis, Emmanouel; Harton, Gary; Traeger-Synodinos, Joanne

    2014-08-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders currently involves polymerase chain reaction (PCR)-based methods, which must be robust, sensitive and highly accurate, precluding misdiagnosis. Twelve adverse misdiagnoses reported to the ESHRE PGD-Consortium are likely an underestimate. This retrospective study, involving six PGD centres, assessed the validity of PCR-based PGD through reanalysis of untransferred embryos from monogenic-PGD cycles. Data were collected on the genotype concordance at PGD and follow-up from 940 untransferred embryos, including details on the parameters of PGD cycles: category of monogenic disease, embryo morphology, embryo biopsy and genotype assay strategy. To determine the validity of PCR-based PGD, the sensitivity (Se), specificity (Sp) and diagnostic accuracy were calculated. Stratified analyses were also conducted to assess the influence of the parameters above on the validity of PCR-based PGD. The analysis of overall data showed that 93.7% of embryos had been correctly classified at the time of PGD, with Se of 99.2% and Sp of 80.9%. The stratified analyses found that diagnostic accuracy is statistically significantly higher when PGD is performed on two cells versus one cell (P=0.001). Se was significantly higher when multiplex protocols versus singleplex protocols were applied (P=0.005), as well as for PGD applied on cells from good compared with poor morphology embryos (P=0.032). Morphology, however, did not affect diagnostic accuracy. Multiplex PCR-based methods on one cell, are as robust as those on two cells regarding false negative rate, which is the most important criteria for clinical PGD applications. Overall, this study demonstrates the validity, robustness and high diagnostic value of PCR-based PGD.

  5. Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model

    DEFF Research Database (Denmark)

    Gao, R.; Liu, Y. X.; Gjesing, A. P.;

    2014-01-01

    Background: Monogenic diabetes is a genetic disease often caused by mutations in genes involved in beta-cell function. Correct sub-categorization of the disease is a prerequisite for appropriate treatment and genetic counseling. Target-region capture sequencing is a combination of genomic region...... diabetes as a study-model. Results: The performance of the assay was evaluated in 70 patients carrying known disease causing mutations previously identified in HNF4A, GCK, HNF1A, HNF1B, INS, or KCNJ11. Target regions with a less than 20-fold sequencing depth were either introns or UTRs. When only...... of monogenic diabetes....

  6. Disease-modifying genes and monogenic disorders: experience in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Gallati S

    2014-07-01

    Full Text Available Sabina Gallati Division of Human Genetics, Department of Pediatrics, and Department of Clinical Research, Inselspital, University of Berne, Berne, Switzerland Abstract: The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene. Keywords: modifier genes, cystic fibrosis, genome wide association studies, candidate gene approach, genotype, phenotype

  7. Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model

    DEFF Research Database (Denmark)

    Gao, Rui; Liu, Yanxia; Gjesing, Anette Marianne Prior;

    2014-01-01

    Monogenic diabetes is a genetic disease often caused by mutations in genes involved in beta-cell function. Correct sub-categorization of the disease is a prerequisite for appropriate treatment and genetic counseling. Target-region capture sequencing is a combination of genomic region enrichment...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  9. Monogenic diabetes mellitus in Norway

    Directory of Open Access Journals (Sweden)

    Oddmund Søvika

    2013-06-01

    Full Text Available Here, we review data on monogenic diabetes mellitus in Norway based on the Norwegian MODY Registry at Haukeland University Hospital, Bergen. This registry comprises established or suspected cases of maturity-onset diabetes of the young (MODY referred to our laboratory for genetic testing. We also present data on neonatal diabetes, another group of monogenic diabetes. To date, we have genetically diagnosed nearly 500 MODY cases in Norway. Mutations in the HNF1A gene (MODY3 were detected in about 50% of families with clinical MODY. GCK-MODY (MODY2 was the second most prevalent type, but may be underreported. We have also found mutations in the monogenic genes ABCC8, CEL, HNF1B, HNF4A, INS, KCNJ11 and NEUROD1. Based on genetic screening in the Norwegian MODY Registry and HUNT2, we estimate the number of MODY cases in Norway to be at least 2500-5000. Founder effects may determine the geographical distribution of MODY mutations in Norway. The molecular genetic testing of MODY and neonatal diabetes is mandatory for correct diagnosis and prognosis as well as choice of therapy

  10. Monogenic diabetes and pregnancy

    OpenAIRE

    Murphy, Rinki

    2015-01-01

    Monogenic diabetes is frequently mistakenly diagnosed as either type 1 or type 2 diabetes, yet accounts for approximately 1–2% of diabetes. Identifying monogenic forms of diabetes has practical implications for specific therapy, screening of family members and genetic counselling. The most common forms of monogenic diabetes are due to glucokinase (GCK), hepatocyte nuclear factor (HNF)-1A and HNF-4A, HNF-1B, m.3243A>G gene defects. Practical aspects of their recognition, diagnosis and manageme...

  11. Phenotypic heterogeneity of monogenic frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Alberto eBenussi

    2015-09-01

    Full Text Available Frontotemporal dementia (FTD is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e. the behavioral variant of FTD (bvFTD, the agrammatic variant of Primary Progressive Aphasia (avPPA and the semantic variant of PPA (svPPA. Some patients have an associated movement disorder, either parkinsonism, as in Progressive Supranuclear Palsy (PSP and Corticobasal Syndrome (CBS, or motor neuron disease (FTD-MND. A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal dominant inheritance. Genetic studies have identified several genes associated to monogenic FTD: microtubule-associated protein tau (MAPT, progranulin (GRN, TAR DNA-binding protein 43 (TARBDP, valosin-containing protein (VCP, charged multivesicular body protein 2B (CHMP2B, fused in sarcoma (FUS and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72 (C9orf72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

  12. The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes

    Science.gov (United States)

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne AL; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-01-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycaemia and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W) but functional studies have shown inconsistent results, there is lack of co-segregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI: 9.79 – 125, P=2x10-21) for diabetes in our MODY cohort compared to controls. p.R114W heterozygotes do not have the increased birth weight of patients with other HNF4A mutations (3476g vs. 4147g, P=0.0004) and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P=0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 compared to 71% for other HNF4A mutations. We re-define p.R114W as a pathogenic mutation causing a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. PMID:27486234

  13. The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

    Science.gov (United States)

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne A L; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-10-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

  14. Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

    NARCIS (Netherlands)

    Jannot, Anne-Sophie; Amiel, Jeanne; Pelet, Anna; Lantieri, Francesca; Fernandez, Raquel M.; Verheij, Joke B. G. M.; Garcia-Barcelo, Merce; Arnold, Stacey; Ceccherini, Isabella; Borrego, Salud; Hofstra, Robert M. W.; Tam, Paul K. H.; Munnich, Arnold; Chakravarti, Aravinda; Clerget-Darpoux, Francoise; Lyonnet, Stanislas

    2012-01-01

    Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations wit

  15. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes

    DEFF Research Database (Denmark)

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders;

    2009-01-01

    of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families...... negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls......). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely...

  16. Animal models of monogenic migraine.

    Science.gov (United States)

    Chen, Shih-Pin; Tolner, Else A; Eikermann-Haerter, Katharina

    2016-06-01

    Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine. © International Headache Society 2016.

  17. Generation of Human Induced Pluripotent Stem Cells from Extraembryonic Tissues of Fetuses Affected by Monogenic Diseases.

    Science.gov (United States)

    Spitalieri, Paola; Talarico, Rosa V; Botta, Annalisa; Murdocca, Michela; D'Apice, Maria Rosaria; Orlandi, Augusto; Giardina, Emiliano; Santoro, Massimo; Brancati, Francesco; Novelli, Giuseppe; Sangiuolo, Federica

    2015-08-01

    The generation of human induced pluripotent stem cells (hiPSCs) derived from an autologous extraembryonic fetal source is an innovative personalized regenerative technology that can transform own-self cells into embryonic stem-like ones. These cells are regarded as a promising candidate for cell-based therapy, as well as an ideal target for disease modeling and drug discovery. Thus, hiPSCs enable researchers to undertake studies for treating diseases or for future applications of in utero therapy. We used a polycistronic lentiviral vector (hSTEMCCA-loxP) encoding OCT4, SOX2, KLF4, and cMYC genes and containing loxP sites, excisible by Cre recombinase, to reprogram patient-specific fetal cells derived from prenatal diagnosis for several genetic disorders, such as myotonic dystrophy type 1 (DM1), β-thalassemia (β-Thal), lymphedema-distichiasis syndrome (LDS), spinal muscular atrophy (SMA), cystic fibrosis (CF), as well as from wild-type (WT) fetal cells. Because cell types tested to create hiPSCs influence both the reprogramming process efficiency and the kinetics, we used chorionic villus (CV) and amniotic fluid (AF) cells, demonstrating how they represent an ideal cell resource for a more efficient generation of hiPSCs. The successful reprogramming of both CV and AF cells into hiPSCs was confirmed by specific morphological, molecular, and immunocytochemical markers and also by their teratogenic potential when inoculated in vivo. We further demonstrated the stability of reprogrammed cells over 10 and more passages and their capability to differentiate into the three embryonic germ layers, as well as into neural cells. These data suggest that hiPSCs-CV/AF can be considered a valid cellular model to accomplish pathogenesis studies and therapeutic applications.

  18. Biological Treatments: New Weapons in the Management of Monogenic Autoinflammatory Disorders

    Directory of Open Access Journals (Sweden)

    Antonio Vitale

    2013-01-01

    Full Text Available Treatment of monogenic autoinflammatory disorders, an expanding group of hereditary diseases characterized by apparently unprovoked recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells, has been revolutionized by the discovery that several of these conditions are caused by mutations in proteins involved in the mechanisms of innate immune response, including components of the inflammasome, cytokine receptors, receptor antagonists, and oversecretion of a network of proinflammatory molecules. Aim of this review is to synthesize the current experience and the most recent evidences about the therapeutic approach with biologic drugs in pediatric and adult patients with monogenic autoinflammatory disorders.

  19. Monogenic human obesity syndromes

    National Research Council Canada - National Science Library

    Farooqi, I S; O'Rahilly, S

    2004-01-01

    .... This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

  20. Long-lasting response to oral therapy in a young male with monogenic diabetes as part of HNF1B-related disease

    Directory of Open Access Journals (Sweden)

    Elena Carrillo

    2017-06-01

    Full Text Available Mutations in hepatocyte nuclear factor 1β gene (HNF1B are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5 and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations.

  1. Monogenic human obesity.

    Science.gov (United States)

    Farooqi, I Sadaf

    2008-01-01

    We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

  2. Management of suspected monogenic lung fibrosis in a specialised centre

    Directory of Open Access Journals (Sweden)

    Raphael Borie

    2017-04-01

    Full Text Available At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis. Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed. The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

  3. Insulin resistance syndromes of monogenic mutations%单基因突变所致的胰岛素抵抗综合征

    Institute of Scientific and Technical Information of China (English)

    江珊; 贾伟平

    2009-01-01

    Several insulin resistance syndromes, such as severe insulin resistance syndrome caused by mutations of insulin receptor gene and lipodystrophy caused by mutations of lamin gene, have been characterized clinically. The gene mutations, pathogenesis and clinical features of these monogenie diseases were reviewed in this article.%临床上存在多种由单基因突变所导致的胰岛素抵抗综合征,如胰岛素受体基因突变造成的严重胰岛素抵抗综合征,核纤层蛋白(LMNA)基因突变导致的脂肪营养不良综合征等,以下将对这些疾病的临床特点、突变基因及发病机制作一综述.

  4. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

    Science.gov (United States)

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

    2015-01-01

    Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes

  5. G protein-coupled receptor mutations and human genetic disease.

    Science.gov (United States)

    Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

    2014-01-01

    Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

  6. Monogenic human obesity syndromes.

    Science.gov (United States)

    Farooqi, I S

    2006-01-01

    Over the past decade we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes, and the novel physiological pathways revealed by those genetic discoveries. Others and we have also recently identified several single gene defects causing severe human obesity. Many of these defects have been in molecules identical or similar to those identified as a cause of obesity in rodents. I will review the human monogenic obesity syndromes that have been characterised to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

  7. Monogenic obesity in humans.

    Science.gov (United States)

    Farooqi, I Sadaf; O'Rahilly, Stephen

    2005-01-01

    Until relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.

  8. Pathogenic mutations in Parkinson disease.

    Science.gov (United States)

    Tan, Eng-King; Skipper, Lisa M

    2007-07-01

    Parkinson disease (PD; Parkinson's) is the second most common neurodegenerative disease, characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies. Increasing evidence suggests that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system (UPS) dysfunction may represent the principal molecular pathways that commonly underlie the pathogenesis. The relative role of genetic and environmental factors has been the focus of research and debate. The recent discovery of a number of disease-causing genes (SNCA, Parkin/PARK2, UCHL1, PINK1, DJ1/PARK7, and LRRK2) in familial and sporadic forms of PD has provided considerable insights into the pathophysiology of this complex disorder. The frequency of these gene mutations may vary according to ethnicity and to the specific gene. A gene dosage effect is observed in some cases, and the phenotype of some of the mutation carriers closely resembles typical PD. Penetrance of some of the recurrent mutations is incomplete and may vary with age. Further research to unravel the etiopathology could identify biochemical or genetic markers for potential neuroprotective trials. (c) 2007 Wiley-Liss, Inc.

  9. DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.

    Science.gov (United States)

    Olgiati, Simone; Quadri, Marialuisa; Fang, Mingyan; Rood, Janneke P M A; Saute, Jonas A; Chien, Hsin Fen; Bouwkamp, Christian G; Graafland, Josja; Minneboo, Michelle; Breedveld, Guido J; Zhang, Jianguo; Verheijen, Frans W; Boon, Agnita J W; Kievit, Anneke J A; Jardim, Laura Bannach; Mandemakers, Wim; Barbosa, Egberto Reis; Rieder, Carlos R M; Leenders, Klaus L; Wang, Jun; Bonifati, Vincenzo

    2016-02-01

    DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. © 2016 American Neurological Association.

  10. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.

    Science.gov (United States)

    Johansen, Christopher T; Dubé, Joseph B; Loyzer, Melissa N; MacDonald, Austin; Carter, David E; McIntyre, Adam D; Cao, Henian; Wang, Jian; Robinson, John F; Hegele, Robert A

    2014-04-01

    We report the design of a targeted resequencing panel for monogenic dyslipidemias, LipidSeq, for the purpose of replacing Sanger sequencing in the clinical detection of dyslipidemia-causing variants. We also evaluate the performance of the LipidSeq approach versus Sanger sequencing in 84 patients with a range of phenotypes including extreme blood lipid concentrations as well as additional dyslipidemias and related metabolic disorders. The panel performs well, with high concordance (95.2%) in samples with known mutations based on Sanger sequencing and a high detection rate (57.9%) of mutations likely to be causative for disease in samples not previously sequenced. Clinical implementation of LipidSeq has the potential to aid in the molecular diagnosis of patients with monogenic dyslipidemias with a high degree of speed and accuracy and at lower cost than either Sanger sequencing or whole exome sequencing. Furthermore, LipidSeq will help to provide a more focused picture of monogenic and polygenic contributors that underlie dyslipidemia while excluding the discovery of incidental pathogenic clinically actionable variants in nonmetabolism-related genes, such as oncogenes, that would otherwise be identified by a whole exome approach, thus minimizing potential ethical issues.

  11. Early onset (childhood) monogenic neuropathies.

    Science.gov (United States)

    Landrieu, Pierre; Baets, Jonathan

    2013-01-01

    Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent 40 genes with various biological functions have been found to be responsible for primary HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait, and some for various types of transmission.

  12. Scalp fibroblasts have a shared expression profile in monogenic craniosynostosis

    OpenAIRE

    2009-01-01

    Background Craniosynostosis can be caused by both genetic and environmental factors, the relative contributions of which vary between patients. Genetic testing identifies a pathogenic mutation or chromosomal abnormality in ∼21% of cases, but it is likely that further causative mutations remain to be discovered. Objective To identify a shared signature of genetically determined craniosynostosis by comparing the expression patterns in three monogenic syndromes with a control group of patients w...

  13. Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus.

    Science.gov (United States)

    Kim, Hanna; Sanchez, Gina A Montealegre; Goldbach-Mansky, Raphaela

    2016-10-01

    Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of "autoinflammatory" and "autoimmune" interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

  14. Mutational analysis of TARDBP in Parkinson's disease

    NARCIS (Netherlands)

    Blitterswijk, M. van; Es, M.A. van; Verbaan, D.; Hilten, J.J. van; Scheffer, H.; Warrenburg, B.P.C. van de; Veldink, J.H.; Berg, L.H. van den

    2013-01-01

    Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson's dise

  15. Monogenic Functions in Conformal Geometry

    Directory of Open Access Journals (Sweden)

    Michael Eastwood

    2007-08-01

    Full Text Available Monogenic functions are basic to Clifford analysis. On Euclidean space they are defined as smooth functions with values in the corresponding Clifford algebra satisfying a certain system of first order differential equations, usually referred to as the Dirac equation. There are two equally natural extensions of these equations to a Riemannian spin manifold only one of which is conformally invariant. We present a straightforward exposition.

  16. Monogenic diabetes syndromes

    DEFF Research Database (Denmark)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers

    2017-01-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1...... for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated...... diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development...

  17. Identification of six new Gaucher disease mutations

    Energy Technology Data Exchange (ETDEWEB)

    Beutler, E.; Gelbart, T.; West, C. (Scripps Research Institute, La Jolla, CA (United States))

    1993-01-01

    The four most common mutations account for 97% of the Gaucher disease-producing alleles in Jewish patients and 75% of the alleles in non-Jewish patients. Although at least 15 other mutations and some examples of gene conversion and/or fusion genes have been described, a number of mutations remain unidentified. We have now identified six new mutations, a deletion of a C at the 72 position of the cDNA, a 481C[yields]T mutation (122p[sup Gly[yields]Ser]), a 751T [yields] C (212 [sup Tyr[yields]His]), a 1549G [yields] A (478[sup Gly[yields]Ser]), a 1604G [yields] A (496 [sup Arg[yields]His]), and a 55-bp deletion. All but one of these were found in single families. The 1604A mutation, however, was observed in four unrelated individuals. 7 refs., 2 tabs.

  18. Inherited retinal diseases in dogs: advances in gene/mutation discovery.

    Science.gov (United States)

    Miyadera, Keiko

    1. Inherited retinal diseases (RDs) are vision-threatening conditions affecting humans as well as many domestic animals. Through many years of clinical studies of the domestic dog population, a wide array of RDs has been phenotypically characterized. Extensive effort to map the causative gene and to identify the underlying mutation followed. Through candidate gene, linkage analysis, genome-wide association studies, and more recently, by means of next-generation sequencing, as many as 31 mutations in 24 genes have been identified as the underlying cause for canine RDs. Most of these genes have been associated with human RDs providing opportunities to study their roles in the disease pathogenesis and in normal visual function. The canine model has also contributed in developing new treatments such as gene therapy which has been clinically applied to human patients. Meanwhile, with increasing knowledge of the molecular architecture of RDs in different subpopulations of dogs, the conventional understanding of RDs as a simple monogenic disease is beginning to change. Emerging evidence of modifiers that alters the disease outcome is complicating the interpretation of DNA tests. In this review, advances in the gene/mutation discovery approaches and the emerging genetic complexity of canine RDs are discussed.

  19. Polar Body Diagnosis for Monogenic Disorders in Regensburg

    Directory of Open Access Journals (Sweden)

    Hehr A

    2009-01-01

    Full Text Available Polar body diagnosis (PBD is currently the only legal option to perform a preimplantation genetic diagnosis (PGD in Germany. The results of PBD for monogenic disorders performed at our center in Regensburg since 2001 are reported. Our data show that PBD can be safely performed on first and second polar bodies within the tight timeframe provided by the German Embryo Protection Act. It requires extensive interdisciplinary counseling of the couple, good and close cooperation between the IVF center and the genetics laboratory as well as meticulous development, validation, and performance of the individual genetic assay. Provided that these prerequisites are met, PBD can today be an acceptable option for German couples at high risk for a particular monogenic disorder in their offspring. Main arguments pro PBD usually include a decline of both conventional prenatal diagnosis and subsequently induced abortion of an affected offspring as well as the birth of an affected child. Major disadvantages of PBD in this situation include the requirement of assisted reproduction for couples in the absence of any obvious fertility problems with their immanent obstacles like pregnancy rate, remaining recurrence risk for the particular monogenic disorder, costs etc. Furthermore, PBD can only be offered for mutations, which are passed on by the female partner with her nuclear DNA (autosomal dominant, X-chromosomal as well as autosomal recessive traits. For heterozygous female mutation carriers of autosomal recessive or X-chromosomal inherited disorders PBD requires discarding all oocytes carrying the mutation, although they may result in healthy offspring if the sperm does not carry the mutation or the Y chromosome, respectively. Finally, both PBD as well as PGD can substantially reduce the recurrence risk for a particular monogenic disorder but not diminish it entirely. Therefore, conventional prenatal diagnosis (PND should still be offered and in fact has been

  20. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    Directory of Open Access Journals (Sweden)

    de Beaufort Carine

    2010-09-01

    Full Text Available Abstract Background To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative for pancreatic autoantibodies [islet cell autoantibodies(ICA, glutamic acid decarboxylase antibodies (GADA and insulinoma-associated antigen-2 antibodies (IA-2A]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. Materials and methods In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. Results Twenty-four patients (9.1% tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002, lower blood glucose (P = 0.004, received less insulin (P = 0.05 and had lower HbA1c (P = 0.02 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8 by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. Conclusion GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

  1. Metabolic dysregulation in monogenic disorders and cancer - finding method in madness.

    Science.gov (United States)

    Erez, Ayelet; DeBerardinis, Ralph J

    2015-07-01

    Cancer is a prime example of a disease process in which carcinogenic and metabolic changes are intertwined to promote cell survival and growth. One approach to unravel this complex relationship is by studying rare, monogenic disorders caused by mutations in genes encoding metabolic enzymes or regulators. There are hundreds of these diseases, most of which manifest in childhood and are collectively termed 'inborn errors of metabolism' (IEMs). Several IEMs demonstrate the consequences of chronic, systemic loss of a particular metabolic activity that can result in malignancy. In this Opinion article, we present a conceptual categorization of IEMs associated with cancer and discuss how assessment of these rare diseases might inform us about the biological foundations of common types of cancer and opportunities for cancer diagnosis and therapy.

  2. Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease.

    Science.gov (United States)

    Jannot, Anne-Sophie; Amiel, Jeanne; Pelet, Anna; Lantieri, Francesca; Fernandez, Raquel M; Verheij, Joke B G M; Garcia-Barcelo, Merce; Arnold, Stacey; Ceccherini, Isabella; Borrego, Salud; Hofstra, Robert M W; Tam, Paul K H; Munnich, Arnold; Chakravarti, Aravinda; Clerget-Darpoux, Françoise; Lyonnet, Stanislas

    2012-09-01

    Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.

  3. Caveolin-3 Mutations in Rippling Muscle Disease

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2003-05-01

    Full Text Available Two unrelated patients with novel homozygous missense mutations (L86P and A92T in caveolin-3 gene (CAV3, presenting with a severe form of rippling muscle disease (RMD, are reported from the University of Bonn, and other centers in Germany.

  4. Mutations in connexin genes and disease.

    Science.gov (United States)

    Pfenniger, Anna; Wohlwend, Annelise; Kwak, Brenda R

    2011-01-01

    Connexins are a family of transmembrane proteins that are widely expressed in the human body. Connexins play an important role in cell-cell communication and homeostasis in various tissues by forming gap junction channels, which enable a direct passage of ions or metabolites from one cell to another. Twenty-one different connexins are expressed in humans, each having distinct expression patterns and regulation properties. Knowledge on this family of proteins can be gained by making an inventory of mutations and associated diseases in human. PubMed and other relevant databases were searched. In addition, key review articles were screened for relevant original publications. Sections of representative organs were photographed and annotated. The crucial role of connexins is highlighted by the discovery of mutations in connexin genes which cause a variety of disorders such as myelin-related diseases, skin disorders, hearing loss, congenital cataract, or more complex syndromes such as the oculodendrodigital dysplasia. This review systematically addresses current knowledge on mutations in connexin genes and disease, focusing on the correlation between genetic defects, cellular phenotypes and clinical manifestations. The review of diseases caused by mutations in connexin genes highlights the essential nature of connexin function and intercellular communication in tissue homeostasis. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

  5. Cis-regulatory mutations in human disease.

    Science.gov (United States)

    Epstein, Douglas J

    2009-07-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.

  6. Monogenic forms of systemic lupus erythematosus: new insights into SLE pathogenesis

    Directory of Open Access Journals (Sweden)

    Belot Alexandre

    2012-08-01

    Full Text Available Abstract The pathogenesis of Systemic Lupus Erythematosus (SLE is complex and remains poorly understood. Infectious triggers, genetic background, immunological abnormalities and environmental factors are all supposed to interact for the disease development. Familial SLE as well as early-onset juvenile SLE studies make it possible to identify monogenic causes of SLE. Identification of these rare inherited conditions is of great interest to understand both SLE pathogenesis and molecular human tolerance mechanisms. Complement deficiencies, genetic overproduction of interferon-α and apoptosis defects are the main situations that can lead to monogenic SLE. Here, we review the different genes involved in monogenic SLE and highlight their importance in SLE pathogenesis.

  7. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene.

    Science.gov (United States)

    Pisciotta, Livia; Fresa, Raffaele; Bellocchio, Antonella; Pino, Elisabetta; Guido, Virgilia; Cantafora, Alfredo; Di Rocco, Maja; Calandra, Sebastiano; Bertolini, Stefano

    2009-06-01

    Cholesteryl Ester Storage Disease (CESD) is a rare recessive disorder due to mutations in LIPA gene encoding the lysosomal acidic lipase (LAL). CESD patients have liver disease associated with mixed hyperlipidemia and low plasma levels of high-density lipoproteins (HDL). The aim of this study was the molecular characterization of three patients with CESD. LAL activity was measured in blood leukocytes. In two patients (twin sisters) the clinical diagnosis of CESD was made at 9 years of age, following the fortuitous discovery of elevated serum liver enzymes in apparently healthy children. They had mixed hyperlipidemia, hepatosplenomegaly, reduced LAL activity (approximately 5% of control) and heteroalleic mutations in LIPA gene coding sequence: (i) the common c.894 G>A mutation and (ii) a novel nonsense mutation c.652 C>T (p.R218X). The other patient was an 80 year-old female who for several years had been treated with simvastatin because of severe hyperlipidemia associated with low plasma HDL. In this patient the sequence of major candidate genes for monogenic hypercholesterolemia and hypoalphalipoproteinemia was negative. She was found to be a compound heterozygote for two LIPA gene mutations resulting in 5% LAL activity: (i) c.894 G>A and (ii) a novel complex insertion/deletion leading to a premature termination codon at position 82. These findings suggest that, in view of the variable severity of its phenotypic expression, CESD may sometimes be difficult to diagnose, but it should be considered in patients with severe type IIb hyperlipidemia associated with low HDL, mildly elevated serum liver enzymes and hepatomegaly.

  8. AIRE-mutations and autoimmune disease.

    Science.gov (United States)

    Bruserud, Øyvind; Oftedal, Bergithe E; Wolff, Anette B; Husebye, Eystein S

    2016-12-01

    The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Mutations that Cause Human Disease: A Computational/Experimental Approach

    Energy Technology Data Exchange (ETDEWEB)

    Beernink, P; Barsky, D; Pesavento, B

    2006-01-11

    International genome sequencing projects have produced billions of nucleotides (letters) of DNA sequence data, including the complete genome sequences of 74 organisms. These genome sequences have created many new scientific opportunities, including the ability to identify sequence variations among individuals within a species. These genetic differences, which are known as single nucleotide polymorphisms (SNPs), are particularly important in understanding the genetic basis for disease susceptibility. Since the report of the complete human genome sequence, over two million human SNPs have been identified, including a large-scale comparison of an entire chromosome from twenty individuals. Of the protein coding SNPs (cSNPs), approximately half leads to a single amino acid change in the encoded protein (non-synonymous coding SNPs). Most of these changes are functionally silent, while the remainder negatively impact the protein and sometimes cause human disease. To date, over 550 SNPs have been found to cause single locus (monogenic) diseases and many others have been associated with polygenic diseases. SNPs have been linked to specific human diseases, including late-onset Parkinson disease, autism, rheumatoid arthritis and cancer. The ability to predict accurately the effects of these SNPs on protein function would represent a major advance toward understanding these diseases. To date several attempts have been made toward predicting the effects of such mutations. The most successful of these is a computational approach called ''Sorting Intolerant From Tolerant'' (SIFT). This method uses sequence conservation among many similar proteins to predict which residues in a protein are functionally important. However, this method suffers from several limitations. First, a query sequence must have a sufficient number of relatives to infer sequence conservation. Second, this method does not make use of or provide any information on protein structure, which

  10. The Wilson disease gene: Haplotypes and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, G.R.; Roberts, E.A.; Cox, D.W. [Hospital for Sick Children, Toronto (Canada); Walshe, J.M. [Middlesex Hospital, London (United Kingdom)

    1994-09-01

    Wilson disease (WND) is an autosomal recessive defect of copper transport. The gene involved in WND, located on chromosome 13, has recently been shown to be a putative copper transporting P-type ATPase, designated ATP7B. The gene is highly similar to ATP7A, located on the X chromosome, which is defective in Menkes disease, another disorder of copper transport. We have available for study WND families from Canada (34 families), the United Kingdom (32 families), Japan (4 families), Iceland (3 families) and Hong Kong (2 families). We have utilized four highly polymorphic CA repeat markers (D13S296, D13S301, D13S314 and D13S316) surrounding the ATP7B locus to construct haplotypes in these families. Analysis indicates that there are many unique WND haplotypes not present on normal chromosomes and that there may be a large number of different WND mutations. We have screened the WND patients for mutations in the ATP7B gene. Fifty six patients, representing all of the identified haplotypes, have been screened using single strand conformational polymorphism (SSCP), followed by selective sequencing. To date, 19 mutations and 12 polymorphisms have been identified. All of the changes are nucleotide substitutions or small insertions/deletions and there is no evidence for larger deletions as seen in the similar gene on the X chromosome, ATP7A. Haplotypes of close markers and the ability to detect some of the mutations present in the gene allow for more reliable molecular diagnosis of presymptomatic sibs of WND patients. A reassessment of individuals previously diagnosed in the presymptomatic phase is now required, as we have have identified some heterozygotes who are biochemically indistinguishable from affected homozygotes. The identification of specific mutations will soon allow direct diagnosis of WND patients with a high level of certainty.

  11. Disease-associated mutations in the HSPD1 gene encoding the large subunit of the mitochondrial HSP60/HSP10 chaperonin complex

    Directory of Open Access Journals (Sweden)

    Peter Bross

    2016-08-01

    Full Text Available Heat shock protein 60 (HSP60 forms together with heat shock protein 10 (HSP10 double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and malfunction cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.

  12. Ichthyosis vulgaris: the filaggrin mutation disease.

    Science.gov (United States)

    Thyssen, J P; Godoy-Gijon, E; Elias, P M

    2013-06-01

    Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. According to the published studies presented in this review article, FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker-skinned populations. This clinical review article provides an overview of ichthyosis vulgaris epidemiology, related disorders and pathomechanisms. Not only does ichthyosis vulgaris possess a wide clinical spectrum, recent studies suggest that carriers of FLG mutations may have a generally altered risk of developing common diseases, even beyond atopic disorders. Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin-deficient skin, and epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels. When relevant, individuals should be informed about an increased risk of developing dermatitis when repeatedly or continuously exposed to nickel or irritants. Moreover, with our current knowledge, individuals with ichthyosis vulgaris should be protected against neonatal exposure to cats to prevent atopic dermatitis and should abstain from smoking to prevent asthma. Finally, they should be advised against excessive exposure to factors that decrease skin barrier functions and increase the risk of atopic dermatitis.

  13. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

    OpenAIRE

    2009-01-01

    Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matche...

  14. Monogenic Diabetes: A Diagnostic Algorithm for Clinicians

    Directory of Open Access Journals (Sweden)

    Richard W. Carroll

    2013-09-01

    Full Text Available Monogenic forms of beta cell diabetes account for approximately 1%–2% of all cases of diabetes, yet remain underdiagnosed. Overlapping clinical features with common forms of diabetes, make diagnosis challenging. A genetic diagnosis of monogenic diabetes in many cases alters therapy, affects prognosis, enables genetic counseling, and has implications for cascade screening of extended family members. We describe those types of monogenic beta cell diabetes which are recognisable by distinct clinical features and have implications for altered management; the cost effectiveness of making a genetic diagnosis in this setting; the use of complementary diagnostic tests to increase the yield among the vast majority of patients who will have commoner types of diabetes which are summarised in a clinical algorithm; and the vital role of cascade genetic testing to enhance case finding.

  15. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    DEFF Research Database (Denmark)

    Pörksen, Sven; Laborie, Lene Bjerke; Nielsen, Lotte

    2010-01-01

    BACKGROUND: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (...

  16. Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease.

    Science.gov (United States)

    Barrett, M J; Hagenah, J; Dhawan, V; Peng, S; Stanley, K; Raymond, D; Deik, A; Gross, S J; Schreiber-Agus, N; Mirelman, A; Marder, K; Ozelius, L J; Eidelberg, D; Bressman, S B; Saunders-Pullman, R

    2013-02-01

    Heterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described. To determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [(18)F]-fluorodeoxyglucose or [(18)F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations. Parkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [(18)F]-fluorodeoxyglucose (n = 3) and [(18)F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease. Both transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. The Genetics of Monogenic Frontotemporal Dementia

    Directory of Open Access Journals (Sweden)

    Leonel T. Takada

    Full Text Available ABSTRACTAround 10-15% of patients diagnosed with frontotemporal dementia (FTD have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin and C9orf72(chromosome 9 open reading frame 72 are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND can be caused by mutations in C9orf72and other genes, such as TARDBP(TAR DNA-binding protein, FUS(fused in sarcoma, UBQLN2(ubiquilin 2. Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP(valosing containing protein and other recently identified genes.

  18. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    DEFF Research Database (Denmark)

    Pörksen, Sven; Laborie, Lene; Nielsen, Lotte

    2010-01-01

    BACKGROUND:To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (I...

  19. Disease causing mutations of calcium channels.

    Science.gov (United States)

    Lorenzon, Nancy M; Beam, Kurt G

    2008-01-01

    Calcium ions play an important role in the electrical excitability of nerve and muscle, as well as serving as a critical second messenger for diverse cellular functions. As a result, mutations of genes encoding calcium channels may have subtle affects on channel function yet strongly perturb cellular behavior. This review discusses the effects of calcium channel mutations on channel function, the pathological consequences for cellular physiology, and possible links between altered channel function and disease. Many cellular functions are directly or indirectly regulated by the free cytosolic calcium concentration. Thus, calcium levels must be very tightly regulated in time and space. Intracellular calcium ions are essential second messengers and play a role in many functions including, action potential generation, neurotransmitter and hormone release, muscle contraction, neurite outgrowth, synaptogenesis, calcium-dependent gene expression, synaptic plasticity and cell death. Calcium ions that control cell activity can be supplied to the cell cytosol from two major sources: the extracellular space or intracellular stores. Voltage-gated and ligand-gated channels are the primary way in which Ca(2+) ions enter from the extracellular space. The sarcoplasm reticulum (SR) in muscle and the endoplasmic reticulum in non-muscle cells are the main intracellular Ca(2+) stores: the ryanodine receptor (RyR) and inositol-triphosphate receptor channels are the major contributors of calcium release from internal stores.

  20. Genetic and environmental factors in cardiac sodium channel disease

    NARCIS (Netherlands)

    Mizusawa, Y.

    2016-01-01

    Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT

  1. Genetic and environmental factors in cardiac sodium channel disease

    NARCIS (Netherlands)

    Mizusawa, Y.

    2016-01-01

    Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT

  2. Mutation analysis of 28 gaucher disease patients: The Australasian experience

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, B.D.; Nelson, P.V.; Robertson, E.F.; Morris, C.P. [Women`s and Children`s Hospital, North Adelaide, South Australia (Australia)

    1994-01-15

    Gaucher disease is the most common lysomal storage disease. It is an autosomal recessive disorder that results from a deficiency of {beta}-glucocerrebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacuteneuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the nonneuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. The authors consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families. 27 refs., 2 figs., 2 tabs.

  3. Molekylaer patogenese ved monogen og polygen fedme

    DEFF Research Database (Denmark)

    Larsen, Philip J; Echwald, Søren Morgenthaler; Sørensen, Thorkild I A

    2006-01-01

    During the last few years, studies of the molecular pathogenesis of obesity both in mouse models and in the rare cases of monogenic obesity in humans have added significantly to our understanding of the key role of the hypothalamus in mediating hunger and satiety. These insights have brought us...

  4. The functional importance of disease-associated mutation

    Directory of Open Access Journals (Sweden)

    Klein Teri E

    2002-09-01

    Full Text Available Abstract Background For many years, scientists believed that point mutations in genes are the genetic switches for somatic and inherited diseases such as cystic fibrosis, phenylketonuria and cancer. Some of these mutations likely alter a protein's function in a manner that is deleterious, and they should occur in functionally important regions of the protein products of genes. Here we show that disease-associated mutations occur in regions of genes that are conserved, and can identify likely disease-causing mutations. Results To show this, we have determined conservation patterns for 6185 non-synonymous and heritable disease-associated mutations in 231 genes. We define a parameter, the conservation ratio, as the ratio of average negative entropy of analyzable positions with reported mutations to that of every analyzable position in the gene sequence. We found that 84.0% of the 231 genes have conservation ratios less than one. 139 genes had eleven or more analyzable mutations and 88.0% of those had conservation ratios less than one. Conclusions These results indicate that phylogenetic information is a powerful tool for the study of disease-associated mutations. Our alignments and analysis has been made available as part of the database at http://cancer.stanford.edu/mut-paper/. Within this dataset, each position is annotated with the analysis, so the most likely disease-causing mutations can be identified.

  5. First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G.

    Science.gov (United States)

    Pomahačová, Renata; Zamboryová, Jana; Sýkora, Josef; Paterová, Petra; Fiklík, Karel; Votava, Tomáš; Černá, Zdeňka; Jehlička, Petr; Lád, Václav; Šubrt, Ivan; Dort, Jiří; Dortová, Eva

    2016-12-22

    Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder caused by mutations in the SLC19A2 gene. To date at least 43 mutations have been reported for the gene encoding a plasma membrane thiamine transporter protein (THTR-1). TRMA has been reported in less than 80 cases worldwide. Here, we illustrate 2 female patients with TRMA first diagnosed in the Czech Republic and in central Europe being confirmed by sequencing of the THTR-1 gene SLC19A2. Both subjects are compound heterozygotes with 3 different mutations in the SLC19A2 gene. In case 2, the SLC19A2 intron 1 mutation c.204+2T>G has never been reported before. TRMA subjects are at risk of diabetic ketoacidosis during intercurrent disease and arrythmias. Thiamine supplementation has prevented hematological disorders over a few years in both pediatric subjects, and improved glycaemic control of diabetes mellitus. Patient 1 was suffering from hearing loss and rod-cone dystrophy at the time of diagnosis, however, she was unresponsive to thiamine substitution. Our patient 2 developed the hearing loss despite the early thiamine substitution, however no visual disorder had developed. The novel mutation described here extends the list of SLC19A2 mutations causing TRMA. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'.

    Science.gov (United States)

    Edwards, Noel; Rice, Sarah J; Raman, Shreya; Hynes, Ann Marie; Srivastava, Shalabh; Moore, Iain; Al-Hamed, Mohamed; Xu, Yaobo; Santibanez-Koref, Mauro; Thwaites, David T; Gale, Daniel P; Sayer, John A

    2015-02-01

    End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.

  7. Lattice isomorphisms of bisimple monogenic orthodox semigroups

    CERN Document Server

    Goberstein, Simon M

    2011-01-01

    Using the classification and description of the structure of bisimple monogenic orthodox semigroups obtained in \\cite{key10}, we prove that every bisimple orthodox semigroup generated by a pair of mutually inverse elements of infinite order is strongly determined by the lattice of its subsemigroups in the class of all semigroups. This theorem substantially extends an earlier result of \\cite{key25} stating that the bicyclic semigroup is strongly lattice determined.

  8. Precision diabetes: learning from monogenic diabetes.

    Science.gov (United States)

    Hattersley, Andrew T; Patel, Kashyap A

    2017-05-01

    The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.

  9. Neurochemistry changes associated with mutations in familial Parkinson's disease.

    Science.gov (United States)

    Siddique, M M; Tan, E K

    2010-01-01

    Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

  10. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location

    NARCIS (Netherlands)

    P. Nieminen; L. Papagiannoulis-Lascarides; J. Waltimo-Siren; P. Ollila; S. Karjalainen; S. Arte; J. Veerkamp; V. Tallon Walton; E. Chimenos Küstner; T. Siltanen; H. Holappa; P.L. Lukinmaa; S. Alaluusua

    2011-01-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic fea

  11. GENE MUTATIONS, GENETIC DISEASE AND PHARMACOGENETIC GENES DISORDER

    OpenAIRE

    Ishak

    2010-01-01

    Somatic cell mutation is able to create genetic variance in a cell population and can induce cancer and tumor when gene mutations took place at repressor gene in controlling cell cycles such as p53 gene. Whereas germline cell mutation can cause genetic disease such as sickle cell anemia, breast cancer, thalassemia, parkinson’s as well as defect of biochemical pathway that influence drug-receptor interaction, which has negative effect and lead to hospitalized of patient. Most of reports mentio...

  12. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease.

    Science.gov (United States)

    Neumann, Juliane; Bras, Jose; Deas, Emma; O'Sullivan, Sean S; Parkkinen, Laura; Lachmann, Robin H; Li, Abi; Holton, Janice; Guerreiro, Rita; Paudel, Reema; Segarane, Badmavady; Singleton, Andrew; Lees, Andrew; Hardy, John; Houlden, Henry; Revesz, Tamas; Wood, Nicholas W

    2009-07-01

    Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses

  13. Mutation analysis of Australasian Gaucher disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, P.V.; Carey, W.F.; Morris, C.P.; Lewis, B.D. [Women`s and Children`s Hospital, North Adelaide, South Australia (Australia)

    1995-09-25

    We have previously reported phenotype and genotype analyses in 28 Australasian Gaucher patients who were screened for several of the common Gaucher mutations: N370S, L444P, 84GG, and R463C. Horowitz and Zimran have reported that the complex alleles recNciI and recTL, which contain several point mutations including L444P, are relatively common, especially in non-Jewish Gaucher patients. Zimran and Horowitz have also stated that these recombinant alleles could easily be missed by laboratories testing only for the common Gaucher point mutations. Failure to correctly identify these mutations would influence any attempt to correlate genotype with phenotype. We have therefore retested our Gaucher patients for recNciI (L444P, A456P, and V46OV) and recTL (D409H, L444P, A456P, and V46OV) by PCR amplification, followed by hybridization with allele-specific oligonucleotides. 4 refs.

  14. Point mutations as a source of de novo genetic disease

    NARCIS (Netherlands)

    Ligt, J. de; Veltman, J.A.; Vissers, L.E.L.M.

    2013-01-01

    Family-based next generation sequencing (NGS) has recently pointed to an important role for de novo germline point mutations in both rare and common genetic disorders associated with reduced fitness. In this review we highlight the impact of the mutational target size on the frequency of diseases ca

  15. Transcriptional, microscopic and macroscopic investigations into monogenic and polygenic interactions of tomato and powdery mildew

    NARCIS (Netherlands)

    Li Chengwei,

    2005-01-01

    Powdery mildew ( Oidium neolycopersici) is a worldwide obligate fungal disease of tomato ( Solanum lycopersicum ). Six monogenic Ol genes and three major QTLs were identified and mapped on tomato genome. In this thesis, the mechanisms of both compatible and incompatible interactions of tomato and O.

  16. Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes.

    Science.gov (United States)

    Yang, Yisheng; Chan, Lawrence

    2016-06-01

    To date, more than 30 genes have been linked to monogenic diabetes. Candidate gene and genome-wide association studies have identified > 50 susceptibility loci for common type 1 diabetes (T1D) and approximately 100 susceptibility loci for type 2 diabetes (T2D). About 1-5% of all cases of diabetes result from single-gene mutations and are called monogenic diabetes. Here, we review the pathophysiological basis of the role of monogenic diabetes genes that have also been found to be associated with common T1D and/or T2D. Variants of approximately one-third of monogenic diabetes genes are associated with T2D, but not T1D. Two of the T2D-associated monogenic diabetes genes-potassium inward-rectifying channel, subfamily J, member 11 (KCNJ11), which controls glucose-stimulated insulin secretion in the β-cell; and peroxisome proliferator-activated receptor γ (PPARG), which impacts multiple tissue targets in relation to inflammation and insulin sensitivity-have been developed as major antidiabetic drug targets. Another monogenic diabetes gene, the preproinsulin gene (INS), is unique in that INS mutations can cause hyperinsulinemia, hyperproinsulinemia, neonatal diabetes mellitus, one type of maturity-onset diabetes of the young (MODY10), and autoantibody-negative T1D. Dominant heterozygous INS mutations are the second most common cause of permanent neonatal diabetes. Moreover, INS gene variants are strongly associated with common T1D (type 1a), but inconsistently with T2D. Variants of the monogenic diabetes gene Gli-similar 3 (GLIS3) are associated with both T1D and T2D. GLIS3 is a key transcription factor in insulin production and β-cell differentiation during embryonic development, which perturbation forms the basis of monogenic diabetes as well as its association with T1D. GLIS3 is also required for compensatory β-cell proliferation in adults; impairment of this function predisposes to T2D. Thus, monogenic forms of diabetes are invaluable "human models" that have

  17. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.

    Science.gov (United States)

    Alcalay, Roy N; Levy, Oren A; Waters, Cheryl C; Fahn, Stanley; Ford, Blair; Kuo, Sheng-Han; Mazzoni, Pietro; Pauciulo, Michael W; Nichols, William C; Gan-Or, Ziv; Rouleau, Guy A; Chung, Wendy K; Wolf, Pavlina; Oliva, Petra; Keutzer, Joan; Marder, Karen; Zhang, Xiaokui

    2015-09-01

    Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson

  18. Incidence of RET mutations in patients with Hirschsprung's disease

    NARCIS (Netherlands)

    Sancandi, M; Ceccherini, [No Value; Costa, M; Fava, M; Chen, B; Wu, Y; Hofstra, R; Laurie, T; Griffths, M; Burge, D; Tam, PKH

    2000-01-01

    Background: RET mutations have been reported variously to affect 7% to 41% of Hirschsprung's disease (HSCR) patients depending on familial or sporadic occurrence of the disease, length of aganglionosis and possible association with other disease phenotypes. The authors report a study of the incidenc

  19. DRUMS: a human disease related unique gene mutation search engine.

    Science.gov (United States)

    Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

    2011-10-01

    With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html.

  20. Harmonic and Monogenic Potentials in Euclidean Halfspace

    Science.gov (United States)

    Brackx, F.; De Bie, H.; De Schepper, H.

    2011-09-01

    In the framework of Clifford analysis a chain of harmonic and monogenic potentials is constructed in the upper half of Euclidean space Rm+1. Their distributional limits at the boundary are computed, obtaining in this way well-known distributions in Rm such as the Dirac distribution, the Hilbert kernel, the square root of the negative Laplace operator, and the like. It is shown how each of those potentials may be recovered from an adjacent kernel in the chain by an appropriate convolution with such a distributional limit.

  1. Clinical disease presentation and ECG characteristics of LMNA mutation carriers

    Science.gov (United States)

    Ollila, Laura; Nikus, Kjell; Holmström, Miia; Jalanko, Mikko; Jurkko, Raija; Kaartinen, Maija; Koskenvuo, Juha; Kuusisto, Johanna; Kärkkäinen, Satu; Palojoki, Eeva; Reissell, Eeva; Piirilä, Päivi; Heliö, Tiina

    2017-01-01

    Objective Mutations in the LMNA gene encoding lamins A and C of the nuclear lamina are a frequent cause of cardiomyopathy accounting for 5–8% of familial dilated cardiomyopathy (DCM). Our aim was to study disease onset, presentation and progression among LMNA mutation carriers. Methods Clinical follow-up data from 27 LMNA mutation carriers and 78 patients with idiopathic DCM without an LMNA mutation were collected. In addition, ECG data were collected and analysed systematically from 20 healthy controls. Results Kaplan-Meier analysis revealed no difference in event-free survival (death, heart transplant, resuscitation and appropriate implantable cardioverter-defibrillator therapy included as events) between LMNA mutation carriers and DCM controls (p=0.5). LMNA mutation carriers presented with atrial fibrillation at a younger age than the DCM controls (47 vs 57 years, p=0.003). Male LMNA mutation carriers presented with clinical manifestations roughly a decade earlier than females. In close follow-up non-sustained ventricular tachycardia was detected in 78% of LMNA mutation carriers. ECG signs of septal remodelling were present in 81% of the LMNA mutation carriers, 21% of the DCM controls and none of the healthy controls giving a high sensitivity and specificity for the standard ECG in distinguishing LMNA mutation carriers from patients with DCM and healthy controls. Conclusions Male LMNA mutation carriers present clinical manifestations at a younger age than females. ECG septal remodelling appears to distinguish LMNA mutation carriers from healthy controls and patients with DCM without LMNA mutations. PMID:28123761

  2. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    Science.gov (United States)

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II. Copyright © 2011 American Society for Bone and Mineral Research.

  3. Prevention of avoidable mutational disease: memorandum from a WHO meeting.

    Science.gov (United States)

    1986-01-01

    About 1% of children are born with a serious disorder which is the direct result of a mutational event in a parent or a more distant ancestor. These disorders, of which several thousand are known, mainly afflict the blood, bone, brain, ear, eye or muscle and the changes are usually irrevocable by the time of diagnosis. Another 1% of individuals will develop a serious genetic disease some time after birth. In addition to these direct consequences of a mutant event, far higher proportions will suffer from the indirect effects of one or several mutations.In view of their chronic and severe nature most of these disorders impose a burden disproportionate to their frequency, and it is sound public health policy to avoid the birth of babies known to have the established mutations and prevent further cases in the immediate or distant future by minimizing the exposure of people at risk to known mutagens. The advantages in permitting certain mutagenic exposures must be assessed against the later costs.Owing to the natural mutation rate and the vast backlog of previous mutations, the prospects of prevention are limited to preventing an increase, rather than to achieving any substantial decrease. This Memorandum describes progress in the ability to dissect and interpret the mutational process, to identify populations at risk, and to evaluate the consequences of the various types of mutational event and emphasizes that the current approach to prevention of mutational disease must involve improving our ability to study populations that appear to be at increased risk.

  4. Common Membrane Trafficking Defects of Disease Associated Dynamin 2 Mutations

    OpenAIRE

    Liu, Ya-Wen; Lukiyanchuk, Vasyl; Schmid, Sandra L.

    2011-01-01

    Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, Centronuclear Myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cell...

  5. Multi-center analysis of glucocerebrosidase mutations in Parkinson disease

    Science.gov (United States)

    Sidransky, Ellen; Nalls, Michael A.; Aasly, Jan O.; Aharon-Peretz, Judith; Annesi, Grazia; Barbosa, Egberto Reis; Bar-Shira, Anat; Berg, Daniela; Bras, Jose; Brice, Alexis; Chen, Chiung-Mei; Clark, Lorraine N.; Condroyer, Christel; De Marco, Elvira Valeria; Dürr, Alexandra; Eblan, Michael J.; Fahn, Stanley; Farrer, Matthew; Fung, Hon-Chung; Gan-Or, Ziv; Gasser, Thomas; Gershoni-Baruch, Ruth; Giladi, Nir; Griffith, Alida; Gurevich, Tanya; Januario, Cristina; Kropp, Peter; Lang, Anthony E.; Lee-Chen, Guey-Jen; Lesage, Suzanne; Marder, Karen; Mata, Ignacio F.; Mirelman, Anat; Mitsui, Jun; Mizuta, Ikuko; Nicoletti, Giuseppe; Oliveira, Catarina; Ottman, Ruth; Orr-Urtreger, Avi; Pereira, Lygia V.; Quattrone, Aldo; Rogaeva, Ekaterina; Rolfs, Arndt; Rosenbaum, Hanna; Rozenberg, Roberto; Samii, Ali; Samaddar, Ted; Schulte, Claudia; Sharma, Manu; Singleton, Andrew; Spitz, Mariana; Tan, Eng-King; Tayebi, Nahid; Toda, Tatsushi; Troiano, André; Tsuji, Shoji; Wittstock, Matthias; Wolfsberg, Tyra G.; Wu, Yih-Ru; Zabetian, Cyrus P.; Zhao, Yi; Ziegler, Shira G.

    2010-01-01

    Background Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease. Methods Sixteen centers participated, including five from the Americas, six from Europe, two from Israel and three from Asia. Each received a standard DNA panel to compare genotyping results. Genotypes and phenotypic data from patients and controls were analyzed using multivariate logistic regression models and the Mantel Haenszel procedure to estimate odds ratios (ORs) across studies. The sample included 5691 patients (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews). Results All 16 centers could detect GBA mutations, L444P and N370S, and the two were found in 15.3% of Ashkenazi patients with Parkinson disease (ORs = 4.95 for L444P and 5.62 for N370S), and in 3.2% of non-Ashkenazi patients (ORs = 9.68 for L444P and 3.30 for N370S). GBA was sequenced in 1642 non-Ashkenazi subjects, yielding a frequency of 6.9% for all mutations, demonstrate that limited mutation screens miss half the mutant alleles. The presence of any GBA mutation was associated with an OR of 5.43 across studies. Clinically, although phenotypes varied, subjects with a GBA mutation presented earlier, and were more likely to have affected relatives and atypical manifestations. Conclusion Data collected from sixteen centers demonstrate that there is a strong association between GBA mutations and Parkinson disease. PMID:19846850

  6. PARK1 gene mutation of autosomal dominant Parkinson's disease family

    Institute of Scientific and Technical Information of China (English)

    Ligang Jiang; Guohua Hu; Qiuhui Chen; Ying Zhang; Xinyu Hu; Jia Fan; Lifeng Liu; Rui Guo; Yajuan Sun; Yixhi Zhang

    2011-01-01

    Studies have shown that PARK1 gene is associated with the autosomal dominant inheritance of Parkinson's disease.PARK1 gene contains two mutation sites, namely Ala30Pro and AIa53Thr, which are located on exons 3 and 4, respectively.However, the genetic loci of the pathogenic genes remain unclear.In this study, blood samples were collected from 11 members of a family with high prevalence of Parkinson's disease, including four affected cases, five suspected cases,and two non-affected cases.Point mutation screening of common mutation sites on PARK1 gene exon 4 was conducted using PCR, to determine the genetic loci of the causative gene for Parkinson's disease.Gene identification and sequencing results showed that a T base deletion mutation was observed in the PARK1 gene exon 4 of all 11 collected samples.It was confirmed that the PARKf gene exon 4 gene mutation is an important pathogenic mutation for Parkinson's disease.

  7. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease.

    Science.gov (United States)

    Beavan, Michelle S; Schapira, Anthony H V

    2013-12-01

    Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease with a lifetime risk in the UK population of almost 5%. An association between PD and Gaucher disease (GD) derived from the observation that GD patients and their heterozygous carrier relatives were at increased risk of PD. GD is an autosomal recessive lysosomal storage disorder caused by homozygous mutations in the gene encoding glucocerebrosidase (GBA). Approximately 5%-10% of PD patients have GBA mutations, making these mutations numerically the most important genetic predisposing risk factor for the development of PD identified to date. GBA mutations result in a phenotype that is virtually indistinguishable clinically, pharmacologically, and pathologically from sporadic PD, except GBA mutations result in a slightly earlier age of onset and more frequent cognitive impairment among PD patients. The mechanisms by which GBA mutations result in PD are not yet understood. Both reduced glucocerebrosidase enzyme (GCase) activity with lysosomal dysfunction, and unfolded protein response (UPR) with endoplasmic reticulum-associated degradation (ERAD) and stress are considered contributory.

  8. Disease-associated mutations prevent GPR56-collagen III interaction.

    Directory of Open Access Journals (Sweden)

    Rong Luo

    Full Text Available GPR56 is a member of the adhesion G protein-coupled receptor (GPCR family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP. Using the N-terminal fragment of GPR56 (GPR56(N as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown.

  9. Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.

    Science.gov (United States)

    Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A; Jenkins, Andrew; Traynelis, Stephen F

    2015-07-01

    The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

  10. Bioenergetic consequences of PINK1 mutations in Parkinson disease.

    Directory of Open Access Journals (Sweden)

    Andrey Yurevich Abramov

    Full Text Available Mutations of the gene for PTEN-induced kinase 1 (PINK1 are a cause of familial Parkinson's disease (PD. PINK1 protein has been localised to mitochondria and PINK1 gene knockout models exhibit abnormal mitochondrial function. The purpose of this study was to determine whether cells derived from PD patients with a range of PINK1 mutations demonstrate similar defects of mitochondrial function, whether the nature and severity of the abnormalities vary between mutations and correlate with clinical features.We investigated mitochondrial bioenergetics in live fibroblasts from PINK1 mutation patients using single cell techniques. We found that fibroblasts from PINK1 mutation patients had significant defects of bioenergetics including reduced mitochondrial membrane potential, altered redox state, a respiratory deficiency that was determined by substrate availability, and enhanced sensitivity to calcium stimulation and associated mitochondrial permeability pore opening. There was an increase in the basal rate of free radical production in the mutant cells. The pattern and severity of abnormality varied between different mutations, and the less severe defects in these cells were associated with later age of onset of PD.The results provide insight into the molecular pathology of PINK1 mutations in PD and also confirm the critical role of substrate availability in determining the biochemical phenotype--thereby offering the potential for novel therapeutic strategies to circumvent these abnormalities.

  11. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

    Science.gov (United States)

    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  12. Mutation@A Glance : an integrative web application for analysing mutations from human genetic diseases

    NARCIS (Netherlands)

    Hijikata, A.; Raju, R.; Keerthikumar, S.; Ramabadran, S.; Balakrishnan, L.; Ramadoss, S.K.; Pandey, A.; Mohan, S.; Ohara, O.

    2010-01-01

    Although mutation analysis serves as a key part in making a definitive diagnosis about a genetic disease, it still remains a time-consuming step to interpret their biological implications through integration of various lines of archived information about genes in question. To expedite this evaluatio

  13. Mutations in Hirschsprung disease : When does a mutation contribute to the phenotype

    NARCIS (Netherlands)

    Hofstra, RMW; Osinga, J; Buys, CHCM

    1997-01-01

    Hirschsprung disease is a congenital disorder clinically characterized by the absence of colonic ganglia and genetically by extensive heterogeneity. Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance. In parti

  14. The relationship between glucocerebrosidase mutations and Parkinson disease.

    Science.gov (United States)

    Migdalska-Richards, Anna; Schapira, Anthony H V

    2016-10-01

    Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold increased risk for the development of PD, and that at least 7-10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD-GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD-GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha-synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD-GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha-synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD-GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD. The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin-proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD

  15. Parkin Somatic Mutations Link Melanoma and Parkinson's Disease.

    Science.gov (United States)

    Levin, Lotan; Srour, Shani; Gartner, Jared; Kapitansky, Oxana; Qutob, Nouar; Dror, Shani; Golan, Tamar; Dayan, Roy; Brener, Ronen; Ziv, Tamar; Khaled, Mehdi; Schueler-Furman, Ora; Samuels, Yardena; Levy, Carmit

    2016-06-20

    Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.

  16. INS-gene mutations: from genetics and beta cell biology to clinical disease.

    Science.gov (United States)

    Liu, Ming; Sun, Jinhong; Cui, Jinqiu; Chen, Wei; Guo, Huan; Barbetti, Fabrizio; Arvan, Peter

    2015-04-01

    A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved.

  17. Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease.

    Directory of Open Access Journals (Sweden)

    James E J Bedard

    Full Text Available Patients with heterotaxy have characteristic cardiovascular malformations, abnormal arrangement of their visceral organs, and midline patterning defects that result from abnormal left-right patterning during embryogenesis. Loss of function of the transcription factor ZIC3 causes X-linked heterotaxy and isolated congenital heart malformations and represents one of the few known monogenic causes of congenital heart disease. The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation. Therefore, cross species comparative sequence alignment was used to identify a putative novel fourth exon, and the existence of a novel alternatively spliced transcript was confirmed by amplification from murine embryonic RNA and subsequent sequencing. This transcript, termed Zic3-B, encompasses exons 1, 2, and 4 whereas Zic3-A encompasses exons 1, 2, and 3. The resulting protein isoforms are 466 and 456 amino acid residues respectively, sharing the first 407 residues. Importantly, the last two amino acids in the fifth zinc finger DNA binding domain are altered in the Zic3-B isoform, indicating a potential functional difference that was further evaluated by expression, subcellular localization, and transactivation analyses. The temporo-spatial expression pattern of Zic3-B overlaps with Zic3-A in vivo, and both isoforms are localized to the nucleus in vitro. Both isoforms can transcriptionally activate a Gli binding site reporter, but only ZIC3-A synergistically activates upon co-transfection with Gli3, suggesting that the isoforms are functionally distinct. Screening 109 familial and sporadic male heterotaxy cases did not identify pathogenic mutations in the newly identified fourth exon and larger studies are necessary to establish the importance of the novel isoform in human disease.

  18. [Monogenic obesity - current status of molecular genetic research and clinical importance].

    Science.gov (United States)

    Aldhoon-Hainerová, Irena; Včelák, Josef; Zamrazilová, Hana

    2014-01-01

    Obesity and its comorbidities represent one of the major health problems worldwide. A positive energy balance due to inappropriate life-style changes plays a key role in the current obesity epidemic. The influence of genetic factors is also significant - several studies concluded that genes contribute to the development of obesity by 40-70%. Genetic variability predisposes an individual to tendency or resistance to increase body weight in obesogenic environment. Polygenic type of inheritance is responsible in most of obese individuals. However, an intensive research of the past 20 years has led to an identification of several genes causing monogenic forms of obesity. To date, several monogenic genes (leptin, leptin receptor, prohormon convertase 1, proopiomelanocortin, melanocortin 4 receptor, single-minded homolog 1, brain-derived neurotrophic factor, neurotrophic tyrosine kinase receptor type 2) that are either involved in the neuronal differentiation of the paraventricular nucleus or in the leptin-melanocortin pathway are known to cause obesity. Mutation carriers apart from severe early onset obesity manifest with additional phenotypic characteristics as adrenal insufficiency, impaired immunity and impaired fertility. This review provides an overview of molecular-genetic and clinical research in the field of monogenic obesities including therapeutical approaches.

  19. Coxsackievirus B3 infection and its mutation in Keshan disease

    Institute of Scientific and Technical Information of China (English)

    Li-Qun Ren; Xiang-Jun Li; Guang-Sheng Li; Zhi-Tao Zhao; Bo Sun; Fei Sun

    2004-01-01

    AIM: To investigate coxsackievirus B3 infection and its gene mutation in Keshan disease.METHODS: The expression of Coxsackievirus B3 RNA was detected in autopsy specimens of acute (12 cases), sub-acute(27 cases) and chronic (15 cases) Keshan disease by in situ hybridization. In sub-acute Keshan disease specimens, 3 cases with positive result by in situ hybridization were selected RT-PCR analysis. The DNA segments were then sequenced.RESULTS: Coxsackievirus B3 RNA was detected in the cytoplasm of myocardiocyte. The positive rate was 83% in acute, 67% in sub-acute and 80% in chronic Keshan disease.In the conservative region of Coxsackievirus B3 genome,there was a mutation in 234 (C-T) compared to the noncardiovirulent strain, CVB3/0.CONCLUSION: Coxsackievirus B3 RNA can survive and replicate in heart muscle of Keshan disease, which may play an important role in the occurrence of Keshan disease. The possible mechanism of occurrence of Keshan disease is associated with point a mutation in Coxsackievirus B3 genome.

  20. Novel GAA mutations in patients with Pompe disease.

    Science.gov (United States)

    Turaça, Lauro Thiago; de Faria, Douglas Oliveira Soares; Kyosen, Sandra Obikawa; Teixeira, Valber Dias; Motta, Fabiana Louise; Pessoa, Juliana Gilbert; Rodrigues E Silva, Marina; de Almeida, Sandro Soares; D'Almeida, Vânia; Munoz Rojas, Maria Verônica; Martins, Ana Maria; Pesquero, João Bosco

    2015-04-25

    Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in the GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 13 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of the Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates.

  1. Melanocortin 4 receptor mutations in obese Czech children

    DEFF Research Database (Denmark)

    Hainerová, Irena; Larsen, Lesli H; Holst, Birgitte

    2007-01-01

    Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity.......Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity....

  2. Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.

    OpenAIRE

    2010-01-01

    7 pages; International audience; Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at

  3. A glycogene mutation map for discovery of diseases of glycosylation

    DEFF Research Database (Denmark)

    Hansen, Lars; Lind-Thomsen, Allan; Joshi, Hiren J;

    2015-01-01

    homologous families. However, Genome-Wide-Association Studies (GWAS) have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole exome sequencing (WES) provides access to mutations in e.g. glycosyltransferase genes...

  4. Hereditary cerebral small vessel disease and stroke

    DEFF Research Database (Denmark)

    Søndergaard, Christian Baastrup; Nielsen, Jørgen Erik; Hansen, Christine Krarup

    2017-01-01

    of this systematic review is to provide a guide for determining when to consider molecular genetic testing in patients presenting with small vessel disease and stroke. CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary...... cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations are described in terms of genetics, pathology, clinical manifestation, imaging, and diagnosis. These monogenic disorders are often characterized by early-age stroke, but also by migraine, mood disturbances, vascular dementia and often gait......Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI. Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified. The purpose...

  5. Mutation of RET gene in Chinese patients with Hirschsprung's disease

    Institute of Scientific and Technical Information of China (English)

    Ji-Cheng Li; Shi-Ping Ding; Ying Song; Min-Ju Li

    2002-01-01

    AIM: To investigate the pathogenic mechanism of Hirschsprung's disease (HD) at the molecular level and to elucidate the relationship between RET oncogene and Chinese patients with HD.METHODS: Exon 13 of RET oncogene from 20 unrelated HD patients was analyzed with polymerase chain reactionsingle strand conformation polymorphism (PCR-SSCP). The positive amplifying products were then sequenced. According to the results of SSCP and DNA sequence, SSCP was done as well for the samples from the family other members of some cases with mutated RET gene.RESULTS: SSCP analysis indicated that mobility abnormality existed in 4 unrelated HD patients. Direct DNA sequence analysis identified a missense mutation, T to G at the nucleotide 18 888 and a frameshift mutation at the nucleotide 18 926 insG. In a HD family, the sicked child and his father were the same heterozygous missense mutation (T to G at nucleotide 18 888).CONCLUSION: Among Chinese HD patients, RET gene mutations may exist in considerable proportion with different patterns. These new discoveries indicate that RET mutations may play an important role in the pathogenesis of unrelated HD in the Chinese population. PCR-SSCP combined with DNA sequence can be used as a tool in the genetic diagnosis of HD.

  6. Disease-associated mutations that alter the RNA structural ensemble.

    Directory of Open Access Journals (Sweden)

    Matthew Halvorsen

    2010-08-01

    Full Text Available Genome-wide association studies (GWAS often identify disease-associated mutations in intergenic and non-coding regions of the genome. Given the high percentage of the human genome that is transcribed, we postulate that for some observed associations the disease phenotype is caused by a structural rearrangement in a regulatory region of the RNA transcript. To identify such mutations, we have performed a genome-wide analysis of all known disease-associated Single Nucleotide Polymorphisms (SNPs from the Human Gene Mutation Database (HGMD that map to the untranslated regions (UTRs of a gene. Rather than using minimum free energy approaches (e.g. mFold, we use a partition function calculation that takes into consideration the ensemble of possible RNA conformations for a given sequence. We identified in the human genome disease-associated SNPs that significantly alter the global conformation of the UTR to which they map. For six disease-states (Hyperferritinemia Cataract Syndrome, beta-Thalassemia, Cartilage-Hair Hypoplasia, Retinoblastoma, Chronic Obstructive Pulmonary Disease (COPD, and Hypertension, we identified multiple SNPs in UTRs that alter the mRNA structural ensemble of the associated genes. Using a Boltzmann sampling procedure for sub-optimal RNA structures, we are able to characterize and visualize the nature of the conformational changes induced by the disease-associated mutations in the structural ensemble. We observe in several cases (specifically the 5' UTRs of FTL and RB1 SNP-induced conformational changes analogous to those observed in bacterial regulatory Riboswitches when specific ligands bind. We propose that the UTR and SNP combinations we identify constitute a "RiboSNitch," that is a regulatory RNA in which a specific SNP has a structural consequence that results in a disease phenotype. Our SNPfold algorithm can help identify RiboSNitches by leveraging GWAS data and an analysis of the mRNA structural ensemble.

  7. Lack of MEF2A mutations in coronary artery disease

    Energy Technology Data Exchange (ETDEWEB)

    Weng, Li; Kavaslar, Nihan; Ustaszewska, Anna; Doelle, Heather; Schackwitz, Wendy; Hebert, Sybil; Cohen, Jonathan; McPherson, Ruth; Pennacchio, Len A.

    2004-12-01

    Mutations in MEF2A have been implicated in an autosomal dominant form of coronary artery disease (adCAD1). In this study we sought to determine whether severe mutations in MEF2A might also explain sporadic cases of coronary artery disease (CAD). To do this, we resequenced the coding sequence and splice sites of MEF2A in {approx}300 patients with premature CAD and failed to find causative mutations in the CAD cohort. However, we did identify the 21 base pair (bp) MEF2A coding sequence deletion originally implicated in adCAD1 in one of 300 elderly control subjects without CAD. Further screening of an additional {approx}1,500 non-CAD patients revealed two more subjects with the MEF2A 21 bp deletion. Genotyping of 19 family members of the three probands with the 21 bp deletion in MEF2A revealed that the mutation did not co-segregate with early CAD. These studies demonstrate that MEF2A mutations are not a common cause of CAD and cast serious doubt on the role of the MEF2A 21 bp deletion in adCAD1.

  8. Parkin gene mutations in younger onset Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Piu Chan; Hua Bai; Rong Chen; J Willian Langston

    2000-01-01

    Objective': To screen for exonic and point mutations in the Parkin gene in both Chinese and American Caucasian younger onset Parkinson's disease (YOPD) patients.Background: Recently, the Autosomal recessive juvenile parkinsonism (ARJP) gene was first mapped to chromosome 6q25.2-27 and was late cloned and designated as Parkin. A wide variety of mutations, including homozygous exonic deletions and point mutations,have been found in at least more than 50 ARJP families of Japanese, European and Jewish origins. However, the distribution of Parkin gene mutations is not known in the Chinese and American Caucasians, It is also not clear how frequent the Parkin gene mutations occur in YOPD patients. Method and Material: Twenty-one Chinese subjects were selected from 121 Chinese PD inpatients who were admitted to the Xuanwu Hospital in Beijing between August of 1998 and April of 1999 and had an onset before age 51. Thirty-eight American subjects were PD patients with an onset before age 41 from the Tissue Bank of the Parkinson′s Institute at California. Homozygous exonic deletion and point mutations in all 12 exons of the Parkin gene were screened using PCR, SSCP and direct sequencing methods. Mutations identified by sequencing were further confirmed by restriction enzyme digestion. Results: Five different types of homozygous deletion mutations (exons 1, 4, 6, 7 and 12) were found in 7 out of 21 Chinese cases but none of the 37 American Caucasian patients in all 12 exons of Parkin gene. One novel and four polymorphic mutationswere found in the American Caucasian YOPD cases.Conclusion: our results suggest that homozygous exonic deletions in the Parkin gene may account for a significant amount of YOPD in the Chinese but not in the American Caucasian YOPD.

  9. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.

    Science.gov (United States)

    Glocker, Erik-Oliver; Kotlarz, Daniel; Boztug, Kaan; Gertz, E Michael; Schäffer, Alejandro A; Noyan, Fatih; Perro, Mario; Diestelhorst, Jana; Allroth, Anna; Murugan, Dhaarini; Hätscher, Nadine; Pfeifer, Dietmar; Sykora, Karl-Walter; Sauer, Martin; Kreipe, Hans; Lacher, Martin; Nustede, Rainer; Woellner, Cristina; Baumann, Ulrich; Salzer, Ulrich; Koletzko, Sibylle; Shah, Neil; Segal, Anthony W; Sauerbrey, Axel; Buderus, Stephan; Snapper, Scott B; Grimbacher, Bodo; Klein, Christoph

    2009-11-19

    The molecular cause of inflammatory bowel disease is largely unknown. We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent "negative feedback" regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient. 2009 Massachusetts Medical Society

  10. The RH boundary value problem of the k-monogenic functions

    Science.gov (United States)

    Bu, Yude; Du, Jinyuan

    2008-11-01

    In this paper we study the Riemann and Hilbert problems of k-monogenic functions. By using Euler operator, we transform the boundary value problem of k-monogenic functions into the boundary value problems of monogenic functions. Then by the Almansi-type theorem of k-monogenic functions, we get the solutions of these problems.

  11. A Boundary Value Problem for Hermitian Monogenic Functions

    Directory of Open Access Journals (Sweden)

    Reyes JuanBory

    2008-01-01

    Full Text Available Abstract We study the problem of finding a Hermitian monogenic function with a given jump on a given hypersurface in . Necessary and sufficient conditions for the solvability of this problem are obtained.

  12. Mutations in DJ-1 are rare in familial Parkinson disease

    Science.gov (United States)

    Pankratz, Nathan; Pauciulo, Michael W.; Elsaesser, Veronika E.; Marek, Diane K.; Halter, Cheryl A.; Wojcieszek, Joanne; Rudolph, Alice; Shults, Clifford W.; Foroud, Tatiana; Nichols Ph.D., William C.

    2006-01-01

    Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD. PMID:16997464

  13. 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.

  14. Mutations in CARD15 and smoking confer susceptibility to Crohn's disease in the Danish population

    DEFF Research Database (Denmark)

    Ernst, Anja; Jacobsen, Bent Ascanius; Østergaard, Mette

    2007-01-01

    Three CAspase Recruitment Domain (CARD15) mutations have shown to predispose to Crohn's disease in Caucasian populations. The aim of this study was to investigate the mutation frequency in patients with inflammatory bowel disease and in healthy controls in Denmark....

  15. Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome

    DEFF Research Database (Denmark)

    Benfield, Thomas L; Dahl, Mortens; Nordestgaard, Borge G

    2005-01-01

    The effect of the coagulation factor V Leiden mutation on infectious disease susceptibility and outcome is controversial.......The effect of the coagulation factor V Leiden mutation on infectious disease susceptibility and outcome is controversial....

  16. Diseases caused by mutations in ORAI1 and STIM1

    Science.gov (United States)

    Lacruz, Rodrigo S.; Feske, Stefan

    2015-01-01

    Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology. PMID:26469693

  17. A Multi-Model Stereo Similarity Function Based on Monogenic Signal Analysis in Poisson Scale Space

    Directory of Open Access Journals (Sweden)

    Jinjun Li

    2011-01-01

    Full Text Available A stereo similarity function based on local multi-model monogenic image feature descriptors (LMFD is proposed to match interest points and estimate disparity map for stereo images. Local multi-model monogenic image features include local orientation and instantaneous phase of the gray monogenic signal, local color phase of the color monogenic signal, and local mean colors in the multiscale color monogenic signal framework. The gray monogenic signal, which is the extension of analytic signal to gray level image using Dirac operator and Laplace equation, consists of local amplitude, local orientation, and instantaneous phase of 2D image signal. The color monogenic signal is the extension of monogenic signal to color image based on Clifford algebras. The local color phase can be estimated by computing geometric product between the color monogenic signal and a unit reference vector in RGB color space. Experiment results on the synthetic and natural stereo images show the performance of the proposed approach.

  18. Cystic fibrosis gene mutations: evaluation and assessment of disease severity

    Directory of Open Access Journals (Sweden)

    Vallières E

    2014-10-01

    Full Text Available Emilie Vallières, Joseph Stuart ElbornCystic Fibrosis and Airways Microbiology Research Group, Queens University Belfast, Belfast, UKAbstract: The cystic fibrosis transmembrane regulator (CFTR gene encodes an ion channel transporter, the CFTR protein. Since its identification in 1989, more than 1,900 sequence variants have been reported, resulting in a wide spectrum of clinical phenotypes. Cystic fibrosis (CF is associated with many CFTR mutants and there is a continuum of disease severity observed. Recent advances in fundamental research have increased our understanding of the consequent molecular defect arising from CF mutations. This knowledge has resulted in the development of CF-specific therapies, targeting either the genetic or the molecular defect. CF care, previously focused on symptom control, is therefore moving toward a "stratified" or "precision" therapeutic approach. This review outlines normal CFTR physiology, the proposed pathologic mechanism underlying CF associated-lung injury, classification of CF mutations, and the CF-specific therapies recently approved or in clinical trials.Keywords: cystic fibrosis, gene mutations, disease severity, evaluation, assessment

  19. Differentiating PFAPA syndrome from monogenic periodic fevers.

    Science.gov (United States)

    Gattorno, Marco; Caorsi, Roberta; Meini, Antonella; Cattalini, Marco; Federici, Silvia; Zulian, Francesco; Cortis, Elisabetta; Calcagno, Giuseppina; Tommasini, Alberto; Consolini, Rita; Simonini, Gabriele; Pelagatti, Maria Antonietta; Baldi, Maurizia; Ceccherini, Isabella; Plebani, Alessandro; Frenkel, Joost; Sormani, Maria Pia; Martini, Alberto

    2009-10-01

    To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

  20. Association of PRPS1 Mutations with Disease Phenotypes

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    Rahul Mittal

    2015-01-01

    Full Text Available Phosphoribosylpyrophosphate synthetase 1 (PRPS1 codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2, Charcot-Marie-Tooth disease-5 (CMTX5, and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2 results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5 and severe PRS-I deficiency (Arts syndrome present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

  1. Founder mutation for Huntington disease in Caucasus Jews.

    Science.gov (United States)

    Melamed, O; Behar, D M; Bram, C; Magal, N; Pras, E; Reznik-Wolf, H; Borochowitz, Z U; Davidov, B; Mor-Cohen, R; Baris, H N

    2015-02-01

    Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Zinc finger nucleases for targeted mutagenesis and repair of the sickle-cell disease mutation: An in-silico study

    Directory of Open Access Journals (Sweden)

    Wayengera Misaki

    2012-05-01

    Full Text Available Abstract Background Sickle cell disease (or simply, SCD is an inherited hemoglobinopathy which is mostly prevalent among persons of African descent. SCD results from a monogenic (Hemoglobin, beta point-mutation (substitution of the base Adenine with Thymine at position six that leads to replacement of the amino acid glutamic acid (E with valine (V. Management of SCD within resource-poor settings is largely syndromic, since the option of cure offered by bone-marrow transplantation (BMT is risky and unaffordable by most affected individuals. Despite previous reports of repair and inhibition of the sickle beta-globin gene and messenger ribonucleic acids (mRNAs, respectively in erythrocyte precursor cells via gene-targeting using an oligomer-restriction enzyme construct and either ribozyme- or RNA-DNA chimeric oligonucleotides (or simply third strand binding, gene-therapy to treat SCD still remains largely preclinical. In the wake of the advances in target- gene- mutagenesis and repair wrought by zinc finger nuclease (ZFN technology, it was hypothesized that SCD may be cured by the same. The goal of this study thus, was constructing a database of zinc finger arrays (ZFAs and engineering ZFNs, that respectively bind and cleave within or around specific sequences in the sickle hemoglobin, beta (−βS gene. Methods and results First, using the complete 1606 genomic DNA base pair (bp sequences of the normal hemoglobin-beta (βA chain gene, and the ZiFiT-CoDA-ZFA software preset at default, 57 three-finger arrays (ZFAs that specifically bind 9 base-pair sequences within the normal hemoglobin-beta chain, were computationally assembled. Second, by serial linkage of these ZFAs to the Flavobacterium okeanokoites endonuclease Fok I― four ZFNs with unique specificity to >24 bp target-sequences at the genomic contextual positions 82, 1333, 1334, and 1413 of the βA chain-gene were constructed in-silico. Third, localizing the point-mutation of SCD at

  3. Two novel mutations in surfactant protein-C, lung function and obstructive lung disease

    DEFF Research Database (Denmark)

    Baekvad-Hansen, Marie; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne

    2010-01-01

    Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lung disease. The frequency of lung disease due to SFTPC mutations in the general population is unknown. The aim of this study was to identify novel SFTPC mutations that are associated with lung function...... pulmonary disease or interstitial lung disease. No Y106X heterozygotes suffered from asthma, chronic obstructive pulmonary disease (COPD), or interstitial lung disease. We identified two novel mutations in highly conserved areas of the SFTPC gene, and show that heterozygotes for the mutations have normal...... lung function and are unaffected by COPD and interstitial lung disease. A53T heterozygotes had increased asthma risk, but further research is required to conclusively determine whether this mutation is associated with asthma....

  4. Mutations in SCG10 are not involved in Hirschsprung disease.

    Directory of Open Access Journals (Sweden)

    Maria M M Alves

    Full Text Available Hirschsprung disease (HSCR is a congenital malformation characterized by the absence of enteric neurons in the distal part of the colon. Several genes have been implicated in the development of this disease that together account for 20% of all cases, implying that other genes are involved. Since HSCR is frequently associated with other congenital malformations, the functional characterization of the proteins encoded by the genes involved in these syndromes can provide insights into the protein-network involved in HSCR development. Recently, we found that KBP, encoded by the gene involved in a HSCR- associated syndrome called Goldberg-Shprintzen syndrome, interacts with SCG10, a stathmin-like protein. To determine if SCG10 is involved in the etiology of HSCR, we determined SCG10 expression levels during development and screened 85 HSCR patients for SCG10 mutations. We showed that SCG10 expression increases during development but no germline mutation was found in any of these patients. In conclusion, this study shows that SCG10 is not directly implicated in HSCR development. However, an indirect involvement of SCG10 cannot be ruled out as this can be due to a secondary effect caused by its direct interactors.

  5. A Boundary Value Problem for Hermitian Monogenic Functions

    Directory of Open Access Journals (Sweden)

    Ricardo Abreu Blaya

    2008-02-01

    Full Text Available We study the problem of finding a Hermitian monogenic function with a given jump on a given hypersurface in ℝm, m=2n. Necessary and sufficient conditions for the solvability of this problem are obtained.

  6. Parkinson disease: α-synuclein mutational screening and new clinical insight into the p.E46K mutation.

    Science.gov (United States)

    Pimentel, Márcia M G; Rodrigues, Fabíola C; Leite, Marco Antônio A; Campos Júnior, Mário; Rosso, Ana Lucia; Nicaretta, Denise H; Pereira, João S; Silva, Delson José; Della Coletta, Marcus V; Vasconcellos, Luiz Felipe R; Abreu, Gabriella M; Dos Santos, Jussara M; Santos-Rebouças, Cíntia B

    2015-06-01

    Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding α-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. In this study, we conducted a molecular screening of α-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real-time PCR. The only alteration identified was the p.E46K mutation in a 60-year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. Our findings add new insight into the preexisting information about α-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in α-synuclein are uncommon among Brazilian patients with Parkinson's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Mutations in inhibin and activin genes associated with human disease.

    Science.gov (United States)

    Shelling, Andrew N

    2012-08-15

    Inhibins and activins are members of the transforming growth factor (TGFβ) superfamily, that includes the TGFβs, inhibins and activins, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). The family members are expressed throughout the human body, and are involved in the regulation of a range of important functions. The precise regulation of the TGFβ pathways is critical, and mutations of individual molecules or even minor alterations of signalling will have a significant affect on function, that may lead to development of disease or predisposition to the development of disease. The inhibins and activins regulate aspects of the male and female reproductive system, therefore, it is not surprising that most of the diseases associated with abnormalities of the inhibin and activin genes are focused on reproductive disorders and reproductive cancers. In this review, I highlight the role of genetic variants in the development of conditions such as premature ovarian failure, pre-eclampsia, and various reproductive cancers. Given the recent advances in human genetic research, such as genome wide association studies and next generation sequencing, it is likely that inhibins and activins will be shown to play more important roles in a range of human genetic diseases in the future.

  8. Cortical atrophy in presymptomatic Alzheimer's disease presenilin 1 mutation carriers.

    Science.gov (United States)

    Quiroz, Yakeel T; Stern, Chantal E; Reiman, Eric M; Brickhouse, Michael; Ruiz, Adriana; Sperling, Reisa A; Lopera, Francisco; Dickerson, Bradford C

    2013-05-01

    Sporadic late-onset Alzheimer's disease (AD) dementia has been associated with a 'signature' of cortical atrophy in paralimbic and heteromodal association regions measured with MRI. To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset. 40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions. Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe. Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.

  9. Derivation, Characterization, and Neural Differentiation of Integration-Free Induced Pluripotent Stem Cell Lines from Parkinson's Disease Patients Carrying SNCA, LRRK2, PARK2, and GBA Mutations.

    Science.gov (United States)

    Momcilovic, Olga; Sivapatham, Renuka; Oron, Tal Ronnen; Meyer, Morten; Mooney, Sean; Rao, Mahendra S; Zeng, Xianmin

    2016-01-01

    We report generation of induced pluripotent stem cell (iPSC) lines from ten Parkinson's disease (PD) patients carrying SNCA, PARK2, LRRK2, and GBA mutations, and one age-matched control. After validation of pluripotency, long-term genome stability, and integration-free reprogramming, eight of these lines (one of each SNCA, LRRK2 and GBA, four PARK2 lines, and the control) were differentiated into neural stem cells (NSC) and subsequently to dopaminergic cultures. We did not observe significant differences in the timeline of neural induction and NSC derivation between the patient and control line, nor amongst the patient lines, although we report considerable variability in the efficiency of dopaminergic differentiation among patient lines. We performed whole genome expression analyses of the lines at each stage of differentiation (fibroblast, iPSC, NSC, and dopaminergic culture) in an attempt to identify alterations by large-scale evaluation. While gene expression profiling clearly distinguished cells at different stages of differentiation, no mutation-specific clustering or difference was observed, though consistent changes in patient lines were detected in genes associated mitochondrial biology. We further examined gene expression in a stress model (MPTP-induced dopaminergic neuronal death) using two clones from the SNCA triplication line, and detected changes in genes associated with mitophagy. Our data suggested that even a well-characterized line of a monogenic disease may not be sufficient to determine the cause or mechanism of the disease, and highlights the need to use more focused strategies for large-scale data analysis.

  10. Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.

    Science.gov (United States)

    Lesage, Suzanne; Patin, Etienne; Condroyer, Christel; Leutenegger, Anne-Louise; Lohmann, Ebba; Giladi, Nir; Bar-Shira, Anat; Belarbi, Soraya; Hecham, Nassima; Pollak, Pierre; Ouvrard-Hernandez, Anne-Marie; Bardien, Soraya; Carr, Jonathan; Benhassine, Traki; Tomiyama, Hiroyuki; Pirkevi, Caroline; Hamadouche, Tarik; Cazeneuve, Cécile; Basak, A Nazli; Hattori, Nobutaka; Dürr, Alexandra; Tazir, Meriem; Orr-Urtreger, Avi; Quintana-Murci, Lluis; Brice, Alexis

    2010-05-15

    Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.

  11. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    Science.gov (United States)

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  12. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    Science.gov (United States)

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  13. A frequent splicing mutation and novel missense mutations color the updated mutational spectrum of classic galactosemia in Portugal.

    Science.gov (United States)

    Coelho, Ana I; Ramos, Ruben; Gaspar, Ana; Costa, Cláudia; Oliveira, Anabela; Diogo, Luísa; Garcia, Paula; Paiva, Sandra; Martins, Esmeralda; Teles, Elisa Leão; Rodrigues, Esmeralda; Cardoso, M Teresa; Ferreira, Elena; Sequeira, Sílvia; Leite, Margarida; Silva, Maria João; de Almeida, Isabel Tavares; Vicente, João B; Rivera, Isabel

    2014-01-01

    Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder.

  14. Candidate SNP markers of gender-biased autoimmune complications of monogenic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

    Directory of Open Access Journals (Sweden)

    Mikhail P. Ponomarenko

    2016-04-01

    Full Text Available Some variations of human genome (for example, single nucleotide polymorphisms [SNPs] are markers of hereditary diseases and drug responses. Analysis of them can help to improve treatment. Computer-based analysis of millions of SNPs in the 1000 Genomes project makes a search for SNP markers more targeted. Here we combined two computer-based approaches: DNA sequence analysis and keyword search in databases. In the binding sites for TATA-binding protein (TBP in human gene promoters, we found candidate SNP markers of gender-biased autoimmune diseases, including rs1143627 (cachexia in rheumatoid arthritis [double prevalence among women]; rs11557611 (demyelinating diseases [thrice more prevalent among young white women than among nonwhite individuals]; rs17231520 and rs569033466 (both: atherosclerosis comorbid with related diseases [double prevalence among women]; rs563763767 (Hughes syndrome-related thrombosis [lethal during pregnancy]; rs2814778 (autoimmune diseases [excluding multiple sclerosis and rheumatoid arthritis] underlying hypergammaglobulinemia in women; rs72661131 and rs562962093 (both: preterm delivery in pregnant diabetic women; and rs35518301, rs34166473, rs34500389, rs33981098, rs33980857, rs397509430, rs34598529, rs33931746, rs281864525, and rs63750953 (all: autoimmune diseases underlying hypergammaglobulinemia in women. Validation of these predicted candidate SNP markers using the clinical standards may advance personalized medicine.

  15. Monogenic primary hypercholesterolaemia in South Africa

    African Journals Online (AJOL)

    group of exons defines a distinct domain of the receptor. (Fig. 3). Exon 1 codes for a .... vesicles is lowered by a proton-driven pump. In the compartment for the ... genetic diseases and has facilitated the design of easy and reliable methods of ...

  16. Germline mutation screening and predictive testing in families with von Hippel-Lindau disease

    Energy Technology Data Exchange (ETDEWEB)

    Brauch, H.; Glavac, D.; Pausch, F. [Univ. of Munich (Germany)] [and others

    1994-09-01

    von Hippel-Lindau (VHL) disease is an autosomal inheritable disease that predisposes gene carriers to develop tumors in the eyes, central nervous system, kidney, adrenal gland, pancreas and epididymis. VHL type 1 is without phenochromocytoma (P); VHL type 2 is with P. Screening for germline mutations and preclinical diagnosis in families with VHL disease has become feasible since the VHL gene was isolated. We applied Southern blotting and hybridization with g7cDNA to detect rearrangements, PCR-SSCP and sequencing to detect missense, nonsense and splice mutations, and primer-specified restriction map modification to detect a P-specific missense mutation. In 48 apparently unrelated VHL families mainly from Germany, we identified 20/48 (42%) VHL mutations: 7 (14.5%) rearrangements, 9/48 (19%) missense mutations affecting nt505, 1/48 (2%) splice site mutation, 2/48 (4%) other missense mutations, and 1/48 (2%) nonsense mutation. The predominance of the nt505 mutation in 9 German families with VHL type 2 suggests that this genotype expresses the VHL/P disease pattern. Predictive testing for VHL gene carriers in families with specific mutations identified 7 asymptomatic gene carriers. VHL manifestations have been confirmed by clinical examination in two individuals. Early molecular diagnosis may result in a successful management of VHL disease and prolong survival of VHL patients.

  17. Orthogonal basis for spherical monogenics by step two branching

    CERN Document Server

    Lavicka, R; Van Lancker, P

    2010-01-01

    Spherical monogenics can be regarded as a basic tool for the study of harmonic analysis of the Dirac operator in Euclidean space R^m. They play a similar role as spherical harmonics do in case of harmonic analysis of the Laplace operator on R^m. Fix the direct sum R^m = R^p x R^q. In this paper we will study the decomposition of the space M_n(R^m;C_m) of spherical monogenics of order n under the action of Spin(p) x Spin(q). As a result we obtain a Spin(p) x Spin(q)-invariant orthonormal basis for M_n(R^m;C_m). In particular, using the construction with p = 2 inductively, this yields a new orthonormal basis for the space M_n(R^m;C_m).

  18. Mutation analysis of presenilin-1 gene in Alzheimer’s disease patients and the effects of its mutation on expression of presenilin-1 and amyloid precursor protein

    Institute of Scientific and Technical Information of China (English)

    刘晓雄

    2013-01-01

    Objective To analyze the presenilin-1(PS-1) gene mutations in Alzheimer’s disease(AD) patients and investigate the influence of the initiation codon mutation on the mRNA expression of PS-1 and amyloid precursor protein

  19. A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease

    NARCIS (Netherlands)

    Aerts, M.B.; Weterman, M.A.; Quadri, M.; Schelhaas, H.J.; Bloem, B.R.; Esselink, R.A.; Baas, F.; Bonifati, V.; Warrenburg, B.P. van de

    2016-01-01

    LRSAM1 mutations have been found in recessive and dominant forms of Charcot-Marie-Tooth disease. Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and

  20. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

    Science.gov (United States)

    Mencacci, Niccolò E.; Isaias, Ioannis U.; Reich, Martin M.; Ganos, Christos; Plagnol, Vincent; Polke, James M.; Bras, Jose; Hersheson, Joshua; Stamelou, Maria; Pittman, Alan M.; Noyce, Alastair J.; Mok, Kin Y.; Opladen, Thomas; Kunstmann, Erdmute; Hodecker, Sybille; Münchau, Alexander; Volkmann, Jens; Samnick, Samuel; Sidle, Katie; Nanji, Tina; Sweeney, Mary G.; Houlden, Henry; Batla, Amit; Zecchinelli, Anna L.; Pezzoli, Gianni; Marotta, Giorgio; Lees, Andrew; Alegria, Paulo; Krack, Paul; Cormier-Dequaire, Florence; Lesage, Suzanne; Brice, Alexis; Heutink, Peter; Gasser, Thomas; Lubbe, Steven J.; Morris, Huw R.; Taba, Pille; Koks, Sulev; Majounie, Elisa; Raphael Gibbs, J.; Singleton, Andrew; Hardy, John; Klebe, Stephan

    2014-01-01

    GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1

  1. Biochemical Characterization of P4-ATPase Mutations Associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine;

    The cholestatic disorders progressive familial intrahepatic cholestasis type 1 (PFIC1, also referred to as Byler’s disease) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1. The substrate of ATP8B1 is very likely to be phosphatidylserine...... families have been investigated, and more than 50 distinct disease mutations have been identified, with roughly half being missense mutations. In this project we try to answer the question whether PFIC1 mutations are generally more disturbing than BRIC1 mutations with respect to expression, structural...... stability and function. We investigate the mutations in our well functioning system of ATP8A2, being expressed in mammalian HEK293T cells, affinity-purified, and reconstituted in lipid vesicles. Well-known mutations from both groups of patients have been selected for study. I91P in ATP8A2 (L127P in ATP8B1...

  2. Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease.

    Directory of Open Access Journals (Sweden)

    Yi-Chu Liao

    Full Text Available Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive.Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability.GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

  3. Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Liao, Yi-Chu; Liu, Yo-Tsen; Tsai, Pei-Chien; Chang, Chia-Ching; Huang, Yen-Hua; Soong, Bing-Wen; Lee, Yi-Chung

    2015-01-01

    Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive. Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability. GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

  4. Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

    Science.gov (United States)

    2014-01-01

    Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (Ptriglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.) PMID:24941081

  5. High-resolution melting facilitates mutation screening of PYGM in patients with McArdle disease

    DEFF Research Database (Denmark)

    Duno, M.; Quinlivan, R.; Vissing, J.

    2009-01-01

    variations. Thirteen of these are pathogenic, and three were classified as polymorphisms. Nine variations had not previously been described. One of the novel mutations, c.2430C > T, was initially predicted to result in a silent G810G change, but cDNA analysis demonstrated that the mutation led to abnormal m......Mutations in PYGM, encoding the muscle-specific glycogen phosphorylase (myophosphorylase), are responsible for McArdle disease. Among Caucasians, a large proportion of patients are homozygous for the R50X mutation, but other mutations can affect all the 20 exons of PYGM, making mutation detection...... laborious. We have developed a high-resolution melting (HRM) assay for mutation detection in PYGM. Twelve McArdle patients were investigated, in whom pre-screening had ruled out homozygosity or compound heterozygosity for the two common G205S and R50X mutations. In total, we identified 16 different...

  6. Relating the disease mutation spectrum to the evolution of the cystic fibrosis transmembrane conductance regulator (CFTR.

    Directory of Open Access Journals (Sweden)

    Lavanya Rishishwar

    Full Text Available Cystic fibrosis (CF is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%, along with the best set of paired sensitivity (58% and specificity (60% values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly

  7. Age-specific Parkinson disease risk in GBA mutation carriers: information for genetic counseling.

    Science.gov (United States)

    Rana, Huma Q; Balwani, Manisha; Bier, Louise; Alcalay, Roy N

    2013-02-01

    We sought to estimate age-specific risk of Parkinson disease in relatives of patients with Gaucher disease, who are obligate carriers of GBA mutations and who were not ascertained by family history of Parkinson disease. A validated family history of Parkinson disease questionnaire was administered to 119 patients with Gaucher disease who were evaluated at the Mount Sinai School of Medicine from 2009 to 2012; the ages of their parents, siblings, and children, history of Parkinson disease, age at onset of Parkinson disease, and ethnic background were obtained. Kaplan-Meier survival curves were used to estimate age-specific Parkinson disease penetrance among parents of patients with Gaucher disease, who are obligatory GBA mutation carriers. Two participants with Gaucher disease were affected by Parkinson disease (5.4% of those who were 60 years or older). Of the 224 informative parents of patients with Gaucher disease, 11 had Parkinson disease (4.9%). Among the parents (obligatory carriers), cumulative risk of Parkinson disease by ages 65 and 85 was estimated to be 2.2% ±2.1% and 10.9% ±7.2%, respectively. We provide useful age-specific estimates of Parkinson disease penetrance in patients with Gaucher disease and GBA heterozygous carriers for genetic counseling. Although GBA mutations may increase the risk for PD, the vast majority of patients with Gaucher disease and heterozygotes may not develop the disease. Further studies are needed to identify what modifies the risk of Parkinson disease in GBA mutation carriers.

  8. Monogenic Auto-inflammatory Syndromes: A Review of the Literature.

    Science.gov (United States)

    Azizi, Gholamreza; Khadem Azarian, Shahin; Nazeri, Sepideh; Mosayebian, Ali; Ghiasy, Saleh; Sadri, Ghazal; Mohebi, Ali; Khan Nazer, Nikoo Hossein; Afraei, Sanaz; Mirshafiey, Abbas

    2016-12-01

    Auto-inflammatory syndromes are a new group of distinct hereditable disorders characterized by episodes of seemingly unprovoked inflammation (most commonly in skin, joints, gut, and eye), the absence of a high titer of auto-antibodies or auto-reactive T cells, and an inborn error of innate immunity. A narrative literature review was carried out of studies related to auto-inflammatory syndromes to discuss the pathogenesis and clinical manifestation of these syndromes. This review showed that the main monogenic auto-inflammatory syndromes are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). The data suggest that correct diagnosis and treatment of monogenic auto-inflammatory diseases relies on the physicians' awareness. Therefore, understanding of the underlying pathogenic mechanisms of auto-inflammatory syndromes, and especially the fact that these disorders are mediated by IL-1 secretion stimulated by monocytes and macrophages, facilitated significant progress in patient management.

  9. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

    Science.gov (United States)

    Gulsuner, Suleyman; Stapleton, Gail A.; Walsh, Tom; Lee, Ming K.; Mandell, Jessica B.; Morales, Augusto; Klevit, Rachel E.; King, Mary-Claire; Rogers, R. Curtis

    2016-01-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  10. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

    Science.gov (United States)

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu-Wai-Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian-Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis-Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard; Barrett, Timothy G

    2017-07-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  11. Neuropsychological manifestations of the genetic mutation for Huntington's disease in presymptomatic individuals.

    Science.gov (United States)

    Brandt, Jason; Shpritz, Barnett; Codori, Ann Marie; Margolis, Russell; Rosenblatt, Adam

    2002-11-01

    A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4 is responsible for Huntington's disease (HD). Presymptomatic genetic testing for this mutation has identified clinically normal persons who are virtually certain to develop this dementing illness if they live a normal lifespan. The present study sought to determine whether these "mutation-positive" persons have impairments in cognitive functioning. Seventy-five mutation-positive persons did not differ from 128 mutation-negative persons on tests selected for their sensitivity to early-stage HD. Interestingly, however, those with the mutation viewed themselves as more likely to develop HD than did those without the mutation. Among mutation-positive subjects, having a longer CAG repeat mutation was likewise not associated with cognitive impairment. However, being closer to estimated disease onset (a product of repeat length and parent's age at onset) was associated with selected cognitive impairments. When viewed in light of previous studies showing atrophy of the caudate nucleus and putamen in mutation-carriers who are close to onset but not those far from onset, these results suggest that subtle changes in brain and behavior may be detected shortly before subjects with the HD mutation develop sufficient signs and symptoms for diagnosis. Conceptual and methodological problems associated with the search for presymptomatic cognitive and behavioral indicators of dementing illness are discussed.

  12. Atopic diseases by filaggrin mutations and birth year

    DEFF Research Database (Denmark)

    Thyssen, J P; Linneberg, A; Johansen, J D;

    2012-01-01

    The prevalence of atopic disorders has increased in recent years. The pathogenesis is complex with genetic and environmental risk factors. Filaggrin loss-of-function mutations are common and associated with atopic disorders. We investigated whether the prevalence of filaggrin mutations increased ...

  13. Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia.

    Science.gov (United States)

    Rubba, Paolo; Gentile, Marco; Marotta, Gennaro; Iannuzzi, Arcangelo; Sodano, Marta; De Simone, Biagio; Jossa, Fabrizio; Iannuzzo, Gabriella; Giacobbe, Carola; Di Taranto, Maria D; Fortunato, Giuliana

    2017-07-01

    Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.

  14. Incidence and mutation rates of Huntington's disease in Spain: experience of 9 years of direct genetic testing

    OpenAIRE

    Ramos-Arroyo, M; Moreno, S.; Valiente, A.

    2005-01-01

    Background: Prior to the discovery of the Huntington's disease (HD) mutation, the prevalence, incidence, and new mutation rates for this disease were based on the presence of progressive choreic movements and a positive family history.

  15. Disruption of a Novel Krüppel-like Transcription Factor p300-regulated Pathway for Insulin Biosynthesis Revealed by Studies of the c.-331 INS Mutation Found in Neonatal Diabetes Mellitus*

    OpenAIRE

    2011-01-01

    Krüppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin ...

  16. Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease

    DEFF Research Database (Denmark)

    Nordestgaard, Liv Tybjærg; Tybjærg-Hansen, Anne; Nordestgaard, Børge G

    2015-01-01

    -brain barrier via apoE-mediated pathways. METHODS: We tested whether a loss-of-function mutation in ABCA1, N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. RESULTS: N1800H AC (0.......2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE (P = 1 × 10(-11)). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32-12.9) for AD, 2.46 (1.10-5.50) for cerebrovascular disease, and 8.28 (2.03-33.7) for the hemorrhagic stroke...... subtype. DISCUSSION: A loss-of-function mutation in ABCA1, present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population....

  17. Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

    Science.gov (United States)

    Crosby, Jacy; Peloso, Gina M; Auer, Paul L; Crosslin, David R; Stitziel, Nathan O; Lange, Leslie A; Lu, Yingchang; Tang, Zheng-zheng; Zhang, He; Hindy, George; Masca, Nicholas; Stirrups, Kathleen; Kanoni, Stavroula; Do, Ron; Jun, Goo; Hu, Youna; Kang, Hyun Min; Xue, Chenyi; Goel, Anuj; Farrall, Martin; Duga, Stefano; Merlini, Pier Angelica; Asselta, Rosanna; Girelli, Domenico; Olivieri, Oliviero; Martinelli, Nicola; Yin, Wu; Reilly, Dermot; Speliotes, Elizabeth; Fox, Caroline S; Hveem, Kristian; Holmen, Oddgeir L; Nikpay, Majid; Farlow, Deborah N; Assimes, Themistocles L; Franceschini, Nora; Robinson, Jennifer; North, Kari E; Martin, Lisa W; DePristo, Mark; Gupta, Namrata; Escher, Stefan A; Jansson, Jan-Håkan; Van Zuydam, Natalie; Palmer, Colin N A; Wareham, Nicholas; Koch, Werner; Meitinger, Thomas; Peters, Annette; Lieb, Wolfgang; Erbel, Raimund; Konig, Inke R; Kruppa, Jochen; Degenhardt, Franziska; Gottesman, Omri; Bottinger, Erwin P; O'Donnell, Christopher J; Psaty, Bruce M; Ballantyne, Christie M; Abecasis, Goncalo; Ordovas, Jose M; Melander, Olle; Watkins, Hugh; Orho-Melander, Marju; Ardissino, Diego; Loos, Ruth J F; McPherson, Ruth; Willer, Cristen J; Erdmann, Jeanette; Hall, Alistair S; Samani, Nilesh J; Deloukas, Panos; Schunkert, Heribert; Wilson, James G; Kooperberg, Charles; Rich, Stephen S; Tracy, Russell P; Lin, Dan-Yu; Altshuler, David; Gabriel, Stacey; Nickerson, Deborah A; Jarvik, Gail P; Cupples, L Adrienne; Reiner, Alex P; Boerwinkle, Eric; Kathiresan, Sekar

    2014-07-03

    Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (Pdisease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

  18. De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Motley, William W; Palaima, Paulius; Yum, Sabrina W; Gonzalez, Michael A; Tao, Feifei; Wanschitz, Julia V; Strickland, Alleene V; Löscher, Wolfgang N; De Vriendt, Els; Koppi, Stefan; Medne, Livija; Janecke, Andreas R; Jordanova, Albena; Zuchner, Stephan; Scherer, Steven S

    2016-06-01

    We performed whole exome sequencing on a patient with Charcot-Marie-Tooth disease type 1 and identified a de novo mutation in PMP2, the gene that encodes the myelin P2 protein. This mutation (p.Ile52Thr) was passed from the proband to his one affected son, and segregates with clinical and electrophysiological evidence of demyelinating neuropathy. We then screened a cohort of 136 European probands with uncharacterized genetic cause of Charcot-Marie-Tooth disease and identified another family with Charcot-Marie-Tooth disease type 1 that has a mutation affecting an adjacent amino acid (p.Thr51Pro), which segregates with disease. Our genetic and clinical findings in these kindred demonstrate that dominant PMP2 mutations cause Charcot-Marie-Tooth disease type 1. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jia Chen

    Full Text Available Mutations of glucocerebrosidase (GBA confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs and 95% confidence intervals (CIs. The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77-10.68, p<0.00001, and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23-26.06, p<0.00001. No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.

  20. Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.

    Science.gov (United States)

    Chen, Jia; Li, Wei; Zhang, Tao; Wang, Yan-jiang; Jiang, Xiao-jiang; Xu, Zhi-qiang

    2014-01-01

    Mutations of glucocerebrosidase (GBA) confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls) and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77-10.68, p<0.00001), and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23-26.06, p<0.00001). No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.

  1. GATA2 mutations in patients with acute myeloid leukemia-paired samples analyses show that the mutation is unstable during disease evolution.

    Science.gov (United States)

    Hou, Hsin-An; Lin, Yun-Chu; Kuo, Yuan-Yeh; Chou, Wen-Chien; Lin, Chien-Chin; Liu, Chieh-Yu; Chen, Chien-Yuan; Lin, Liang-In; Tseng, Mei-Hsuan; Huang, Chi-Fei; Chiang, Ying-Chieh; Liu, Ming-Chih; Liu, Chia-Wen; Tang, Jih-Luh; Yao, Ming; Huang, Shang-Yi; Ko, Bor-Sheng; Hsu, Szu-Chun; Wu, Shang-Ju; Tsay, Woei; Chen, Yao-Chang; Tien, Hwei-Fang

    2015-02-01

    Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA (double-mut)), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA (double-mut), CEBPA (single-mut), and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.

  2. The emerging role of SMPD1 mutations in Parkinson's disease: Implications for future studies.

    Science.gov (United States)

    Gan-Or, Ziv; Orr-Urtreger, Avi; Alcalay, Roy N; Bressman, Susan; Giladi, Nir; Rouleau, Guy A

    2015-10-01

    Recently, an additional study confirmed the association between SMPD1 mutations and Parkinson's disease (PD). While the first study on SMPD1 and PD suggested that only one SMPD1 mutations is responsible for the association to PD, the recent study argued that all SMPD1 mutations may be associated with an increased risk for PD. Since SMPD1 mutations are being routinely screened in some populations with high carrier frequencies, and since it will be further screened in additional PD populations, it is important to better define the association between SMPD1 and PD. We reanalyzed the data from the recent and previous papers, and we show that the association between SMPD1 and PD is indeed not driven by only one mutation, but it is also not driven by all SMPD1 mutations. In the Ashkenazi-Jewish population, the p.fs330P (OR = 3.03, p = 0.0026) and p.L302P (OR = 9.62, p < 0.0001) are associated with PD, and the p.R496L mutation is not (OR = 0.84, p = 0.71), and similar observation was noted in the Chinese population. Thus, we conclude that similar to the GBA gene where different mutations have differential effects, SMPD1 mutations also have a differential effects on the risk for PD. Future studies should therefore examine the association by mutation and not by accumulative risk of all mutations.

  3. Asian origin for the worldwide-spread mutational event in Machado-Joseph disease

    NARCIS (Netherlands)

    Martins, Sandra; Calafell, Francesc; Gaspar, Claudia; Wong, Virginia C. N.; Silveira, Isabel; Nicholson, Garth A.; Brunt, Ewout R.; Tranebjaerg, Lisbeth; Stevanin, Giovanni; Hsieh, Mingli; Soong, Bing-Wen; Loureiro, Leal; Duerr, Alexandra; Tsuji, Shoji; Watanabe, Mitsunori; Jardim, Laura B.; Giunti, Paola; Riess, Olaf; Ranum, Laura P. W.; Brice, Alexis; Rouleau, Guy A.; Coutinho, Paula; Amorim, Antonio; Sequeiros, Jorge

    2007-01-01

    Background: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution. Objectives: To trace back in history the main mutational events in M

  4. Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease

    DEFF Research Database (Denmark)

    Lesca, Gaetan; Boutry-Kryza, Nadia; de Toffol, Bertrand

    2010-01-01

    Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients ...

  5. A new mutation for Huntington disease following maternal transmission of an intermediate allele

    NARCIS (Netherlands)

    Semaka, Alicia; Kay, Chris; Belfroid, Rene D. M.; Bijlsma, Emilia K.; Losekoot, Monique; van Langen, Irene M.; van Maarle, Merel C.; Oosterloo, Mayke; Hayden, Michael R.; van Belzen, Martine J.

    2015-01-01

    New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (>= 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the pa

  6. Low frequency of filaggrin null mutations in Croatia and their relation with allergic diseases.

    Science.gov (United States)

    Sabolić Pipinić, I; Varnai, V M; Turk, R; Breljak, D; Kezić, S; Macan, J

    2013-06-01

    Filaggrin gene (FLG) null mutations are considered associated with atopic dermatitis. This study was conducted to determine the prevalence of FLG null mutations R501X, 2282del4, R2447X and S3247X in the Croatian population and their role in the occurrence of allergic diseases including atopic dermatitis, allergic rhinitis, asthma and allergic contact dermatitis (ACD). Study enrolled 440 freshmen with defined allergic diseases by means of both present symptoms in International Study of Asthma and Allergies in Childhood questionnaire (relevant respiratory and/or skin symptoms) and markers of allergic sensitization (positive skin prick and/or patch test). FLG null mutations were successfully genotyped in 423 students of which 11 (2.6%) were carriers of FLG null mutation: 1/423 (0.2%) was heterozygous for R501X and 10/423 (2.4%) were heterozygous for 2282del4. No carriers of R2447X and S3247X mutations were identified. In wild-type FLG carriers (412 subjects), atopic dermatitis was present in 45 (11%), allergic rhinitis in 70 (17%) and allergic asthma in 29 (7%) students. Twenty-five of 393 (7%) patch-tested wild-type FLG carriers had ACD. Among 11 FLG null mutation carriers, four had one or more allergic diseases, and five had reported skin symptoms without defined allergic sensitization (positive skin prick test and/or patch test). FLG null mutations were not confirmed as a predictor of analysed allergic diseases, but were confirmed as an independent predictor of skin symptoms (OR 17.19, 95% CI 3.41-86.6, P null mutations in the studied Croatian population supporting a theory of a latitude-dependent distribution of FGL null mutations in Europe, with a decreasing north-south gradient of R501X and 2282del4 mutation frequency. The relation between FLG null mutations and skin disorders was confirmed.

  7. DiMeX: A Text Mining System for Mutation-Disease Association Extraction.

    Science.gov (United States)

    Mahmood, A S M Ashique; Wu, Tsung-Jung; Mazumder, Raja; Vijay-Shanker, K

    2016-01-01

    The number of published articles describing associations between mutations and diseases is increasing at a fast pace. There is a pressing need to gather such mutation-disease associations into public knowledge bases, but manual curation slows down the growth of such databases. We have addressed this problem by developing a text-mining system (DiMeX) to extract mutation to disease associations from publication abstracts. DiMeX consists of a series of natural language processing modules that preprocess input text and apply syntactic and semantic patterns to extract mutation-disease associations. DiMeX achieves high precision and recall with F-scores of 0.88, 0.91 and 0.89 when evaluated on three different datasets for mutation-disease associations. DiMeX includes a separate component that extracts mutation mentions in text and associates them with genes. This component has been also evaluated on different datasets and shown to achieve state-of-the-art performance. The results indicate that our system outperforms the existing mutation-disease association tools, addressing the low precision problems suffered by most approaches. DiMeX was applied on a large set of abstracts from Medline to extract mutation-disease associations, as well as other relevant information including patient/cohort size and population data. The results are stored in a database that can be queried and downloaded at http://biotm.cis.udel.edu/dimex/. We conclude that this high-throughput text-mining approach has the potential to significantly assist researchers and curators to enrich mutation databases.

  8. Detection of non-ΔGT NCF-1 mutations in chronic granulomatous disease

    DEFF Research Database (Denmark)

    Jakobsen, Marianne Antonius; Pedersen, Svend Stenvang; Barington, Torben

    2009-01-01

    to the functional NCF-1 has complicated the identification of other mutations in the gene. The aim of this study was to find a general technique for detection of non-GT deletion mutations in the coding region of NCF-1. RESULTS: A technique involving GeneScan analysis followed by amplification of cDNA with intact...... dinucleotide repeat was set up and used to identify a novel mutation in exon 7 of NCF-1 in a patient with autosomal recessive CGD, explaining the disease by changing a UGG codon to a premature UGA STOP codon. CONCLUSION: The method is generally applicable for the detection of NCF-1 mutations in patients...

  9. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Yu Chaowen

    2011-12-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: PKD1 (16p13.3 and PKD2 (4q21. Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of PKD1 gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both PKD1 and PKD2 genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC. Methods Both PKD1 and PKD2 genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources. Results A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65. About 69% (20/29 of the mutations are first reported with a recurrent mutation rate of 31%. Conclusions Mutation study of PKD1 and PKD2 genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.

  10. Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY).

    Science.gov (United States)

    Yamagata, Kazuya

    2014-01-01

    Mutations in the genes encoding hepatocyte nuclear factor (HNF)1α and HNF4α cause a monogenic form of diabetes mellitus known as maturity-onset diabetes of the young (MODY). The primary cause of MODY is an impairment of glucose-stimulated insulin secretion by pancreatic β-cells, indicating the important roles of HNF1α and HNF4α in β-cells. Large-scale genetic studies have clarified that the common variants of HNF1α and HNF4α genes are also associated with type 2 diabetes, suggesting that they are involved in the pathogenesis of both diseases. Recent experimental studies revealed that HNF1α controls both β-cell function and growth by regulating target genes such as glucose transporter 2, pyruvate kinase, collectrin, hepatocyte growth factor activator, and HNF4α. In contrast, HNF4α mainly regulates the function of β-cells. Although direct target genes of HNF4α in β-cells are largely unknown, we recently identified Anks4b as a novel target of HNF4α that regulates β-cell susceptibility to endoplasmic reticulum stress. Studies of MODY have led to a better understanding of the molecular mechanism of glucose-stimulated insulin secretion by pancreatic β-cells.

  11. Gaucher disease: Pseudoreversion of a disease mutation`s effects--implications for structure/function and genotype/phenotype correlations

    Energy Technology Data Exchange (ETDEWEB)

    Ponce, E.; Mear, J; Grabowski, G.A. [Children`s Hospital Research Foundation, Cincinnati, OH (United States)

    1994-09-01

    Numerous mutations ({approximately}45) of the acid {beta}-glucosidase gene have been identified in patients with Gaucher disease. Many of these have been characterized by partial sequencing of cDNAs derived by RT-PCR or PCR of genomic DNA. In addition, genotype/phenotype correlations have been based on screening for known mutations. Thus, only a part of the gene is characterized in any population of affected patients. Several Gaucher disease alleles contain multiple, authentic point mutations that raises concern about conclusions based on only partial genetic characterization. Several wild-type cDNAs for acid {beta}-glucosidase have been sequenced. One contained a cloning artifact encoding R495H. We expressed this cDNA and showed that the R495H enzyme had normal kinetic and stability properties. A disease-associated allele encoding R496H has been found by several groups. The close association and similarities of these two substitutions led us to question the disease casuality of the R496H allele. To evaluate this, we created and/or expressed cDNAs encoding R495, R496 (wild-type), (R495H, R496), (R495, R496H) and (R495H, R496H). The (wild-type) and (R495H, R496) enzymes had indistinguishable properties whereas the (R495, R496H) enzyme was essentially inactive. The introduction of both mutations (R495H, R496H) produced an enzyme whose activity was 25 to 50% of the wild-type. These results indicate that a pseudoreversion to a functional enzyme can occur by introducing a functionally neutral mutation together with a severe mutation. These results have major implications to structure/function and genotype/phenotype correlations in this disease.

  12. Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease.

    Science.gov (United States)

    Gratten, Jacob; Visscher, Peter M; Mowry, Bryan J; Wray, Naomi R

    2013-03-01

    Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease.

  13. Wilson disease: Identification of two novel mutations and clinical correlation in Eastern Chinese patients

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To study mutations in the P-type ATPase (ATP7B)gene responsible for Wilson disease (WD) in the Eastern Chinese population, and the possible correlation of specific mutations with clinical characteristics.METHODS: Mutations of the ATP7B gene were sought by means of direct sequencing in 50 Eastern Chinese WD patients of Han ethnic origin.RESULTS: Two novel mutations, Asp96Gly and Asp196Glu, were first identified. We also compared the characterization of mutations in ATP7B with the clinical findings, and a significant correlation with hepatic manifestations between patients carrying the Arg778Leu mutation and those without was found.CONCLUSION: Gene sequencing analysis was shown to have a high detection rate and accuracy. It may become the first priority in screening of WD patients.

  14. Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

    Science.gov (United States)

    Guo, Dong-Chuan; Papke, Christina L.; Tran-Fadulu, Van; Regalado, Ellen S.; Avidan, Nili; Johnson, Ralph Jay; Kim, Dong H.; Pannu, Hariyadarshi; Willing, Marcia C.; Sparks, Elizabeth; Pyeritz, Reed E.; Singh, Michael N.; Dalman, Ronald L.; Grotta, James C.; Marian, Ali J.; Boerwinkle, Eric A.; Frazier, Lorraine Q.; LeMaire, Scott A.; Coselli, Joseph S.; Estrera, Anthony L.; Safi, Hazim J.; Veeraraghavan, Sudha; Muzny, Donna M.; Wheeler, David A.; Willerson, James T.; Yu, Robert K.; Shete, Sanjay S.; Scherer, Steven E.; Raman, C.S.; Buja, L. Maximilian; Milewicz, Dianna M.

    2009-01-01

    The vascular smooth muscle cell (SMC)-specific isoform of α-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases. PMID:19409525

  15. A New PKD1 Mutation Discovered in a Chinese Family with Autosomal Polycystic Kidney Disease

    OpenAIRE

    Zhendi Wang; Yang Wang; Jing Xiong

    2014-01-01

    Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD), a heterogeneous genetic disorder characterized by massive kidney enlargement and progressive chronic kidney disease, is due to abnormal proliferation of renal tubular epithelium. ADPKD is known to be caused by mutations in PKD1 and PKD2 genes. Methods: In the present study, the mutation analysis of PKD genes was performed in a new Chinese family with ADPKD using Long-Range (LR) PCR sequencing and targeted next-generation s...

  16. Intragenic Deletion as a Novel Type of Mutation in Wolman Disease

    OpenAIRE

    Lee, Teresa M.; Welsh, Mariko; Benhamed, Sonia; Chung, Wendy K.

    2011-01-01

    Two clinically distinct disorders, Wolman disease (WD) and cholesteryl ester storage disease (CESD), are allelic autosomal recessive disorders caused by different mutations in lysosomal acid lipase (LIPA) which encodes for an essential enzyme involved in the hydrolysis of intracellular cholesteryl esters and triglycerides. We describe a case of lysosomal acid lipase deficiency in an infant with WD and report on a novel mutation type, intragenic deletion.

  17. [Molecular analysis of the p.Asn 370 Ser mutation in Gaucher disease].

    Science.gov (United States)

    Dandana, A; Ferchichi, S; Ben Khelifa, S; Jaidane, Z; Monastiri, K; Chkioua, L; Maire, I; Froissart, R; Bonnet, V; Laradi, S; Miled, A

    2008-03-01

    Gaucher disease is one of the most prevalent lysosomal disorders. In this present study, we report a diagnostic strategy of type 1 Gaucher disease. The application of combined methods in molecular biology allowed us to analyse the p.Asn 370 Ser mutation. The affected individual activity is very low. First, we have to used the enzymatic digestion method. Then, we have to identified the mutation by the refractory mutation system technique using specific primers for the p.Asn 370 Ser mutation. These analyses are supplemented by the direct sequencing in order to seek and confirm this mutation. Finally, the absence of the 55 pb deletion in exon 9 among corroborated the presence of the homozygous genotype of this p.Asn 370 Ser in the patient DNA.

  18. Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.

    Directory of Open Access Journals (Sweden)

    Xiwei Hao

    Full Text Available BACKGROUND: Mutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established. METHODS: Whole exome sequencing (WES was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin. RESULTS: A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala, and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*. This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes. CONCLUSIONS: Our findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.

  19. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

    Science.gov (United States)

    Hou, H-A; Chou, W-C; Kuo, Y-Y; Liu, C-Y; Lin, L-I; Tseng, M-H; Chiang, Y-C; Liu, M-C; Liu, C-W; Tang, J-L; Yao, M; Li, C-C; Huang, S-Y; Ko, B-S; Hsu, S-C; Chen, C-Y; Lin, C-T; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

    2015-07-31

    The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

  20. Mild Lesch-Nyhan Disease in a Boy with a Null Mutation inHPRT1

    DEFF Research Database (Denmark)

    Bayat, Allan; Christensen, Mette; Wibrand, Flemming

    2015-01-01

    are generally associated with the classic Lesch-Nyhan disease (LND) phenotype with intellectual disability, motor handicap and self-injurious behaviour. Mutations that permit a higher residual HPRT activity are seen in some patients with the milder LND variant phenotypes with varying degrees of cognitive, motor......-injurious behaviour. KEY CLINICAL MESSAGE: HPRT1 mutations that result in very low or no hypoxanthine-guanine phosphoribosyltransferase enzyme activities are generally associated with the classic Lesch-Nyhan disease. This report presents one of the rare cases with a null mutation in the HPRT1 gene that associates...

  1. Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease

    Directory of Open Access Journals (Sweden)

    Jayesh Sheth

    2014-01-01

    Full Text Available Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52, resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay–Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (C (D175A and c.805G>C (p.G269R in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57 and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i c.532C>T (p.R178C, (ii c.964G>T (p.D322Y, and (iii c.1385A>T (p.E462V; two nonsense mutations (i c.709C>T (p.Q237X and (ii c.1528C>T (p.R510X, one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5 and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay–Sachs disease with clustering of ~73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

  2. Expanding the spectrum of HEXA mutations in Indian patients with Tay-Sachs disease.

    Science.gov (United States)

    Sheth, Jayesh; Mistri, Mehul; Datar, Chaitanya; Kalane, Umesh; Patil, Shekhar; Kamate, Mahesh; Shah, Harshuti; Nampoothiri, Sheela; Gupta, Sarita; Sheth, Frenny

    2014-01-01

    Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay-Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

  3. Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

    Science.gov (United States)

    Monroy-Jaramillo, Nancy; Guerrero-Camacho, Jorge Luis; Rodríguez-Violante, Mayela; Boll-Woehrlen, Marie-Catherine; Yescas-Gómez, Petra; Alonso-Vilatela, María Elisa; López-López, Marisol

    2014-04-01

    Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

  4. Natural history of five children with surfactant protein C mutations and interstitial lung disease.

    Science.gov (United States)

    Avital, Avraham; Hevroni, Avigdor; Godfrey, Simon; Cohen, Shlomo; Maayan, Channa; Nusair, Samir; Nogee, Lawrence M; Springer, Chaim

    2014-11-01

    Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7-38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung function, while two of the patients, both females, aged 28 and 37 years, conduct normal activities of daily living, have healthy children but have clinical, physiological and rentgenological evidence of restrictive lung disease. All five patients were found to have surfactant protein C gene (SFTPC) mutations, three of them with the most common mutation (p.I73T) and the other two with new mutations of surfactant protein C gene (p.I38F and p.V39L). We conclude that detection of surfactant protein mutations should be attempted in all children presenting with interstitial lung disease. Furthermore, treatment with hydroxychloroquine should be considered in children with SFTPC mutations. Prospective evaluation of hydroxychloroquine therapy in a greater number of patients is needed.

  5. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

    DEFF Research Database (Denmark)

    Gregersen, N; Andresen, B S; Corydon, M J;

    2001-01-01

    Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation...... these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders...... systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages...

  6. 2004 Annual Meeting - Genes, Mutations and Disease: The Environmental Connection

    Energy Technology Data Exchange (ETDEWEB)

    Leona D. Samson, Ph.D.

    2004-08-23

    The Meeting consisted of 9 Symposia, 4 Keynote Lectures, 3 Platform Sessions and 4 Poster Sessions. In addition there were Breakfast Meetings for Special Interest Groups designed to inform attendees about the latest advances in environmental mutagenesis research. Several of the topics to be covered at this broad meeting will be of interest to the Department of Energy, Office of Science. The relevance of this meeting to the DOE derives from the fact that low dose radiation may represent one of the most significant sources of human mutations that are attributable to the environment. The EMS membership, and those who attended the EMS Annual Meeting were interested in both chemical and radiation induced biological effects, such as cell death, mutation, teratogenesis, carcinogenesis and aging. These topics thate were presented at the 2004 EMS Annual meeting that were of clear interest to DOE include: human variation in cancer susceptibility, unusual mechanisms of mutation, germ and stem cell mutagenesis, recombination and the maintenance of genomic stability, multiple roles for DNA mismatch repair, DNA helicases, mutation, cancer and aging, Genome-wide transcriptional responses to environmental change, Telomeres and genomic stability: when ends don?t meet, systems biology approach to cell phenotypic decision processes, and the surprising biology of short RNAs. Poster and platform sessions addressed topics related to environmental mutagen exposure, DNA repair, mechanisms of mutagenesis, epidemiology, genomic and proteomics and bioinformatics. These sessions were designed to give student, postdocs and more junior scientists a chance to present their workl.

  7. DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

    NARCIS (Netherlands)

    S. Olgiati (Simone); M. Quadri (Marialuisa); M. Fang (Mingyan); J.P.M.A. Rood (Janneke P.M.A.); J.A. Saute (Jonas A.); H.F. Chien (Hsin Fen); C.G. Bouwkamp (Christian); J. Graafland (Josja); M. Minneboo (Michelle); G.J. Breedveld (Guido J.); J. Zhang (Jianguo); F.W. Verheijen (Frans W.); A.J.W. Boon (Agnita J.W.); A.J.A. Kievit (Anneke J.A.); L.B. Jardim (L.); W.J. Mandemakers (Wim); E.R. Barbosa (Egberto Reis); C.R.M. Rieder (Carlos); K.L. Leenders (Klaus L.); J. Wang (Jinxia); V. Bonifati (Vincenzo)

    2016-01-01

    markdownabstract_Objective_ DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the

  8. DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease

    NARCIS (Netherlands)

    Olgiati, Simone; Quadri, Marialuisa; Fang, Mingyan; Rood, Janneke P. M. A.; Saute, Jonas A.; Chien, Hsin Fen; Bouwkamp, Christian G.; Graafland, Josja; Minneboo, Michelle; Breedveld, Guido J.; Zhang, Jianguo; Verheijen, Frans W.; Boon, Agnita J. W.; Kievit, Anneke J. A.; Jardim, Laura Bannach; Mandemakers, Wim; Barbosa, Egberto Reis; Rieder, Carlos R. M.; Leenders, Klaus L.; Wang, Jun; Bonifati, Vincenzo

    ObjectiveDNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age MethodsThe DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity

  9. A sodium-channel mutation causes isolated cardiac conduction disease

    NARCIS (Netherlands)

    Tan, HL; Bink-Boelkens, MTE; Bezzina, CR; Viswanathan, PC; Beaufort-Krol, GCM; van Tintelen, PJ; van den Berg, MP; Wilde, AAM; Balser, [No Value

    2001-01-01

    Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening(1-3); however, a

  10. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease.

    Science.gov (United States)

    Oeda, Tomoko; Umemura, Atsushi; Mori, Yuko; Tomita, Satoshi; Kohsaka, Masayuki; Park, Kwiyoung; Inoue, Kimiko; Fujimura, Harutoshi; Hasegawa, Hiroshi; Sugiyama, Hiroshi; Sawada, Hideyuki

    2015-12-01

    Homozygous mutations of the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), and heterozygous mutations of GBA are a major risk factor for Parkinson's disease (PD). This study examined the impact of GBA mutations on the longitudinal clinical course of PD patients by retrospective cohort design. GBA-coding regions were fully sequenced in 215 PD patients and GD-associated GBA mutations were identified in 19 (8.8%) PD patients. In a retrospective cohort study, time to develop dementia, psychosis, wearing-off, and dyskinesia were examined. Survival time analysis followed a maximum 12-year observation (median 6.0 years), revealing that PD patients with GD-associated mutations developed dementia and psychosis significantly earlier than those without mutations (p < 0.001 and p = 0.017, respectively). Adjusted hazard ratios of GBA mutations were 8.3 for dementia (p < 0.001) and 3.1 for psychosis (p = 0.002). No statistically significant differences were observed for wearing-off and dyskinesia between the groups. N-isopropyl-p[(123)I] iodoamphetamine single-photon emission tomography pixel-by-pixel analysis revealed that regional cerebral blood flow was reduced in the bilateral parietal cortex, including the precuneus of GD-associated mutant PD patients, compared with matched PD controls without mutations.

  11. Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.

    Science.gov (United States)

    Futai, Eugene; Osawa, Satoko; Cai, Tetsuo; Fujisawa, Tomoya; Ishiura, Shoichi; Tomita, Taisuke

    2016-01-01

    γ-Secretase is a multisubunit membrane protein complex containing presenilin (PS1) as a catalytic subunit. Familial Alzheimer disease (FAD) mutations within PS1 were analyzed in yeast cells artificially expressing membrane-bound substrate, amyloid precursor protein, or Notch fused to Gal4 transcriptional activator. The FAD mutations, L166P and G384A (Leu-166 to Pro and Gly-384 to Ala substitution, respectively), were loss-of-function in yeast. We identified five amino acid substitutions that suppress the FAD mutations. The cleavage of amyloid precursor protein or Notch was recovered by the secondary mutations. We also found that secondary mutations alone activated the γ-secretase activity. FAD mutants with suppressor mutations, L432M or S438P within TMD9 together with a missense mutation in the second or sixth loops, regained γ-secretase activity when introduced into presenilin null mouse fibroblasts. Notably, the cells with suppressor mutants produced a decreased amount of Aβ42, which is responsible for Alzheimer disease. These results indicate that the yeast system is useful to screen for mutations and chemicals that modulate γ-secretase activity.

  12. Cognitive deficits in familial Alzheimer's disease associated with M239V mutation of presenilin 2.

    Science.gov (United States)

    Giovagnoli, Anna Rita; Marcon, Gabriella; Giaccone, Giorgio; Confaloni, Anna Maria; Tagliavini, Fabrizio

    2006-01-01

    The neuropsychological assessment of non-demented subjects with gene mutation of familial Alzheimer's disease (AD) provides a model for exploring the early cognitive features of the disease. We evaluated 1 patient and 6 non-demented subjects belonging to a family with AD with M239V mutation of the presenilin 2 gene, aiming to verify the contribution of specific cognitive patterns to the characterization of familial AD. One patient, 3 non-demented subjects with M239V mutation and 3 subjects without mutation from the same family underwent neuropsychological testing. The patient's cognitive profile was characterized by anosognosia, visuospatial agnosia, apraxia and fluent aphasia. Of the 3 non-demented subjects with mutation, 1 showed no deficits, another constructive apraxia and the third spatial perception and memory deficits. The 3 subjects without mutation showed normal abilities. The cognitive deficits of the non-demented subjects with mutations indicate focal dysfunction of the posterior cortical areas, resembling the more extended parieto-occipito-temporal dysfunction of the demented patient. Such grading of visuospatial, praxis, and language impairments highlights a distinctive pattern related to the M239V mutation of the presenilin 2 gene.

  13. Spectrum of mutations in Finnish patients with Charcot-Marie-Tooth disease and related neuropathies.

    Science.gov (United States)

    Silander, K; Meretoja, P; Juvonen, V; Ignatius, J; Pihko, H; Saarinen, A; Wallden, T; Herrgård, E; Aula, P; Savontaus, M L

    1998-01-01

    Our patient material included families and sporadic patients of Finnish origin with the diagnosis of Charcot-Marie-Tooth (CMT) disease types 1 and 2, Dejerine-Sottas syndrome (DSS), and hereditary neuropathy with liability to pressure palsies (HNPP). We screened for mutations in the peripheral myelin protein genes connexin 32 (Cx32), myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) by direct sequencing. All patients chosen for mutation screening were negative for the 1.5 Mb duplication/deletion at 17p11.2-p12. Eleven Cx32 mutations were found in 12 families, six with a CMT2 diagnosis, three with a CMT1 diagnosis and three with unclassified CMT. The total number of patients in these 12 CMTX families was 61, giving a minimum prevalence of 1.2/100,000 for CMTX in Finland. Four of the mutations, Pro58Arg, Pro172Leu, Asn175Asp and Leu204Phe, have not been previously reported. One male patient with an early onset CMT had a double Cx32 mutation, Arg22Gln and Val63Ile. The double de novo mutation was found to be of maternal grandpaternal origin. In the P0 gene a Ser78Leu mutation was found in one family with severe CMT1 and a de novo Tyr82Cys mutation was found in one DSS patient. Both mutations have been previously reported in other CMT1 families. A novel PMP22 mutation, deletion of Phe84, was found in one sporadic DSS patient. Our mutation screening results show the necessity of molecular diagnosis, in addition to clinical and electrophysiological evaluation, for proper subtyping of the disease and for accurate genetic counseling.

  14. Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations.

    Science.gov (United States)

    Moreno-Loshuertos, Raquel; Ferrín, Gustavo; Acín-Pérez, Rebeca; Gallardo, M Esther; Viscomi, Carlo; Pérez-Martos, Acisclo; Zeviani, Massimo; Fernández-Silva, Patricio; Enríquez, José Antonio

    2011-04-01

    About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNA(Ile) that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both.

  15. A novel CLCN5 mutation in a Chinese boy with Dent's disease

    Institute of Scientific and Technical Information of China (English)

    Li-Na Ji; Chao-Ying Chen; Jing-Jing Wang; Li Cao

    2014-01-01

    Background: Dent's disease is a rare X-linked recessive hereditary disease caused by mutations in either the CLCN5 or OCRL1 genes. This disease is characterized by manifestations of proximal renal tubule dysfunction associated with low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. Methods: We report a Chinese boy with Dent's disease, clinically diagnosed by LMWP and hypercalciuria. Genetic analysis was made of the CLCN5 and OCRL1 genes. Related studies were also reviewed. Results: A splice site mutation IVS6, +2T>C of the CLCN5 gene was revealed in this case, and it was not reported previously. Conclusions: Clinical and genetic analysis is valuable for the diagnosis of Dent's disease. A novel mutation in the CLCN5 gene was identifi ed in our patient.

  16. Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson's disease in Chinese population.

    Science.gov (United States)

    Sun, Qi-Ying; Guo, Ji-Feng; Wang, Lei; Yu, Ren-He; Zuo, Xing; Yao, Ling-Yan; Pan, Qian; Xia, Kun; Tang, Bei-Sha

    2010-06-15

    An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson's disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age- and sex-matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non-Jewish populations, we conducted a meta-analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83-25.06. In the non-Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21-18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population.

  17. Transcription factor HAND2 mutations in sporadic Chinese patients with congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    SHEN Lei; LI Xiao-feng; SHEN A-dong; WANG Qiang; LIU Cai-xia; GUO Ya-jie; SONG Zhen-jiang; LI Zhong-zhi

    2010-01-01

    Background The basic helix-loop-helix transcription factor HAND2 plays an essential role in cardiac morphogenesis.However, the prevalence of HAND2 mutations in congenial heart disease (CHD) and the correlation between the HAND2 genotype and CHD phenotype have not been studied extensively. Methods We amplified the exons and the flanking intron sequences of the HAND2 gene in 131 patients diagnosed with congenital defects of the right ventricle, outflow tract, aortic artery or cardiac cushion and confirmed the mutations by sequencing.Results Seven mutations including three missense mutations (P11R, S36N and V83L), one isonymous mutation (H14H)and three mutations in untranslated region (241 A>G, 604C>T and 3237T>A) were identified in 12 out of the 131 patients.Both nonisonymous mutations are located in the transcriptional activation domain on the N-terminus. Only one mutation (S36N) was identified in 250 normal healthy controls. The distribution of 3637T>A is the unique one which was differentbetween the 2 groups.Conclusions HAND2 may be a potential candidate gene of stenosis of the right ventricle, outflow tract. Further study of those with a family history of HAND2 mutations will help convincingly relate their genotype to the pathogenesis of CHD.

  18. Three novel mutations in Iranian patients with Tay-Sachs disease.

    Science.gov (United States)

    Jamali, Solmaz; Eskandari, Nasim; Aryani, Omid; Salehpour, Shadab; Zaman, Talieh; Kamalidehghan, Behnam; Houshmand, Massoud

    2014-01-01

    Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.

  19. Gene Editing and Genetic Lung Disease. Basic Research Meets Therapeutic Application.

    Science.gov (United States)

    Alapati, Deepthi; Morrisey, Edward E

    2017-03-01

    Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations. Recent reports have provided proof of concept by using CRISPR/Cas9 to successfully repair or inactivate mutations in animal models of monogenic human diseases. Potential pulmonary applications of CRISPR/Cas9 gene editing include gene correction of monogenic diseases in pre- or postnatal lungs and ex vivo gene editing of patient-specific airway stem cells followed by autologous cell transplant. Strategies to enhance gene-editing efficiency and eliminate off-target effects by targeting pulmonary stem/progenitor cells and the assessment of short-term and long-term effects of gene editing are important considerations as the field advances. If methods continue to advance rapidly, CRISPR/Cas9-mediated gene editing may provide a novel opportunity to correct monogenic diseases of the respiratory system.

  20. Functional recurrent mutations in the human mitochondrial phylogeny: dual roles in evolution and disease.

    Science.gov (United States)

    Levin, Liron; Zhidkov, Ilia; Gurman, Yotam; Hawlena, Hadas; Mishmar, Dan

    2013-01-01

    Mutations frequently reoccur in the human mitochondrial DNA (mtDNA). However, it is unclear whether recurrent mtDNA nodal mutations (RNMs), that is, recurrent mutations in stems of unrelated phylogenetic nodes, are functional and hence selectively constrained. To answer this question, we performed comprehensive parsimony and maximum likelihood analyses of 9,868 publicly available whole human mtDNAs revealing 1,606 single nodal mutations (SNMs) and 679 RNMs. We then evaluated the potential functionality of synonymous, nonsynonymous and RNA SNMs and RNMs. For synonymous mutations, we have implemented the Codon Adaptation Index. For nonsynonymous mutations, we assessed evolutionary conservation, and employed previously described pathogenicity score assessment tools. For RNA genes' mutations, we designed a bioinformatic tool which compiled evolutionary conservation and potential effect on RNA structure. While comparing the functionality scores of nonsynonymous and RNA SNMs and RNMs with those of disease-causing mtDNA mutations, we found significant difference (P < 0.001). However, 24 RNMs and 67 SNMs had comparable values with disease-causing mutations reflecting their potential function thus being the best candidates to participate in adaptive events of unrelated lineages. Strikingly, some functional RNMs occurred in unrelated mtDNA lineages that independently altered susceptibility to the same diseases, thus suggesting common functionality. To our knowledge, this is the most comprehensive analysis of selective signatures in the mtDNA not only within proteins but also within RNA genes. For the first time, we discover virtually all positively selected RNMs in our phylogeny while emphasizing their dual role in past evolutionary events and in disease today.

  1. Array CGH improves detection of mutations in the GALC gene associated with Krabbe disease

    Directory of Open Access Journals (Sweden)

    Tanner Alice K

    2012-06-01

    Full Text Available Abstract Background Krabbe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GALC gene. The most common mutation in the Caucasian population is a 30-kb deletion of exons 11 through 17. There are few other reports of intragenic GALC deletions or duplications, due in part to difficulties detecting them. Methods and results We used gene-targeted array comparative genomic hybridization (CGH to analyze the GALC gene in individuals with Krabbe disease in whom sequence analysis with 30-kb deletion analysis identified only one mutation. In our sample of 33 cases, traditional approaches failed to identify two pathogenic mutations in five (15.2% individuals with confirmed Krabbe disease. The addition of array CGH deletion/duplication analysis to the genetic testing strategy led to the identification of a second pathogenic mutation in three (9.1% of these five individuals. In all three cases, the deletion or duplication identified through array CGH was a novel GALC mutation, including the only reported duplication in the GALC gene, which would have been missed by traditional testing methodologies. We report these three cases in detail. The second mutation remains unknown in the remaining two individuals (6.1%, despite our full battery of testing. Conclusions Analysis of the GALC gene using array CGH deletion/duplication testing increased the two-mutation detection rate from 84.8% to 93.9% in affected individuals. Better mutation detection rates are important for improving molecular diagnosis of Krabbe disease, as well as for providing prenatal and carrier testing in family members.

  2. A dichotomy for upper domination in monogenic classes

    KAUST Repository

    AbouEisha, Hassan M.

    2014-01-01

    An upper dominating set in a graph is a minimal (with respect to set inclusion) dominating set of maximum cardinality. The problem of finding an upper dominating set is NP-hard for general graphs and in many restricted graph families. In the present paper, we study the computational complexity of this problem in monogenic classes of graphs (i.e. classes defined by a single forbidden induced subgraph) and show that the problem admits a dichotomy in this family. In particular, we prove that if the only forbidden induced subgraph is a P4 or a 2K2 (or any induced subgraph of these graphs), then the problem can be solved in polynomial time. Otherwise, it is NP-hard.

  3. Dataset of eye disease-related proteins analyzed using the unfolding mutation screen

    Science.gov (United States)

    McCafferty, Caitlyn L.; Sergeev, Yuri V.

    2016-01-01

    A number of genetic diseases are a result of missense mutations in protein structure. These mutations can lead to severe protein destabilization and misfolding. The unfolding mutation screen (UMS) is a computational method that calculates unfolding propensities for every possible missense mutation in a protein structure. The UMS validation demonstrated a good agreement with experimental and phenotypical data. 15 protein structures (a combination of homology models and crystal structures) were analyzed using UMS. The standard and clustered heat maps, and patterned protein structure from the analysis were stored in a UMS library. The library is currently composed of 15 protein structures from 14 inherited eye diseases including retina degenerations, glaucoma, and cataracts, and contains data for 181,110 mutations. The UMS protein library introduces 13 new human models of eye disease related proteins and is the first collection of the consistently calculated unfolding propensities, which could be used as a tool for the express analysis of novel mutations in clinical practice, next generation sequencing, and genotype-to-phenotype relationships in inherited eye disease. PMID:27922631

  4. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease.

    Science.gov (United States)

    Ziegler, Shira G; Eblan, Michael J; Gutti, Usha; Hruska, Kathleen S; Stubblefield, Barbara K; Goker-Alpan, Ozlem; LaMarca, Mary E; Sidransky, Ellen

    2007-06-01

    An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.

  5. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

    Science.gov (United States)

    Vouk, Katja; Strmecki, Lana; Stekrova, Jitka; Reiterova, Jana; Bidovec, Matjaz; Hudler, Petra; Kenig, Anton; Jereb, Simona; Zupanic-Pajnic, Irena; Balazic, Joze; Haarpaintner, Guido; Leskovar, Bostjan; Adamlje, Anton; Skoflic, Antun; Dovc, Reina; Hojs, Radovan; Komel, Radovan

    2006-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course. PMID:16430766

  6. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Adamlje Anton

    2006-01-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2 and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423. Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed. We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course.

  7. Advances in Human Mitochondrial Diseases Molecular Genetic Analysis of Pathogenic mtDNA Mutations.

    Science.gov (United States)

    Davidson, E; King, M P

    1997-01-01

    The mitochondrial diseases are a heterogeneous group of disorders that have been defined by specific morphological alterations in muscle and by deficits of the mitochondrial respiratory chain. The morphological hallmarks of these diseases include ragged-red fibers (an extensive proliferation of mitochondria in muscle fibers) and abnormal paracrystalline inclusions and membrane structures in mitochondria. The identification of pathogenic mutations in mitochondrial DNA (mtDNA) has resulted in a genetic classification of mitochondrial diseases. Investigations are being conducted to understand the molecular basis for the biochemical and morphological alterations of mitochondria associated with mtDNA mutations. © 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:16-24).

  8. A Personalized Approach to Parkinson’s Disease Patients Based on Founder Mutation Analysis

    Science.gov (United States)

    Giladi, Nir; Mirelman, Anat; Thaler, Avner; Orr-Urtreger, Avi

    2016-01-01

    While the phenotype of Parkinson disease (PD) is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables, including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient’s quality of life. PMID:27242656

  9. Diseases caused by mutations in Nav1.5 interacting proteins.

    Science.gov (United States)

    Kyle, John W; Makielski, Jonathan C

    2014-12-01

    Sodium current in the heart flows principally through the pore protein NaV1.5, which is part of a complex of interacting proteins that serve both to target and localize the complex in the membrane, and to modulate function by such post-translational modifications as phosphorylation and nitrosylation. Multiple mutations in seven different NaV1.5 interacting proteins have been associated with dysfunctional sodium current and inherited cardiac diseases, including long QT syndrome, Brugada syndrome, atrial fibrillation, and cardiomyopathy, as well as sudden infant death syndrome (SIDS). Mutations in as yet unidentified interacting proteins may account for cardiac disease for which a genetic basis has not yet been established. Characterizing the mechanisms by which these mutations cause disease may give insight into etiologies and treatments of more common acquired cardiac disease, such as ischemia and heart failure.

  10. A Personalized Approach to Parkinson's disease patients based on founder mutation analysis

    Directory of Open Access Journals (Sweden)

    Nir eGiladi

    2016-05-01

    Full Text Available While the phenotype of Parkinson disease (PD is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient's quality of life.

  11. Genetic mosaicism of a frameshift mutation in the RET gene in a family with Hirschsprung disease.

    Science.gov (United States)

    Müller, Charlotte M; Haase, Michael G; Kemnitz, Ivonne; Fitze, Guido

    2014-05-10

    Mutations and polymorphisms in the RET gene are a major cause of Hirschsprung disease (HSCR). Theoretically, all true heterozygous patients with a new manifestation of a genetically determined disease must have parents with a genetic mosaicism of some extent. However, no genetic mosaicism has been described for the RET gene in HSCR yet. Therefore, we analyzed families with mutations in the RET gene for genetic mosaicism in the parents of the patients. Blood samples were taken from patients with HSCR and their families/parents to sequence the RET coding region. Among 125 families with HSCR, 33 families with RET mutations were analyzed. In one family, we detected a frameshift mutation due to a loss of one in a row of four cytosines in codon 117/118 of the RET gene (c.352delC) leading to a frameshift mutation in the protein (p.Leu118Cysfs*105) that affected two siblings. In the blood sample of the asymptomatic father we found a genetic mosaicism of this mutation which was confirmed in two independent samples of saliva and hair roots. Quantification of peak-heights and comparison with different mixtures of normal and mutated plasmid DNA suggested that the mutation occurred in the early morula stadium of the founder, between the 4- and 8-cell stages. We conclude that the presence of a RET mutation leading to loss of one functional allele in 20 to 25% of the cells is not sufficient to cause HSCR. The possibility of a mosaicism has to be kept in mind during genetic counseling for inherited diseases.

  12. Guanine holes are prominent targets for mutation in cancer and inherited disease.

    Directory of Open Access Journals (Sweden)

    Albino Bacolla

    Full Text Available Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G • C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials. Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.

  13. Mutations in NR4A2 associated with familial Parkinson disease.

    Science.gov (United States)

    Le, Wei-Dong; Xu, Pingyi; Jankovic, Joseph; Jiang, Hong; Appel, Stanley H; Smith, Roy G; Vassilatis, Demetrios K

    2003-01-01

    NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.

  14. A Truncating De Novo Point Mutation in a Young Infant with Severe Menkes Disease.

    Science.gov (United States)

    Lin, Yi-Jie; Ho, Che-Sheng; Hsu, Chyong-Hsin; Lin, Ju-Li; Chuang, Chih-Kuang; Tsai, Jen-Daw; Chiu, Nan-Chang; Lin, Hsiang-Yu; Lin, Shuan-Pei

    2017-02-01

    Menkes disease is a rare neurodegenerative disorder caused by mutations in ATP7A gene. Deficiency in copper-dependent enzymes results in the unique kinky hair appearance, neurodegeneration, developmental delay, seizures, failure to thrive and other connective tissue or organ abnormalities. Other than biochemical tests, DNA-based diagnosis is now playing an important role. More than two hundred mutations in ATP7A gene were identified. Early copper supplementation can help improve neurological symptoms, but not non-neurological problems. Further molecular studies are needed to identify additional mutation types and to understand the mechanism of pathogenesis. This may help in discovering the possible treatment measures to cure the disease. We present a case with the clinical features and biochemical findings, abnormal brain magnetic resonance imaging as well as the effects of treatment with copper-histidine. Direct sequencing of ATP7A gene revealed a de novo point mutation which resulted in an early stop codon with truncated protein.

  15. Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

    Science.gov (United States)

    Tsuboi, Masaya; Watanabe, Manabu; Nibe, Kazumi; Yoshimi, Natsuko; Kato, Akihisa; Sakaguchi, Masahiro; Yamato, Osamu; Tanaka, Miyuu; Kuwamura, Mitsuru; Kushida, Kazuya; Harada, Tomoyuki; Chambers, James Kenn; Sugano, Sumio; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2017-01-01

    Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as “spheroids,” throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be “deleterious” by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases. PMID:28107443

  16. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease

    DEFF Research Database (Denmark)

    Jørgensen, Anders Berg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G;

    2014-01-01

    BACKGROUND: High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk...... of ischemic cardiovascular disease in the general population is unknown. METHODS: Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease....... Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10...

  17. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. The 1448C mutation in Chinese with type 1 and 2 Gaucher disease

    Energy Technology Data Exchange (ETDEWEB)

    Tsai, F.J.; Tsai, C.H. [Pediatrics Dept. China Medical College Hospital, Taichung (Taiwan, Province of China)

    1994-09-01

    Gaucher disease (GD) is the most common glycolipid storage disorder. Just 5 mutations account for over 97% of all the alleles that produce enzyme deficiency in the Ashkenazic Jewish population. However, GD occurs in all populations but with a much lower frequency, as is the case with other mutations that are common in a single ethnic group. To characterize the molecular basis of Chinese with GD, two cases of GD was analyzed (type 1 and type 2) by selective amplification and restriction endonuclease analysis. Homozygosity of this mutation seems to result in neuronopathic GD (type 2 or 3), but some exceptional cases have been reported. Our results show that the existence of the 1448C mutation in Chinese patients is similar to that of other ethnic groups. In our case 2, who had a homozygotic 1448C mutation but without any CNS manifestation, type 1 GD was diagnosed. In view of the young age of the patient (11 year old), he may develop neurological disease later in life. We suggest that such a case should be followed to observe if any neurological sign becomes present. Patients with GD sharing identical genotypes can exhibit different phenotypic pictures. Thus one cannot rely solely on DNA mutation analysis to predict prognosis in GD. The Chinese mutation data of GD presented here can support this hypothesis.

  19. Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Horowitz, M.; Tzuri, G.; Eyal, N. (Tel Aviv Univ., Ramat Aviv (Israel)); Berebi, A. (Kaplan Hospital, Rehovot (Israel)); Kolodny, E.H. (New York Univ. School of Medicine, New York, NY (United States)); Brady, R.O.; Barton, N.W. (National Institutes of Health, Bethesda, MD (United States)); Abrahamov, A.; Zimran, A. (Shaare Zedek Medical Center, Jerusalem (Israel))

    1993-10-01

    The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewis patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS2+1 mutation constituted 2.26% of the disease alleles among Jewish Patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated [open quotes]RecNcil[close quotes] and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations-D409H and R463C- was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, is 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection. 33 refs, 3 figs., 4 tabs.

  20. The potential for induction of autoimmune disease by a randomly-mutated self-antigen

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm

    2007-01-01

    , a relation to an infectious disease is described, and it is thought that microbes can play a direct role in induction of autoimmunity, for instance by molecular mimicry or bystander activation of autoreactive T cells. In contrast, less attention has been given to the possibility that modified self......-antigen is not a germline self-antigen, but rather a mutated self-antigen. This mutated self-antigen might interfere with peripheral tolerance if presented to the immune system during an infection. The infection lead to bystander activation of naïve T and B cells with specificity for mutated self-antigen and this can lead...

  1. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases

    Directory of Open Access Journals (Sweden)

    Gelsi-Boyer Véronique

    2012-03-01

    Full Text Available Abstract The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN, myelodysplastic syndromes (MDS, chronic myelomonocytic leukemia (CMML and acute myeloid leukemia (AML. They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment.

  2. Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease

    OpenAIRE

    2012-01-01

    Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possi...

  3. Glucocerebrosidase L444P Mutation Confers Genetic Risk for Parkinson’s Disease in Central China

    OpenAIRE

    2012-01-01

    Abstract Background Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. Methods In this project, we conducted a controlled...

  4. Inherited Cardiac Diseases Caused by Mutations in the Nav1.5 Sodium Channel

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Jacob; Winkel, Bo Gregers; Grunnet, Morten

    2009-01-01

    Cardiac Diseases Caused by SCN5A Mutations. A prerequisite for a normal cardiac function is a proper generation and propagation of electrical impulses. Contraction of the heart is obtained through a delicate matched transmission of the electrical impulses. A pivotal element of the impulse propaga......-QT syndrome, Brugada syndrome, and AF, reported to be associated with mutations in SCN5A, are thoroughly described. (J Cardiovasc Electrophysiol, Vol. pp. 1-9)....

  5. LRRK2 mutations and Parkinson's disease in Sardinia--A Mediterranean genetic isolate.

    Science.gov (United States)

    Cossu, Giovanni; van Doeselaar, Marina; Deriu, Marcello; Melis, Maurizio; Molari, Andrea; Di Fonzo, Alessio; Oostra, Ben A; Bonifati, Vincenzo

    2007-02-01

    The Leucine-Rich Repeat Kinase 2 (LRRK2) Gly2019Ser mutation is frequent among Parkinson's disease (PD) patients from the Arab, Jewish, and Iberian populations, while another mutation, Arg1441Gly, is common in the Basque population. We studied the prevalence of these mutations in Sardinia, a Mediterranean genetic isolate with peculiar structure and similarities with the Basque population. Among 98 Sardinian PD probands we detected one heterozygous Gly2019Ser carrier. This mutation was also found in one of 55 Sardinian controls, an 85-year-old man, later shown to have a positive family history of parkinsonism. No carriers of Arg1441Gly, Arg1441Cys, or Arg1441His mutations were found among cases and controls. Our results suggest that the "Basque"LRRK2 mutation is absent or very rare in Sardinia. The Gly2019Ser mutation is present but its frequency is lower than that in Iberian, Arab, or Jewish populations. The identification of an 85-year-old, healthy Gly2019Ser carrier supports the concept that this mutation displays incomplete penetrance.

  6. Mutational analysis of the GLA gene in Mexican families with Fabry disease

    Indian Academy of Sciences (India)

    BIANCA ETHEL GUTIÉRREZ-AMAVIZCA; ANDREAS GAL; ROCÍO ORTÍZ-OROZCO; ULRICH ORTH; ERNESTO PRADO MONTES DE OCA; JAIME PAUL GUTIÉRREZ-AMAVIZCA; LUIS E. FIGUERA

    2017-03-01

    Fabry disease (FD) is a lysosomal storage disorder, which develops due to a deficiency in the hydrolytic enzyme, α-galactosidase A (α-Gal A). Alpha-Gal A hydrolyzes glycosphingolipid globotriaosylceramide (Gb3), and an α-Gal Adeficiency leads to Gb3 accumulation in tissues and cells in the body. This pathology is likely to involve multiple systems, but it is generally considered to affect primarily vascular endothelium. In this study, we investigated mutations in the GLA gene, which encodes α-Gal A, in Mexican families with FD. We included seven probands with FD that carried known mutations. We analysed pedigrees of the probands, and performed molecular screening in 65 relatives with the potential of carrying a GLA mutation. Five mutations (P40S, IVS4+4, G328V, R363H, R404del) were detected in seven unrelated Mexican familieswith the classic FD phenotype. Of the 65 relatives examined, 42 (64.6%) had a GLA gene mutation. In summary, among seven Mexican probands with FD, 65 relatives were at risk of carrying a known GLA mutation, and molecular screening identified 42 individuals with the mutation. Thus, our findings showed that it is important to perform molecular analysis in families with FD to detect mutations and to provide accurate diagnoses for individuals that could be affected.

  7. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease.

    Science.gov (United States)

    Clark, L N; Wang, Y; Karlins, E; Saito, L; Mejia-Santana, H; Harris, J; Louis, E D; Cote, L J; Andrews, H; Fahn, S; Waters, C; Ford, B; Frucht, S; Ottman, R; Marder, K

    2006-11-28

    To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD). We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in the 50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

  8. Disease causing mutations of troponin alter regulated actin state distributions.

    Science.gov (United States)

    Chalovich, Joseph M

    2012-12-01

    Striated muscle contraction is regulated primarily through the action of tropomyosin and troponin that are bound to actin. Activation requires Ca(2+) binding to troponin and/or binding of high affinity myosin complexes to actin. Mutations within components of the regulatory complex may lead to familial cardiomyopathies and myopathies. In several cases examined, either physiological or pathological changes in troponin alter the distribution among states of actin-tropomyosin-troponin that differ in their abilities to stimulate myosin ATPase activity. These observations open possibilities for managing disorders of the troponin complex. Furthermore, analyses of mutant forms of troponin give insights into the regulation of striated muscle contraction.

  9. A New PKD1 Mutation Discovered in a Chinese Family with Autosomal Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Zhendi Wang

    2014-04-01

    Full Text Available Background/Aims: Autosomal-dominant polycystic kidney disease (ADPKD, a heterogeneous genetic disorder characterized by massive kidney enlargement and progressive chronic kidney disease, is due to abnormal proliferation of renal tubular epithelium. ADPKD is known to be caused by mutations in PKD1 and PKD2 genes. Methods: In the present study, the mutation analysis of PKD genes was performed in a new Chinese family with ADPKD using Long-Range (LR PCR sequencing and targeted next-generation sequencing (targeted DNA-HiSeq. Results: A unique 28 bp deletion (c.12605_12632del28 in exon 46 of the PKD1 gene was identified in two affected family members by LR PCR method, but not in any unaffected relatives or unrelated controls. Higher accuracy and less missing detection presented in LR PCR method compared with targeted DNA-HiSeq. This mutation c.12605_12632del28 (p.Arg4202ProextX146 resulted in a delayed termination of amino acid code, and was highly speculated pathogenic in this ADPKD family. Moreover, this newly identified frame-shift change was compared to the PKD gene database, but no similar mutation was yet reported. Conclusion: A novel frame-shift mutation, c. 12605_12632del28, in the PKD1 gene was found in a Chinese ADPKD family. All evidence available suggested that it might be the mutation responsible for the disease in that family.

  10. Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.

    Science.gov (United States)

    Hwang, Daw-Yang; Kohl, Stefan; Fan, Xueping; Vivante, Asaf; Chan, Stefanie; Dworschak, Gabriel C; Schulz, Julian; van Eerde, Albertien M; Hilger, Alina C; Gee, Heon Yung; Pennimpede, Tracie; Herrmann, Bernhard G; van de Hoek, Glenn; Renkema, Kirsten Y; Schell, Christoph; Huber, Tobias B; Reutter, Heiko M; Soliman, Neveen A; Stajic, Natasa; Bogdanovic, Radovan; Kehinde, Elijah O; Lifton, Richard P; Tasic, Velibor; Lu, Weining; Hildebrandt, Friedhelm

    2015-08-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.

  11. Novel insertion mutation in a non-Jewish Caucasian type 1 Gaucher disease patient

    Energy Technology Data Exchange (ETDEWEB)

    Choy, F.Y.M.; Humphries, M.L. [Univ. of Victoria, British Columbia (Canada); Ferreira, P. [Univ. of Alberta, Edmonton (Canada)

    1997-01-20

    Gaucher disease is the most prevalent lysosomal storage disorder. It is autosomal recessive, resulting in lysosomal glucocerebrosidase deficiency. Three clinical forms of Gaucher disease have been described: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). We performed PCR-thermal cycle sequence analysis of glucocerebrosidase genomic DNA and identified a novel mutation in a non-Jewish type 1 Gaucher disease patient. It is a C insertion in exon 3 at cDNA nucleotide position 122 and genomic nucleotide position 1626. This mutation causes a frameshift and, subsequently, four of the five codons immediately downstream of the insertion were changed while the sixth was converted to a stop codon, resulting in premature termination of protein translation. The 122CC insertion abolishes a Cac81 restriction endonuclease cleavage site, allowing a convenient and reliable method for detection using RFLP analysis of PCR-amplified glucocerebrosidase genomic DNA. The mutation in the other Gaucher allele was found to be an A{r_arrow}G substitution at glucocerebrosidase cDNA nucleotide position 1226 that so far has only been reported among type 1 Gaucher disease patients. Since mutation 122CC causes a frameshift and early termination of protein translation, it most likely results in a meaningless transcript and subsequently no residual glucocerebrosidase enzyme activity. We speculate that mutation 122CC may result in a worse prognosis than mutations associated with partial activity. When present in the homozygous form, it could be a lethal allele similar to what has been postulated for the other known insertion mutation, 84GG. Our patient, who is a compound heterozygote 122CC/1226G, has moderately severe type 1 Gaucher disease. Her clinical response to Ceredase{reg_sign} therapy that began 31 months ago has been favorable, though incomplete. 30 refs., 3 figs., 2 tabs.

  12. Mutations in SCG10 Are Not Involved in Hirschsprung Disease

    NARCIS (Netherlands)

    Alves, Maria M. M.; Osinga, Jan; Verheij, Joke B. G. M.; Metzger, Marco; Eggen, Bart J. L.; Hofstra, Robert M. W.

    2010-01-01

    Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of enteric neurons in the distal part of the colon. Several genes have been implicated in the development of this disease that together account for 20% of all cases, implying that other genes are involved. Since HS

  13. Database for Parkinson Disease Mutations and Rare Variants

    Science.gov (United States)

    2015-07-01

    G.W., Van Broeckhoven C, Vance, J.M.: “Parkinson Disease Variant Database ”. MDS 19th International Congress of Parkinson’s Disease and Movement...abstracts submitted to ( international ) meetings and announcements of seminars including presentation of the database . Page 9 ABSTRACT NUYTEMANS UDALL...

  14. 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.

  15. 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.

  16. A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease.

    Science.gov (United States)

    Rodriguez, M-M; Peoc'h, K; Haïk, S; Bouchet, C; Vernengo, L; Mañana, G; Salamano, R; Carrasco, L; Lenne, M; Beaudry, P; Launay, J-M; Laplanche, J-L

    2005-04-26

    Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.

  17. Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

    Science.gov (United States)

    Higuchi, Yujiro; Hashiguchi, Akihiro; Yuan, Junhui; Yoshimura, Akiko; Mitsui, Jun; Ishiura, Hiroyuki; Tanaka, Masaki; Ishihara, Satoshi; Tanabe, Hajime; Nozuma, Satoshi; Okamoto, Yuji; Matsuura, Eiji; Ohkubo, Ryuichi; Inamizu, Saeko; Shiraishi, Wataru; Yamasaki, Ryo; Ohyagi, Yasumasa; Kira, Jun‐ichi; Oya, Yasushi; Yabe, Hayato; Nishikawa, Noriko; Tobisawa, Shinsuke; Matsuda, Nozomu; Masuda, Masayuki; Kugimoto, Chiharu; Fukushima, Kazuhiro; Yano, Satoshi; Yoshimura, Jun; Doi, Koichiro; Nakagawa, Masanori; Morishita, Shinichi; Tsuji, Shoji

    2016-01-01

    Objective The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT. Methods To efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation. Results We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging. Interpretation Our results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672 PMID:26991897

  18. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations.

    Science.gov (United States)

    Gómez-Tortosa, Estrella; Barquero, Sagrario; Barón, Manuel; Gil-Neciga, Eulogio; Castellanos, Fernando; Zurdo, Martín; Manzano, Sagrario; Muñoz, David G; Jiménez-Huete, Adolfo; Rábano, Alberto; Sainz, M José; Guerrero, Rosa; Gobernado, Isabel; Pérez-Pérez, Julián; Jiménez-Escrig, Adriano

    2010-01-01

    We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

  19. A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease.

    Science.gov (United States)

    Gonzalez, Michael A; Feely, Shawna M; Speziani, Fiorella; Strickland, Alleene V; Danzi, Matt; Bacon, Chelsea; Lee, Youjin; Chou, Tsui-Fen; Blanton, Susan H; Weihl, Conrad C; Zuchner, Stephan; Shy, Michael E

    2014-11-01

    Mutations in VCP have been reported to account for a spectrum of phenotypes that include inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia, hereditary spastic paraplegia, and 1-2% of familial amyotrophic lateral sclerosis. We identified a novel VCP mutation (p.Glu185Lys) segregating in an autosomal dominant Charcot-Marie-Tooth disease type 2 family. Functional studies showed that the Glu185Lys variant impaired autophagic function leading to the accumulation of immature autophagosomes. VCP mutations should thus be considered for genetically undefined Charcot-Marie-Tooth disease type 2. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations.

    Science.gov (United States)

    Ringman, John M; O'Neill, Joseph; Geschwind, Daniel; Medina, Luis; Apostolova, Liana G; Rodriguez, Yaneth; Schaffer, Barbara; Varpetian, Arousiak; Tseng, Benjamin; Ortiz, Freddy; Fitten, Jaime; Cummings, Jeffrey L; Bartzokis, George

    2007-07-01

    Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white

  1. Disease Mutations in the Ryanodine Receptor Central Region: Crystal Structures of a Phosphorylation Hot Spot Domain

    Energy Technology Data Exchange (ETDEWEB)

    Yuchi, Zhiguang; Lau, Kelvin; Van Petegem, Filip (UBC)

    2015-02-09

    Ryanodine Receptors (RyRs) are huge Ca{sup 2+} release channels in the endoplasmic reticulum membrane and form targets for phosphorylation and disease mutations. We present crystal structures of a domain in three RyR isoforms, containing the Ser2843 (RyR1) and Ser2808/Ser2814 (RyR2) phosphorylation sites. The RyR1 domain is the target for 11 disease mutations. Several of these are clustered near the phosphorylation sites, suggesting that phosphorylation and disease mutations may affect the same interface. The L2867G mutation causes a drastic thermal destabilization and aggregation at room temperature. Crystal structures for other disease mutants show that they affect surface properties and intradomain salt bridges. In vitro phosphorylation experiments show that up to five residues in one long loop of RyR2 can be phosphorylated by PKA or CaMKII. Docking into cryo-electron microscopy maps suggests a putative location in the clamp region, implying that mutations and phosphorylation may affect the allosteric motions within this area.

  2. Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia

    Institute of Scientific and Technical Information of China (English)

    Jin-Fa Tou; Min-Ju Li; Tao Guan; Ji-Cheng Li; Xiong-Kai Zhu; Zhi-Gang Feng

    2006-01-01

    AIM: To investigate the genetic relationship between Hirschsprung's disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population.METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control.Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR).The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP)and sequencing of the positive amplified products was performed.RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11at nucleotide 15165 G→A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1missense mutation in exon 13 at nucleotide 18919 A→G (K756E) and 1silent mutation in exon 15 at nucleotide 20692 G→A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13at nucleotide 18888 T→G (L745L) were detected. No mutation was found in IND patients and controls.CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD.

  3. Mutational analysis of ATP7B in Chinese Wilson disease patients

    Science.gov (United States)

    Hua, Rui; Hua, Fang; Jiao, Yonggeng; Pan, Yu; Yang, Xu; Peng, Shanshan; Niu, Junqi

    2016-01-01

    Wilson Disease (WD) is an inborn error of copper metabolism inherited in an autosomal recessive manner caused by the mutations in the P-type ATPase gene (ATP7B). In this study, we screen and detect the mutations of the ATP7B gene in unrelated Chinese WD patients. A total of 68 individuals from ten provinces of China with WD were recruited. Of them, 43 were males and 25 were females, and their onset ages were from 1 to 48 years with a median onset age of 22.2 years. All the exons and exon/intron boundaries of ATP7B gene of the patients were sequenced and aligned to the referred ATP7B gene sequence. The results suggested that 66 of the 68 patents carried with at least one mutation and 48 different mutations were identified including 34 missense, one synonymous, two nonsense, two splicing, and nine frameshift mutations (five insertion and four deletion). Among these mutations, c.2333G>T, c.2310C>G, c.2975C>T, and c.3443T>C were the most prevalent mutants and c.2310C>G always linked with c.2333G>T. The eighth, 11th, and 18th exons carried more mutations (6/48, 5/48, and 5/48, respectively) than others. After comparing with the mutations reported previously, 22 out of the 48 mutations were identified as novel mutations. A popular algorithm, Polyphen-2, was used to predict the effects of the amino-acid substitution due to the mutations on the structure and function of ATP7B function and the predicted results indicated that all the missense mutations were unfavorable except c.121A>G and c.748G>A. Phenotype/genotype correlation analysis suggested that the patients with c.2975C>T or c.3809A>G often presented WD features before 12 years old while the patients with c.3443T>C almost presented WD after 12 years old. This is the first time to identify the common mutations contributing to early onset age in Chinese WD patients. Our study will broaden our knowledge about ATP7B mutations in WD patients. PMID:27398169

  4. Mutational analysis of ATP7B in Chinese Wilson disease patients.

    Science.gov (United States)

    Hua, Rui; Hua, Fang; Jiao, Yonggeng; Pan, Yu; Yang, Xu; Peng, Shanshan; Niu, Junqi

    2016-01-01

    Wilson Disease (WD) is an inborn error of copper metabolism inherited in an autosomal recessive manner caused by the mutations in the P-type ATPase gene (ATP7B). In this study, we screen and detect the mutations of the ATP7B gene in unrelated Chinese WD patients. A total of 68 individuals from ten provinces of China with WD were recruited. Of them, 43 were males and 25 were females, and their onset ages were from 1 to 48 years with a median onset age of 22.2 years. All the exons and exon/intron boundaries of ATP7B gene of the patients were sequenced and aligned to the referred ATP7B gene sequence. The results suggested that 66 of the 68 patents carried with at least one mutation and 48 different mutations were identified including 34 missense, one synonymous, two nonsense, two splicing, and nine frameshift mutations (five insertion and four deletion). Among these mutations, c.2333G>T, c.2310C>G, c.2975C>T, and c.3443T>C were the most prevalent mutants and c.2310C>G always linked with c.2333G>T. The eighth, 11(th), and 18(th) exons carried more mutations (6/48, 5/48, and 5/48, respectively) than others. After comparing with the mutations reported previously, 22 out of the 48 mutations were identified as novel mutations. A popular algorithm, Polyphen-2, was used to predict the effects of the amino-acid substitution due to the mutations on the structure and function of ATP7B function and the predicted results indicated that all the missense mutations were unfavorable except c.121A>G and c.748G>A. Phenotype/genotype correlation analysis suggested that the patients with c.2975C>T or c.3809A>G often presented WD features before 12 years old while the patients with c.3443T>C almost presented WD after 12 years old. This is the first time to identify the common mutations contributing to early onset age in Chinese WD patients. Our study will broaden our knowledge about ATP7B mutations in WD patients.

  5. Iron homeostasis and H63D mutations in alcoholics with and without liver disease

    Institute of Scientific and Technical Information of China (English)

    Mariana Verdelho Machado; Paula Ravasco; Alexandra Martins; Maria Ermelinda Camilo; Helena Cortez-Pinto; Maria Rosario Almeida

    2009-01-01

    AIM: To evaluate the prevalence of HFE gene mutation and indices of disturbed iron homeostasis in alcoholics with and without liver disease. METHODS: One hundred and fifty-three heavy drinkers (defined as alcohol consumption > 80 g/d for at least 5 years) were included in the study. These comprised 78 patients with liver disease [liver disease alcoholics (LDA)] in whom the presence of liver disease was confirmed by liver biopsy or clinical evidence of hepatic decompensation, and 75 subjects with no evidence of liver disease, determined by normal liver tests on two occasions [non-liver disease alcoholics (NLDA)], were consecutively enrolled. Serum markers of iron status and HFE C282Y and H63D mutations were determined. HFE genotyping was compared with data obtained in healthy blood donors from the same geographical area. RESULTS: Gender ratio was similar in both study groups. LDA patients were older than NLDA patients third and one fifth of the study population had serum transferrin saturation (TS) greater than 45% and 60% respectively. Serum iron levels were similar in both groups. However, LDA patients had higher TS for having liver disease with TS greater than 45% was 2.20 (95% confidence interval (CI): 1.37-3.54). There was no difference in C282Y allelic frequency between the two groups. However, H63D was more frequent in LDA patients (0.25 vs 0.16, P = 0.03). LDA patients had a greater probability of carrying at least one HFE mutation than NLDA patients (49.5% vs 31.6%, P = 0.02). The odds ratio for LDA in patients with H63D mutation was 1.57 (95% CI: 1.02-2.40).CONCLUSION: The present study confirms the presence of iron overload in alcoholics, which was more severe in the subset of subjects with liver disease,in parallel with an increased frequency of H63D HFE mutation.

  6. Disease evolution and outcomes in familial AML with germline CEBPA mutations

    DEFF Research Database (Denmark)

    Tawana, Kiran; Wang, Jun; Renneville, Aline

    2015-01-01

    therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.......In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were...

  7. Splicing mosaic of the myophosphorylase gene due to a silent mutation in McArdle disease.

    Science.gov (United States)

    Fernandez-Cadenas, I; Andreu, A L; Gamez, J; Gonzalo, R; Martín, M A; Rubio, J C; Arenas, J

    2003-11-25

    The authors report the molecular findings in a patient with McArdle disease who harbored a silent polymorphism (K608K) in the myophosphorylase gene. cDNA studies demonstrated that this polymorphism leads to a severe mosaic alteration in mRNA splicing, including exon skipping, activation of cryptic splice-sites, and exon-intron reorganizations. These findings suggest that, in patients with McArdle disease in whom no pathogenic mutation has been found, any a priori silent polymorphism should be re-evaluated as a putative splicing mutation.

  8. Detection of point mutation in K-ras oncogene at codon 12 in pancreatic diseases

    Institute of Scientific and Technical Information of China (English)

    Yue-Xin Ren; Guo-Ming Xu; Zhao-Shen Li; Yu-Gang Song

    2004-01-01

    AIM: To investigate frequency and clinical significance of Kras mutations in pancreatic diseases and to identify its diagnostic values in pancreatic carcinoma. METHODS: 117 ductal lesions were identified in the available sections from pancreatic resection specimens of pancreatic ductal adenocarcinoma, comprising 24 pancreatic ductal adenocarcinoma, 19 peritumoral ductal atypical hyperplasia, 58 peritumoral ductal hyperplasia and 19 normal duct at the tumor free resection margin. 24 ductal lesions were got from 24 chronic pancreatitis. DNA was extracted. Codon 12 K-ras mutations were examined using the twostep polymerase chain reaction (PCR) combined with restriction enzyme digestion, followed by nonradioisotopic single-strand conformation polymorphism (SSCP) analysis and by means of automated DNA sequencing. RESULTS: K-ras mutation rate of the pancreatic carcinoma was 79%(19/24) which was significantly higher than that in the chronic pancreatitis 33%(8/24) (P<0.01). It was also found that K-ras mutation rate was progressively increased from normal duct at the tumor free resection margin, peritumoral ductal hyperplasia, peritumoral ductal atypical hyperplasia to pancreatic ductal adenocarcinoma. The mutation pattern of K ras 12 coclon of chronic pancreatitis was GGT→GAT, GGT and CGT, which is identical to that in pancreatic carcinoma.CONCLUSION: K-fas mutation may play a role in the malignant transformation of pancreatic ductal cell. K-ras mutation was not specific enough to diagnose pancreatic carcinoma.

  9. Functional analysis LRP6 novel mutations in patients with coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Yujun Xu

    Full Text Available BACKGROUND: Genetic architecture of coronary artery disease (CAD is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6 gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients. METHODS: We systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese. RESULTS: In total, we identified 5 patient-specific mutations including K82N (two patients, S488Y (one patient, P1066T (two patients, P1206H (two patients and I1264V (one patient All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs when compared with wild type (WT LRP6. CONCLUSION: Our results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD.

  10. Neuropsychological profile of parkin mutation carriers with and without Parkinson disease: the CORE-PD study

    Science.gov (United States)

    Caccappolo, Elise; Alcalay, Roy N.; Mejia-Santana, Helen; Tang, Ming-X.; Rakitin, Brian; Rosado, Llency; Louis, Elan D.; Comella, Cynthia L.; Colcher, Amy; Jennings, Danna; Nance, Martha A.; Bressman, Susan; Scott, William K.; Tanner, Caroline M.; Mickel, Susan F.; Andrews, Howard F.; Waters, Cheryl; Fahn, Stanley; Cote, Lucien J.; Frucht, Steven; Ford, Blair; Rezak, Michael; Novak, Kevin; Friedman, Joseph H.; Pfeiffer, Ronald F.; Marsh, Laura; Hiner, Brad; Siderowf, Andrew D.; Ross, Barbara M.; Verbitsky, Miguel; Kisselev, Sergey; Ottman, Ruth; Clark, Lorraine N.; Marder, Karen S.

    2012-01-01

    Background The cognitive profile of early onset Parkinson’s disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. Methods EOPD probands and their first-degree relatives who did not have Parkinson’s disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N=43) and without (N=52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. Results No significant differences in neuropsychological test performance were found between parkin carrier and non-carrier probands. Performance also did not differ between EOPD non-carriers and carrier subgroups (i.e. heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Conclusions Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to non-carriers. The cognitive functioning of parkin carriers over time warrants further study. PMID:21092386

  11. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease.

    Science.gov (United States)

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.

  12. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease

    Science.gov (United States)

    Gambardella, Stefano; Biagioni, Francesca; Ferese, Rosangela; Busceti, Carla L.; Frati, Alessandro; Novelli, Giuseppe; Ruggieri, Stefano; Fornai, Francesco

    2016-01-01

    Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD. PMID:27932943

  13. The interplay of mutations and electronic properties in disease-related genes

    Science.gov (United States)

    Shih, Chi-Tin; Wells, Stephen A.; Hsu, Ching-Ling; Cheng, Yun-Yin; Römer, Rudolf A.

    2012-02-01

    Electronic properties of DNA are believed to play a crucial role in many phenomena in living organisms, for example the location of DNA lesions by base excision repair (BER) glycosylases and the regulation of tumor-suppressor genes such as p53 by detection of oxidative damage. However, the reproducible measurement and modelling of charge migration through DNA molecules at the nanometer scale remains a challenging and controversial subject even after more than a decade of intense efforts. Here we show, by analysing 162 disease-related genes from a variety of medical databases with a total of almost 20,000 observed pathogenic mutations, a significant difference in the electronic properties of the population of observed mutations compared to the set of all possible mutations. Our results have implications for the role of the electronic properties of DNA in cellular processes, and hint at the possibility of prediction, early diagnosis and detection of mutation hotspots.

  14. Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Cosima Rhein

    2015-06-01

    Full Text Available Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668–6676.

  15. The hands in health and disease of individuals with filaggrin loss-of-function mutations

    DEFF Research Database (Denmark)

    Kaae, Jeanette; Menné, Torkil; Carlsen, Berit C

    2012-01-01

    During the last 2 years, we have performed filaggrin genotyping in patients with eczema seen in our hand eczema clinic. We present pictures of healthy and diseased hands from individuals with filaggrin gene (FLG) mutations to describe a clinical entity of hand eczema. We show that xerosis...... and hyperkeratosis on the dorsal aspects of the hands and fingers, as well as palmar hyperlinearity, should alert the clinician about a possible inherited barrier abnormality of the skin resulting from FLG mutations. The series of photographs range from the hands of an individual with FLG mutations but no history...... of eczema, to the hands of individuals with typical and atypical filaggrin hand eczema, and finally to the hands of an individual with FLG mutations and hand eczema caused by exposure to irritants and allergens. We briefly discuss this possible subtype of hand eczema, present pathomechanisms, and indicate...

  16. Splicing factor gene mutations in the myelodysplastic syndromes: impact on disease phenotype and therapeutic applications.

    Science.gov (United States)

    Pellagatti, Andrea; Boultwood, Jacqueline

    2017-01-01

    Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

  17. Biochemical characterization of P4-ATPase mutations associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine

    Progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1 that flips phospholipid from the exoplasmic leaflet to the cytoplasmic leaflet of canalicular membranes. It is hypothesized...... that PFIC1 mutations are the most disturbing with respect to expression, structural stability and/or function. Although recent data indicates that the specific phospholipid substrate of ATP8B1 is phosphatidylcholine (PC) [1] whereas ATP8A2 flips phosphatidylserine (PS) and phosphatidylethanolamine (PE......), there may be several mechanistic similarities between ATP8B1 and ATP8A2, and here we investigate known disease mutations using our well-functioning methodology for expression, affinity purification and assay of the partial reactions of ATP8A2. Mutations I91P (L127P in ATP8B1) and L308F (I344F) are located...

  18. HFE MUTATIONS AND IRON OVERLOAD IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

    Directory of Open Access Journals (Sweden)

    Luis COSTA-MATOS

    2013-03-01

    Full Text Available Context Alcoholic liver disease (ALD is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE gene mutations and the severity of liver disease in alcoholic patients. Objectives To compare the prevalence of mutations in the hemochromatosis (HFE gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. Methods Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment and 52 healthy controls (during elective cholecystectomy. All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations. Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. Results ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05, but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI: 2.09-142.34, P = 0.008. However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003. Conclusions ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no

  19. Hepatitis B virus pre-S2 start codon mutations in Indonesian liver disease patients

    Institute of Scientific and Technical Information of China (English)

    Andi Utama; Marlinang Diarta Siburian; Ismail Fanany; Mariana Destila Bayu Intan; Rama Dhenni; Tri Shinta Kurniasih; Syafruddin AR Lelosuta

    2012-01-01

    AIM:To identify the prevalence of pre-S2 start codon mutations and to assess their association with liver disease progression.METHODS:The mutations were identified by direct sequencing from 73 asymptomatic carriers,66 chronic hepatitis (CH),66 liver cirrhosis (LC) and 63 hepatocellular carcinoma (HCC) patients.Statistical significances were determined using Fisher's exact test,x2 test,and t-test analyses whenever appropriate.Pre-S mutation as a risk factor for advanced liver disease was estimated by unconditional logistic regression model adjusted with age,sex,and hepatitis B e antigen (HBeAg).P <0.05 was considered significant.RESULTS:Mutation of the hepatitis B virus (HBV)pre-S2 start codon was found in 59 samples from 268subjects (22.0%),with higher prevalence in patients with cirrhosis 27/66 (40.9%) followed by HCC 18/63(28.6%),chronic hepatitis 12/66 (18.2%) and asymptomatic carriers 2/73 (2.7%) (P < 0.001).Logistic regression analysis showed that pre-S2 start codon mutation was an independent factor for progressive liver disease.Other mutations,at T130,Q132,and A138,were also associated with LC and HCC,although this was not statistically significant when adjusted for age,sex,and HBeAg.The prevalence of pre-S2 start codon mutation was higher in HBV/B than in HBV/C (23.0%vs 19.1%),whilst the prevalence of T130,Q132,and A138 mutation was higher in HBV/C than in HBV/B.The prevalence of pre-S2 start codon mutation was higher in LC (38.9%) and HCC (40.0%) than CH (5.6%)in HBeAg(+) group,but it was similar between CH,LC and HCC in HBeAg(-) group.CONCLUSION:Pre-S2 start codon mutation was higher in Indonesian patients compared to other Asian countries,and its prevalence was associated with advanced liver disease,particularly in HBeAg(+) patients.

  20. Atypical presentation of infantile-onset farber disease with novel ASAH1 mutations.

    Science.gov (United States)

    Kim, Soo Yeon; Choi, Sun Ah; Lee, Sangmoon; Lee, Jin Sook; Hong, Che Ry; Lim, Byung Chan; Kang, Hyoung Jin; Kim, Ki Joong; Park, Sung-Hye; Choi, Murim; Chae, Jong-Hee

    2016-11-01

    Farber disease is a very rare autosomal recessive disease caused by mutation of ASAH1 that results in the accumulation of ceramide in various tissues. Clinical symptoms of classic Farber disease comprise painful joint deformity, hoarseness of voice, and subcutaneous nodules. Here, we describe a patient with Farber disease with atypical presentation of early onset hypotonia, sacral mass, congenital heart disease, and dysmorphic face since birth. Severe cognitive disability, failure to gain motor skills, failure to thrive, and joint contractures developed. Using whole-exome sequencing, we identified the compound heterozygote missense mutations of ASAH1 (p.R333C and p.G235R). Because of the diagnostic delay, she underwent sacral mass excision, which revealed enlarged lysosomes and zebra bodies. We report an atypical presentation of Farber disease with her pathology and associated genetic defect. This case expands the phenotypic spectrum of Farber disease to include novel mutations of ASAH1, which pose a diagnostic challenge. We also discuss the clinical utility of whole-exome sequencing for diagnosis of ultra-rare diseases. © 2016 Wiley Periodicals, Inc.

  1. Thoracic Aortic Disease in Two Patients with Juvenile Polyposis Syndrome and SMAD4 mutations

    Science.gov (United States)

    Teekakirikul, Polakit; Milewicz, Dianna M.; Miller, David T.; Lacro, Ronald V.; Regalado, Ellen S.; Rosales, Ana Maria; Ryan, Daniel P.; Toler, Tomi L.; Lin, Angela E.

    2012-01-01

    Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD. PMID:23239472

  2. Genetic analysis of LRRK2 mutations in patients with Parkinson disease.

    Science.gov (United States)

    Deng, Hao; Le, WeiDong; Guo, Yi; Hunter, Christine B; Xie, WenJie; Huang, MaoSheng; Jankovic, Joseph

    2006-12-21

    In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype-phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

  3. Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?

    Science.gov (United States)

    Marinozzi, Maria Chiara; Vergoz, Laura; Rybkine, Tania; Ngo, Stephanie; Bettoni, Serena; Pashov, Anastas; Cayla, Mathieu; Tabarin, Fanny; Jablonski, Mathieu; Hue, Christophe; Smith, Richard J.; Noris, Marina; Halbwachs-Mecarelli, Lise; Donadelli, Roberta; Fremeaux-Bacchi, Veronique

    2014-01-01

    Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association. PMID:24652797

  4. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

    Science.gov (United States)

    Alcalay, Roy N; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Mejia Santana, Helen; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L; Lubarr, Naomi; San Luciano, Marta; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

    2013-12-01

    The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P 5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

  5. Clinical presentation and mutations in Danish patients with Wilson disease

    DEFF Research Database (Denmark)

    Møller, Lisbeth Birk; Horn, Nina; Jeppesen, Tina Dysgaard

    2011-01-01

    This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49¿500. Among routinely used diagnostic tests, none were consiste......This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49¿500. Among routinely used diagnostic tests, none were...

  6. Clinical presentation and mutations in Danish patients with Wilson disease

    DEFF Research Database (Denmark)

    Møller, Lisbeth Birk; Horn, Nina; Jeppesen, Tina Dysgaard

    2011-01-01

    This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consiste......This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990-2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were...

  7. Hepatitis B virus gene mutations in liver diseases: a report from New Delhi.

    Directory of Open Access Journals (Sweden)

    Abdul Malik

    Full Text Available OBJECTIVES: The study was designed to characterize the surface, core promoter, precore/core region sequences for the presence of mutations in hepatitis B virus (HBV associated with different liver diseases. METHODS: 567 HBV associated patients with different liver diseases were enrolled in this study. All samples were analyzed for HBV surface, core promoter, precore/core region mutations and genotypes using PCR and direct sequencing. RESULTS: HBV genotype D (72.8% was the predominant type followed by genotype A (27.2%. The serum viral load of HBV was highest in HBsAg carriers group and lowest in patients with hepatocellular carcinoma. 17.9% patients with cirrhosis and 24.6% hepatocellular carcinoma cases were ADV-resistant with rtA181T/V mutations in the S-gene. A1896T was found more frequently in fulminant hepatic failure compared to acute viral hepatitis patients (p = 0.038. T1753V mutation was significantly higher in patients with cirrhosis of liver (34.6% than in chronic hepatitis (18.9% and hepatocellular carcinoma patients (21.2%; p = 0.001. T1762/A1764 mutation was observed in all the groups. C1914G core gene mutation was associated with the hepatocellular carcinoma (32.2% compared to other groups. HBV genotype D predominated in comparison to genotype A. An increased frequency of precore mutation and BCP double mutations amongst the population studied was also observed. CONCLUSION: Mutations such as T1762/A1764, T1753V and C1914G were usually associated with advanced forms of liver disease and had an increased risk of HCC. The nucleotide variability in the basal core promoter and precore regions possibly plays a role in the progression of HBV disease. Prospective studies on the sequence variations of the preC/C region of the HBV genome and the molecular mechanisms in relation to progression of liver disease would aid in better understanding of the biological significance of HBV strains in India.

  8. POSSIBLE ROLE OF MITOCHONDRIAL GENOME MUTATIONS IN CORONARY HEART DISEASE

    Directory of Open Access Journals (Sweden)

    L. A. Egorova

    2014-07-01

    Full Text Available Mitochondria are not only the major producers of adenosine triphosphate, but also an endogenous source of reactive oxygen species. Mitochondrialdysfunction plays a key role in the trigger and progression of atherosclerotic lesion. Impaired function in the mitochondria due to their elevated level of oxidized oxygen species, the accumulation of mitochondrial DNA damages, and the exhaustion of respiratory chains induces dysfunction and apoptosis in the endothelial cells; activation of matrix metalloproteinases; growth of vascular smooth muscle cells and their migration into the intima; expression of adhesion molecules, and oxidation of low-density lipoproteins. Mitochondrial dysfunction may be an important unifying mechanism that accounts for the atherogenic effect of major cardiovascular risk factors. Small clinical pilot studies have shown an association of different mitochondrial genome mutations with atherosclerotic lesion in the artery. Taking into account the available data on the possible role of mitochondria in atherogenesis, novel drugs are now being designed to affect mitochondrial function.

  9. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain.

    Science.gov (United States)

    Shelbourne, Peggy F; Keller-McGandy, Christine; Bi, Wenya Linda; Yoon, Song-Ro; Dubeau, Louis; Veitch, Nicola J; Vonsattel, Jean Paul; Wexler, Nancy S; Arnheim, Norman; Augood, Sarah J

    2007-05-15

    Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

  10. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.

    LENUS (Irish Health Repository)

    Arsov, Todor

    2011-05-13

    The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.

  11. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

    Science.gov (United States)

    Bierzynska, Agnieszka; McCarthy, Hugh J; Soderquest, Katrina; Sen, Ethan S; Colby, Elizabeth; Ding, Wen Y; Nabhan, Marwa M; Kerecuk, Larissa; Hegde, Shivram; Hughes, David; Marks, Stephen; Feather, Sally; Jones, Caroline; Webb, Nicholas J A; Ognjanovic, Milos; Christian, Martin; Gilbert, Rodney D; Sinha, Manish D; Lord, Graham M; Simpson, Michael; Koziell, Ania B; Welsh, Gavin I; Saleem, Moin A

    2017-04-01

    Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

  12. Progress study on the mechanism of CAG repeats dynamic mutation in polyQ disease

    Directory of Open Access Journals (Sweden)

    WANG Chun-rong

    2012-06-01

    Full Text Available Polyglutamine (polyQ disease is a group of neurodegenerative disorders caused by abnormal expansion of CAG repeats within coding regions of certain causative genes, which are translated into a series of abnormally expanded polyQ tracts causing cytotoxicity. So far, nine diseases caused by expanded polyQ tracts have been demonstrated including Huntington's disease (HD, spinobulbar muscular atrophy (SBMA, dentatorubral-pallidoluysian atrophy (DRPLA and several spinocerebellar ataxias subtypes (SCA. In human, long CAG repeats tend to expand during transmissions from parent to offspring, named as dynamic mutation, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. The review presents some novel mechanisms based on dynamic mutation.

  13. Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease

    NARCIS (Netherlands)

    Szperl, Agata M; Golachowska, Magdalena R; Bruinenberg, Marcel; Prekeris, Rytis; Thunnissen, Andy-Mark W H; Karrenbeld, Arend; Dijkstra, Gerard; Hoekstra, Dick; Mercer, David; Ksiazyk, Janusz; Wijmenga, Cisca; Wapenaar, Martin C; Rings, Edmond H H M; van IJzendoorn, Sven C D

    2011-01-01

    Objectives: Microvillus inclusion disease (MVID) is a rare autosomal recessive enteropathy characterized by intractable diarrhea and malabsorption. Recently, various MYO5B gene mutations have been identified in patients with MVID. Interestingly, several patients with MVID showed only a MYO5B mutatio

  14. Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Umayal Sivagnanalingam

    Full Text Available Cytogenetically normal acute myeloid leukemia (CN-AML patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH. Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.

  15. MUTATION ANALYSIS OF THE RET RECEPTOR TYROSINE KINASE IN HIRSCHSPRUNG DISEASE

    NARCIS (Netherlands)

    ANGRIST, M; BOLK, S; THIEL, B; PUFFENBERGER, EG; HOFSTRA, RM; BUYS, CHCM; CASS, DT; CHAKRAVARTI, A

    1995-01-01

    Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. Recently, linkage of an incompletely penetrant, dominant form of HSCR was reported, followed by identification of mutations in the RE

  16. Features of 5'-splice-site efficiency derived from disease-causing mutations and comparative genomics

    DEFF Research Database (Denmark)

    Roca, Xavier; Olson, Andrew J; Rao, Atmakuri R

    2007-01-01

    Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5'-splice-site (5'ss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies...

  17. Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's Disease

    DEFF Research Database (Denmark)

    Somavarapu, Arun Kumar; Kepp, Kasper Planeta

    2016-01-01

    Nearly 200 mutations in the gene coding for presenilin 1 (PSEN1) cause early-onset Alzheimer's Disease, yet the molecular mechanism remains obscure. As a meta-analysis, we compiled available clinical and biochemical data for PSEN1 variants and correlated these to chemical properties of the mutants...

  18. 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,

  19. Screening of 99 Danish patients with congenital heart disease for GATA4 mutations

    DEFF Research Database (Denmark)

    Zhang, Litu; Tümer, Zeynep; Jacobsen, Joes Ramsøe;

    2006-01-01

    Congenital heart disease (CHD) affects nearly 1% of the population, but only few genes involved in human CHD are presently known. Germ-line mutations in the zinc finger transcription factor GATA4 have been associated with familial cases of atrial and ventricular septal defects and pulmonary...

  20. Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

    Directory of Open Access Journals (Sweden)

    Selina Wray

    Full Text Available Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

  1. A novel deletion mutation of ATP7A gene in a Chinese family with Menkes disease

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li-ping; L(U) Jun-lan; WANG Xiao-hui; ZOU Li-ping

    2008-01-01

    @@ Menkes disease is a rare X-linked recessive hereditary disorder first described bv Menkes et al in 1962.1The gene mutation results in clinical features including pili torti, unusual facies, mental/growth retardation and metabolic dysfunction.The Dathogenic gene ATP7A was identified in 1993.

  2. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene.

    Science.gov (United States)

    Kabzinska, D; Drac, H; Sherman, D L; Kostera-Pruszczyk, A; Brophy, P J; Kochanski, A; Hausmanowa-Petrusewicz, I

    2006-03-14

    Charcot-Marie-Tooth type 4F disease (CMT4F) is an autosomal recessive neuropathy caused by mutations in the PRX gene. To date, only seven mutations have been identified in the PRX gene. In this study, the authors report a novel S399fsX410 mutation in the PRX gene and its effects at the protein level, which was identified in an 8-year-old patient with early-onset CMT disease.

  3. Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes.

    Science.gov (United States)

    Godic, Aleksandar; Strazisar, Mojca; Zupan, Andrej; Korosec, Branka; Kansky, Aleksej; Glavac, Damjan

    2010-01-01

    ATP2A2 encodes the sarco/endoplasmic reticulum Ca2+- ATPase (SERCA2) and has been identified as a defective gene in Darier disease (DD). It is an autosomal dominant genodermatosis, which is characterized by loss of adhesion between suprabasal epidermal keratinocytes (acantholysis) and abnormal keratinization (dyskeratosis). We examined 28 Slovenian patients with DD (the cohort of patients represents over 50% of all DD patients in Slovenia) and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 544+1del6, and 1762-6del18. We also found two previously described polymorphisms 2741+54 G>A in intron XVIII and 2172 G>A (A724A) in exon 15, with allele frequencies of 64.2% and 11.3%, respectively. The mutations are scattered throughout the gene and affect the actuator, phosphorylation, stalk and transmembrane domains of SERCA2. A P160L mutation in a Slovene patient with severe DD and a history of deafness is another consistent genotype-phenotype correlation. It seems that mutations of the ATP2A2 gene may also play a role in the pathogenesis of deafness, which seems to be a new phenotypic characteristic of DD patients.

  4. Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa.

    Science.gov (United States)

    Nishioka, Kenya; Vilariño-Güell, Carles; Cobb, Stephanie A; Kachergus, Jennifer M; Ross, Owen A; Wider, Christian; Gibson, Rachel A; Hentati, Faycal; Farrer, Matthew J

    2010-06-21

    Mutations in the glucocerebrosidase gene (GBA) have recently been associated with an increased risk of Parkinson disease (PD). GBA mutations have been observed to be particularly prevalent in the Ashkenazi Jewish population. Interestingly, this population also has a high incidence of the Lrrk2 p.G2019S mutation which is similar in North African Arab-Berber populations. Herein, our sequencing of the GBA gene, in 33 North African Arab-Berber familial parkinsonism probands, identified two novel mutations in three individuals (p.K-26R and p.K186R). Segregation analysis of these two variants did not support a pathogenic role. Genotyping of p.K-26R, p.K186R and the common p.N370S in an ethnically matched series consisting of 395 patients with PD and 372 control subjects did not show a statistically significant association (P>0.05). The p.N370S mutation was only identified in 1 sporadic patient with PD and 3 control subjects indicating that the frequency of this mutation in the North African Arab-Berber population is much lower than that observed in Ashkenazi Jews, and therefore arose in the latter after expansion of the Lrrk2 p.G2019S variant in North Africa.

  5. GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

    Science.gov (United States)

    Prust, M; Wang, J; Morizono, H; Messing, A; Brenner, M; Gordon, E; Hartka, T; Sokohl, A; Schiffmann, R; Gordish-Dressman, H; Albin, R; Amartino, H; Brockman, K; Dinopoulos, A; Dotti, M T; Fain, D; Fernandez, R; Ferreira, J; Fleming, J; Gill, D; Griebel, M; Heilstedt, H; Kaplan, P; Lewis, D; Nakagawa, M; Pedersen, R; Reddy, A; Sawaishi, Y; Schneider, M; Sherr, E; Takiyama, Y; Wakabayashi, K; Gorospe, J R; Vanderver, A

    2011-09-27

    To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

  6. Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations.

    Science.gov (United States)

    Fusco, Francesca; Pescatore, Alessandra; Bal, Elodie; Ghoul, Aida; Paciolla, Mariateresa; Lioi, Maria Brigida; D'Urso, Michele; Rabia, Smail Hadj; Bodemer, Christine; Bonnefont, Jean Paul; Munnich, Arnold; Miano, Maria Giuseppina; Smahi, Asma; Ursini, Matilde Valeria

    2008-05-01

    Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP- and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (>65%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families.

  7. Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2

    Science.gov (United States)

    McCorquodale, Donald S.; Montenegro, Gladys; Peguero, Ainsley; Carlson, Nicole; Speziani, Fiorella; Price, Justin; Taylor, Sean W.; Melanson, Michel; Vance, Jeffery M.

    2011-01-01

    Charcot-Marie-Tooth (CMT) disease is among the most common inherited neurological disorders. Mutations in the gene mitofusin 2 (MFN2) cause the axonal subtype CMT2A, which has also been shown to be associated with optic atrophy, clinical signs of first motor neuron involvement, and early onset stroke. Mutations in MFN2 account for up to 20–30% of all axonal CMT type 2 cases. To further investigate the prevalence of MFN2 mutations and to add to the genotypic spectrum, we sequenced all exons of MFN2 in a cohort of 39 CMT2 patients. We identified seven variants, four of which are novel. One previously described change was co-inherited with a PMP22 duplication, which itself causes the demyelinating form CMT1A. Another mutation was a novel in frame deletion, which is a rare occurrence in the genotypic spectrum of MFN2 characterized mainly by missense mutations. Our results confirm a MFN2 mutation rate of ~ 15–20% in CMT2. PMID:21258814

  8. Clinical relevance of precore mutations of hepatitis B virus in chronic liver disease

    Directory of Open Access Journals (Sweden)

    Chaloska-Ivanova Viktorija

    2014-07-01

    Full Text Available Introduction: Hepatitis B is one of the most frequent etiological factors for chronic liver diseases worldwide. Recent studies have suggested the important role of the genetic diversity of the virus on natural course of hepatitis B. Hepatitis B e-antigen negative type of chronic hepatitis is associated with mutations in the precore region and basic core promoter of hepatitis B viral genome. Aim of study was to identify precore mutations in viral genome of patients with chronic hepatitis B and to evaluate clinical patterns of liver disease related to this type of hepatitis B. Methods: Sixty seven patients with hepatitis B were included in the study. In order to evaluate the clinical patterns of chronic liver disease related to hepatitis B viral infection, biochemical and virological investigations were done, as well as a quantification of serum viral load. All patients underwent liver biopsy and semiquantification of necroinflammation and/or fibrosis according to Knodell scoring was done. In the group of e antigen-negative patients, molecular analysis was performed in order to identify presence of mutations in precore region of the virus. Results: Study group was divided in 25 HBeAg-positive and 42 HBeAg-negative subjects. Al anin-aminotransferase activity and level of viral load were higher in HBeAg-positive (p < 0.05, but average age and histology activity index were significantly higher in the HBeAg-negative patients (p < 0.01. Precore mutants were found in 38 of 42 patients with HBeAg-negative hepatitis (90%. Fibrosis was found in 30/38 cases with mutations. Discussion: Mutations in precore region of HBV in HBeAg-negative patients were more prevalent in older age and were associated with higher rate of fibrosis in liver tissue, meaning more advanced stage of the disease. This could be a consequence of longer duration of HBV infection or more severe clinical course of the disease. Conclusion: Our results suggest that precore mutations are

  9. Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein.

    Science.gov (United States)

    Guo, Rong-Bing; Rigolet, Pascal; Ren, Hua; Zhang, Bo; Zhang, Xing-Dong; Dou, Shuo-Xing; Wang, Peng-Ye; Amor-Gueret, Mounira; Xi, Xu Guang

    2007-01-01

    Bloom syndrome (BS) is an autosomal recessive disorder characterized by genomic instability and the early development of many types of cancer. Missense mutations have been identified in the BLM gene (encoding a RecQ helicase) in affected individuals, but the molecular mechanism and the structural basis of the effects of these mutations remain to be elucidated. We analysed five disease-causing missense mutations that are localized in the BLM helicase core region: Q672R, I841T, C878R, G891E and C901Y. The disease-causing mutants had low ATPase and helicase activities but their ATP binding abilities were normal, except for Q672, whose ATP binding activity was lower than that of the intact BLM helicase. Mutants C878R, mapping near motif IV, and G891E and C901Y, mapping in motif IV, displayed severe DNA-binding defects. We used molecular modelling to analyse these mutations. Our work provides insights into the molecular basis of BLM pathology, and reveals structural elements implicated in coupling DNA binding to ATP hydrolysis and DNA unwinding. Our findings will help to explain the mechanism underlying BLM catalysis and interpreting new BLM causing mutations identified in the future.

  10. The LRRK2 G2019S mutation as the cause of Parkinson's disease in Ashkenazi Jews.

    Science.gov (United States)

    Thaler, Avner; Ash, Elissa; Gan-Or, Ziv; Orr-Urtreger, Avi; Giladi, Nir

    2009-11-01

    Mutations in the leucine rich repeat kinase 2 gene (LRRK2) are recognized as the most common cause of genetic Parkinsonism to date. The G2019S mutation has been implicated as an important determinant of Parkinson's disease (PD) in both Ashkenazi Jewish and North African Arab populations with carrier frequency of 29.7% among familial and 6% in sporadic Ashkenazi Jewish PD cases. PD patients with the G2019S mutation display similar clinical characteristics to patients with sporadic PD. While the function of the LRRK2 protein has yet to be fully determined, its distribution coincides with brain areas most affected by PD. The G2019S mutation is believed to be responsible for up-regulation of LRRK2 kinase activity, which may ultimately play a role in neuronal loss. The utility of LRRK2 G2019S screening in family members of Ashkenazi PD patients is discussed. LRRK2 G2019S mutation carriers without PD may be an ideal population for the study of possible neuroprotective strategies as they become available, and for furthering the understanding of the pathogenesis and long-term clinical outcomes of the disease.

  11. DYT1 mutations in early onset primary torsion dystonia and Parkinson disease patients in Chinese populations.

    Science.gov (United States)

    Yang, Jing-Fang; Wu, Tao; Li, Jian-Yu; Li, Yong-Jie; Zhang, Yan-Li; Chan, Piu

    2009-01-30

    Torsion dystonia is an autosomal dominant movement disorder characterized by involuntary, repetitive muscle contractions and twisted postures. The most severe early onset form of dystonia has been linked to mutations in the human DYT1 (TOR1A) gene encoding a protein termed torsinA. Moreover, dystonia and Parkinson disease share the common feature of reduced dopamine neurotransmission in the striatum, so we assumed that mutations in the DYT1 gene might have the same role in cases of early onset primary torsion dystonia (EOPTD) and early onset Parkinson disease (EOPD) that present dystonia. In this present study, 17 patients with EOPTD, 221 patients with EOPD and 164 control subjects were screened for mutations of the DYT1 gene by denaturing high performance liquid chromatography (DHPLC), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing. Our results showed that the GAG deletion was identified in 7 EOPTD patients, which results in Glu302del of DYT1 gene. No mutations were found in EOPD patients and control subjects. By carefully reviewing the available literature on studies of sporadic, non-Ashkenazi Jewish populations, the results showed that the prevalence rate of DYT1 mutation was not significantly different (p=0.267) between European (27.3%) and Asian (22.2%) patients with early onset primary torsion dystonia.

  12. Point Mutation in the Parkin Gene on Patients with Parkinson's Disease

    Institute of Scientific and Technical Information of China (English)

    王涛; 梁直厚; 孙圣刚; 曹学兵; 彭海; 曹非; 刘红进; 童萼塘

    2003-01-01

    Summary: To investigate the distribution of possible novel mutations from parkin gene in variant sub-set of patients with Parkinson's disease (PD) in China and explore whether parkin gene plays an im-portant role in the pathogenesis of PD, 70 patients were divided into early-onset group and late-onsetgroup; 70 healthy subjects were included as controls. Genomic DNA from 70 normal controls andfrom those of PD patients were extracted from peripheral blood leukocytes by using standard proce-dures. Mutations of parkin gene (exon 1-12) in all the subjects were screened by PCR-single strandconformation polymorphism (SSCP), and further sequencing was performed in the samples with ab-normal SSCP results, in order to confirm the mutation and its location. A new missense mutationGly284Arg in a patient and 3 abnormal bands in SSCP electrophoresis from samples of another 3 pa-tients were found. All the DNA variants were sourced from the samples of the patients with early-on-set PD. It was concluded that Parkin point mutation also partially contributes to the development ofearly-onset Parkinson's disease in Chinese.

  13. Novel Mutations in Sandhoff Disease: A Molecular Analysis Among Iranian Cohort of Infantile Patients

    Directory of Open Access Journals (Sweden)

    T Zaman

    2012-04-01

    Full Text Available Background: Sandhoff disease is an autosomal recessive disorder caused by β-hexosaminidase deficiency and accumulation of GM2 ganglioside resulting in progressive motor neuron manifestations and death from respiratory failure and infections in infantiles. Pathogenic mutations in HEXB gene were observed which leads to enzyme activity reduction and interruption of normal metabolic cycle of GM2 ganglioside in sandhoff patients.Methods: Six infantile index patients with typical biochemical and clinical picture of the disease were studied at the molecular level. After DNA extraction and amplification, probands and their parents, were evaluated by direct sequencing of amplicons.Results: We identified 7 different mutations among which 4 were novel. The most prevalent finding (50% among our population was a 16 kb deletion including the promoter and exons 1-5. The other findings included c.1552delG and c.410G>A, c.362 A>G, c.550delT, c.1597C>T, c.1752delTG.Conclusion: We conclude that Cys137Tyr and R533C mutations may be pathogenic because of changing amino acid and locating at the conserved region and also they have not been observed in hundred controls. Besides, four mutations including: Cys137Tyr, c.1552delG, c.1597C>T and c.550delT fulfilled almost criteria for pathogenic mutation.

  14. Maple syrup urine disease (MSUD): screening for known mutations in Italian patients.

    Science.gov (United States)

    Parrella, T; Surrey, S; Iolascon, A; Sartore, M; Heidenreich, R; Diamond, G; Ponzone, A; Guardamagna, O; Burlina, A B; Cerone, R

    1994-01-01

    Maple syrup urine disease (MSUD) is an autosomal recessive disease due to deficiency of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) caused by a large number of mutations. In the present study, DNA from Italian patients and their relatives was examined for three point mutations (Y393N in the E1 alpha gene, T841G and G1031A in the E2 gene) and two deletions (-G at the intron/exon border of exon 8 in the E2 gene and an 11 bp deletion in exon 1 of the E1 beta gene) using the polymerase chain reaction (PCR) followed by allele-specific oligonucleotide (ASO) hybridization, gene-scanning size analysis of fluorescent-tagged PCR products and/or automated DNA sequence analysis. Our results show that two different mutations account for 7 of the 20 mutant MSUD alleles. Two unrelated affected children, two of their parents and one sibling were carriers for the 11 bp deletion in the E1 beta gene, one patient and her mother were heterozygous for Y393N in E1 alpha, while T841G, G1031A and the -G deletion in E2 were not detected. This study is the first attempt to characterize at a nucleic acid level MSUD mutations in Italy. Our results indicate that additional defects are present in the Italian population and that, unlike the Mennonites, a number of different MSUD mutations exist in Italians.

  15. Exome sequencing identifies ZNF644 mutations in high myopia.

    Directory of Open Access Journals (Sweden)

    Yi Shi

    2011-06-01

    Full Text Available Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644 was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3'UTR+12 C>G, and 3'UTR+592 G>A in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE. Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

  16. Capturing all disease-causing mutations for clinical and research use : Toward an effortless system for the Human Variome Project

    NARCIS (Netherlands)

    Cotton, Richard G. H.; Al Aqeel, Aida I.; Al-Mulla, Fahd; Carrera, Paola; Claustres, Mireille; Ekong, Rosemary; Hyland, Valentine J.; Macrae, Finlay A.; Marafie, Makia J.; Paalman, Mark H.; Patrinos, George P.; Qi, Ming; Ramesar, Rajkumar S.; Scott, Rodney J.; Sijmons, Rolf H.; Sobrido, Maria-Jesus; Vihinen, Mauno

    2009-01-01

    The collection of genetic variants that cause inherited disease (causative mutation) has occurred for decades albeit in an ad hoc way, for research and clinical purposes. More recently, the access to collections of mutations causing specific diseases has become essential for appropriate genetic heal

  17. Mutation databases for inherited renal disease: are they complete, accurate, clinically relevant, and freely available?

    Science.gov (United States)

    Savige, Judy; Dagher, Hayat; Povey, Sue

    2014-07-01

    This study examined whether gene-specific DNA variant databases for inherited diseases of the kidney fulfilled the Human Variome Project recommendations of being complete, accurate, clinically relevant and freely available. A recent review identified 60 inherited renal diseases caused by mutations in 132 genes. The disease name, MIM number, gene name, together with "mutation" or "database," were used to identify web-based databases. Fifty-nine diseases (98%) due to mutations in 128 genes had a variant database. Altogether there were 349 databases (a median of 3 per gene, range 0-6), but no gene had two databases with the same number of variants, and 165 (50%) databases included fewer than 10 variants. About half the databases (180, 54%) had been updated in the previous year. Few (77, 23%) were curated by "experts" but these included nine of the 11 with the most variants. Even fewer databases (41, 12%) included clinical features apart from the name of the associated disease. Most (223, 67%) could be accessed without charge, including those for 50 genes (40%) with the maximum number of variants. Future efforts should focus on encouraging experts to collaborate on a single database for each gene affected in inherited renal disease, including both unpublished variants, and clinical phenotypes. © 2014 WILEY PERIODICALS, INC.

  18. Identification of functional mutations in GATA4 in patients with congenital heart disease.

    Directory of Open Access Journals (Sweden)

    Erli Wang

    Full Text Available Congenital heart disease (CHD is one of the most prevalent developmental anomalies and the leading cause of noninfectious morbidity and mortality in newborns. Despite its prevalence and clinical significance, the etiology of CHD remains largely unknown. GATA4 is a highly conserved transcription factor that regulates a variety of physiological processes and has been extensively studied, particularly on its role in heart development. With the combination of TBX5 and MEF2C, GATA4 can reprogram postnatal fibroblasts into functional cardiomyocytes directly. In the past decade, a variety of GATA4 mutations were identified and these findings originally came from familial CHD pedigree studies. Given that familial and sporadic CHD cases allegedly share a basic genetic basis, we explore the GATA4 mutations in different types of CHD. In this study, via direct sequencing of the GATA4 coding region and exon-intron boundaries in 384 sporadic Chinese CHD patients, we identified 12 heterozygous non-synonymous mutations, among which 8 mutations were only found in CHD patients when compared with 957 controls. Six of these non-synonymous mutations have not been previously reported. Subsequent functional analyses revealed that the transcriptional activity, subcellular localization and DNA binding affinity of some mutant GATA4 proteins were significantly altered. Our results expand the spectrum of GATA4 mutations linked to cardiac defects. Together with the newly reported mutations, approximately 110 non-synonymous mutations have currently been identified in GATA4. Our future analysis will explore why the evolutionarily conserved GATA4 appears to be hypermutable.

  19. Screening for Fabry Disease in Left Ventricular Hypertrophy: Documentation of a Novel Mutation

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    Baptista, Ana, E-mail: baptista-ana@hotmail.com; Magalhães, Pedro; Leão, Sílvia; Carvalho, Sofia; Mateus, Pedro; Moreira, Ilídio [Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade de Vila Real (Portugal)

    2015-08-15

    Fabry disease is a lysosomal storage disease caused by enzyme α-galactosidase A deficiency as a result of mutations in the GLA gene. Cardiac involvement is characterized by progressive left ventricular hypertrophy. To estimate the prevalence of Fabry disease in a population with left ventricular hypertrophy. The patients were assessed for the presence of left ventricular hypertrophy defined as a left ventricular mass index ≥ 96 g/m{sup 2} for women or ≥ 116 g/m{sup 2} for men. Severe aortic stenosis and arterial hypertension with mild left ventricular hypertrophy were exclusion criteria. All patients included were assessed for enzyme α-galactosidase A activity using dry spot testing. Genetic study was performed whenever the enzyme activity was decreased. A total of 47 patients with a mean left ventricular mass index of 141.1 g/m{sup 2} (± 28.5; 99.2 to 228.5 g/m{sup 2}] were included. Most of the patients were females (51.1%). Nine (19.1%) showed decreased α-galactosidase A activity, but only one positive genetic test − [GLA] c.785G>T; p.W262L (exon 5), a mutation not previously described in the literature. This clinical investigation was able to establish the association between the mutation and the clinical presentation. In a population of patients with left ventricular hypertrophy, we documented a Fabry disease prevalence of 2.1%. This novel case was defined in the sequence of a mutation of unknown meaning in the GLA gene with further pathogenicity study. Thus, this study permitted the definition of a novel causal mutation for Fabry disease - [GLA] c.785G>T; p.W262L (exon 5)

  20. Comprehensive mutation screening for 10 genes in Chinese patients suffering very early onset inflammatory bowel disease

    Science.gov (United States)

    Xiao, Yuan; Wang, Xin-Qiong; Yu, Yi; Guo, Yan; Xu, Xu; Gong, Ling; Zhou, Tong; Li, Xiao-Qin; Xu, Chun-Di

    2016-01-01

    AIM: To perform sequencing analysis in patients with very early-onset inflammatory bowel disease (VEO-IBD) to determine the genetic basis for VEO-IBD in Chinese pediatric patients. METHODS: A total of 13 Chinese pediatric patients with VEO-IBD were diagnosed from May 2012 and August 2014. The relevant clinical characteristics of these patients were analyzed. Then DNA in the peripheral blood from patients was extracted. Next generation sequencing (NGS) based on an Illumina-Miseq platform was used to analyze the exons in the coding regions of 10 candidate genes: IL-10, IL-10RA, IL-10RB, NOD2, FUT2, IL23R, GPR35, GPR65, TNFSF15, and ADAM30. The Sanger sequencing was used to verify the variations detected in NGS. RESULTS: Out of the 13 pediatric patients, ten were diagnosed with Crohn’s disease, and three diagnosed with ulcerative colitis. Mutations in IL-10RA and IL-10RB were detected in five patients. There were four patients who had single nucleotide polymorphisms associated with IBD. Two patients had IL-10RA and FUT2 polymorphisms, and two patients had IL-10RB and FUT2 polymorphisms. Gene variations were not found in the rest four patients. Children with mutations had lower percentile body weight (1.0% vs 27.5%, P = 0.002) and hemoglobin (87.4 g/L vs 108.5 g/L, P = 0.040) when compared with children without mutations. Although the age of onset was earlier, height was shorter, and the response to treatment was poorer in the mutation group, there was no significant difference in these factors between groups. CONCLUSION: IL-10RA and IL-10RB mutations are common in Chinese children with VEO-IBD. Patients with mutations have an earlier disease onset, lower body weight and hemoglobin, and poorer prognosis. PMID:27350736

  1. Mutations in POLE and survival of colorectal cancer patients – link to disease stage and treatment

    Science.gov (United States)

    Stenzinger, Albrecht; Pfarr, Nicole; Endris, Volker; Penzel, Roland; Jansen, Lina; Wolf, Thomas; Herpel, Esther; Warth, Arne; Klauschen, Frederick; Kloor, Matthias; Roth, Wilfried; Bläker, Hendrik; Chang-Claude, Jenny; Brenner, Hermann; Hoffmeister, Michael; Weichert, Wilko

    2014-01-01

    Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ε (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410–491) as well as in exon 9 and exon 11 (corresponding to aa 268–303 and aa 341–369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82–2.25) and 1.44 (0.81–2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02–3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies. PMID:25124163

  2. Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

    Science.gov (United States)

    Stenzinger, Albrecht; Pfarr, Nicole; Endris, Volker; Penzel, Roland; Jansen, Lina; Wolf, Thomas; Herpel, Esther; Warth, Arne; Klauschen, Frederick; Kloor, Matthias; Roth, Wilfried; Bläker, Hendrik; Chang-Claude, Jenny; Brenner, Hermann; Hoffmeister, Michael; Weichert, Wilko

    2014-12-01

    Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ϵ (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410-491) as well as in exon 9 and exon 11 (corresponding to aa 268-303 and aa 341-369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82-2.25) and 1.44 (0.81-2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02-3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies.

  3. Factor V leiden mutation in Behcet’s disease and the relationship with clinical manifestations

    Directory of Open Access Journals (Sweden)

    Mowla K

    2010-05-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Behcet's disease (BD is a multisystemic inflammatory disease with unknown origin characterized by recurrent oral aphtous ulcers, genital, ocular and skin lesions. A single point mutation 1691G to A in the factor V gene increases the risk of venous thrombosis. This study designed to determine factor V Leiden mutation in Behcet's disease, and to find out it's relationship with the clinical manifestations in Khuzestan province, Iran. "n"nMethods: One hundred patients with Behcet's Disease (44 males and 56 females based on international diagnostic criteria and 70 healthy subjects were included in the study. Patients and controls were tested for the presence of factor V Leiden mutation using polymerase chain reaction method."n"nResults: The prevalence of factor V Leiden mutation was significantly higher in BD (10 out of 100, 10% compared with healthy control subjects (1 out of 70, 1.4%, (p=0.025. Vascular lesions in this study were deep vein thrombosis (DVT (7%, subcutaneous thrombophlebitis (5%, stroke (1% and retinal vasculitis (39%. It was found that there was no association between venous thrombosis and the factor V Leiden mutation in Khuzestanian patients. Also, no association between

  4. Nonalcoholic fatty liver disease and HFE gene mutations:A Polish study

    Institute of Scientific and Technical Information of China (English)

    Joanna; Raszeja-Wyszomirska; Grzegorz; Kurzawski; Malg

    2010-01-01

    AIM:To describe a Polish population with nonalcoholic fatty liver disease(NAFLD)with regard to HFE gene mutations,as well as analyzing demographic and clinical data.METHODS:Sixty-two consecutive patients with biopsy-proven NAFLD were included in the study.Demographic,clinical,and laboratory data were summarized in a database.C282Y and H63D mutations of the HFE gene were analyzed using polymerase chain reactionrestriction fragment lenght polymorphism.RESULTS:The analyzed cohort consisted of 62 homo-geneic Ca...

  5. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease.

    Science.gov (United States)

    Indrieri, Alessia; van Rahden, Vanessa Alexandra; Tiranti, Valeria; Morleo, Manuela; Iaconis, Daniela; Tammaro, Roberta; D'Amato, Ilaria; Conte, Ivan; Maystadt, Isabelle; Demuth, Stephanie; Zvulunov, Alex; Kutsche, Kerstin; Zeviani, Massimo; Franco, Brunella

    2012-11-02

    Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.

  6. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

    Science.gov (United States)

    Hernandez, Dena G; Reed, Xylena; Singleton, Andrew B

    2016-10-01

    Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special

  7. Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state

    Energy Technology Data Exchange (ETDEWEB)

    Beutler, E.; Gelbart, T.; Kuhl, W.; Sorge, J.; West, C. (Scripps Research Inst., La Jolla, CA (United States))

    1991-12-01

    Gaucher disease is an autosomal recessive glycolipid storage disease characterized by a deficiency of glucocerebrosidase. The disease is most common in persons of Ashkenazi Jewish ancestry and the most common mutation, accounting for about 75% of the mutant alleles in this population, is known to be an A {yields} G substitution at cDNA nucleotide (nt) 1,226. Screening for this disease has not been possible because nearly 25% of the mutant alleles had not been identified, but linkage analysis led to the suggestion that most of these could be accounted for by a single mutation. The authors now report the discovery of this mutation. The insertion of a single nucleotide, a second guanine at cDNA nt 84 (the 84GG mutation), has been detected in the 5{prime} coding region of the glucocerebrosidase gene. The amount mRNA produced is shown to be normal but since the frameshift produces early termination, no translation product is seen. This finding is consistent with the virtual absence of antigen found in patients carrying this mutation. The 84GG mutation accounts for most of the previously unidentified Gaucher disease mutations in Jewish patients. The common Jewish mutation at nt 1,448 accounted for 95% of all of the Gaucher disease-producing alleles in 71 Jewish patients. This now makes it possible to screen for heterozygotes on a DNA level with a relatively low risk of missing couples at risk for producing infants with Gaucher disease.

  8. Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

    DEFF Research Database (Denmark)

    Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.;

    2006-01-01

    on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.......0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased...... viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS...

  9. Syndromic and non-syndromic disease-linked Cx43 mutations.

    Science.gov (United States)

    Laird, Dale W

    2014-04-17

    There are now at least 14 distinct diseases linked to germ line mutations in the 21 genes that encode the connexin (Cx) family of gap junction proteins. This review focuses on the links between germ-line mutations in the gene encoding Cx43 (GJA1) and the human disease termed oculodentodigital dysplasia (ODDD). This disease is clinically characterized by soft tissue fusion of the digits, abnormal craniofacial bone development, small eyes and loss of tooth enamel. However, the disease is considerably more complex and somewhat degenerative as patients often suffer from other syndromic effects that include incontinence, glaucoma, skin diseases and neuropathies that become more pronounced during aging. The challenge continues to be understanding how distinct Cx43 gene mutations cause such a diverse range of tissue phenotypes and pathophysiological changes while other Cx43-rich organs are relatively unaffected. This review will provide an overview of many of these studies and distill some themes and outstanding questions that need to be addressed in the coming years. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  10. Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.

    Science.gov (United States)

    Lee, Winston; Xie, Yajing; Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H; Lupski, James R; Allikmets, Rando

    2016-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants and copy number variants that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

  11. Visual short-term memory deficits associated with GBA mutation and Parkinson's disease.

    Science.gov (United States)

    Zokaei, Nahid; McNeill, Alisdair; Proukakis, Christos; Beavan, Michelle; Jarman, Paul; Korlipara, Prasad; Hughes, Derralynn; Mehta, Atul; Hu, Michele T M; Schapira, Anthony H V; Husain, Masud

    2014-08-01

    Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short

  12. Patient with FMF and Triple MEFV Gene Mutations.

    Science.gov (United States)

    Salehzadeh, Farhad; Fathi, Afshin

    2015-08-01

    Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease with monogenic (MEditerranean FeVer -MEFV- gene) inherited pattern. It mainly affects ethnic groups living along the eastern Mediterranean Sea: Turks, Sephardic Jews, Armenians, and Arabs [1]. Today FMF is not rare disease in other Mediterranean ethnicities, such as Greeks, Italians, and Iranians. Here we report a child with complex allele mutations E148Q/V726A/R761H, whilst, whose mother showed E148Q/V726A and his father had R761H/wt in analysis. The severity of the disease and genotype-phenotype correlation of patient showed no significant differences with his mother and other patients with the same two mutations, V726A/R761H, E148Q/V726A, and E148Q/R761H. This type of mutation is the first report of triple mutations in FMF patients with no specific phenotype correlation.

  13. Text mining facilitates database curation - extraction of mutation-disease associations from Bio-medical literature.

    Science.gov (United States)

    Ravikumar, Komandur Elayavilli; Wagholikar, Kavishwar B; Li, Dingcheng; Kocher, Jean-Pierre; Liu, Hongfang

    2015-06-06

    Advances in the next generation sequencing technology has accelerated the pace of individualized medicine (IM), which aims to incorporate genetic/genomic information into medicine. One immediate need in interpreting sequencing data is the assembly of information about genetic variants and their corresponding associations with other entities (e.g., diseases or medications). Even with dedicated effort to capture such information in biological databases, much of this information remains 'locked' in the unstructured text of biomedical publications. There is a substantial lag between the publication and the subsequent abstraction of such information into databases. Multiple text mining systems have been developed, but most of them focus on the sentence level association extraction with performance evaluation based on gold standard text annotations specifically prepared for text mining systems. We developed and evaluated a text mining system, MutD, which extracts protein mutation-disease associations from MEDLINE abstracts by incorporating discourse level analysis, using a benchmark data set extracted from curated database records. MutD achieves an F-measure of 64.3% for reconstructing protein mutation disease associations in curated database records. Discourse level analysis component of MutD contributed to a gain of more than 10% in F-measure when compared against the sentence level association extraction. Our error analysis indicates that 23 of the 64 precision errors are true associations that were not captured by database curators and 68 of the 113 recall errors are caused by the absence of associated disease entities in the abstract. After adjusting for the defects in the curated database, the revised F-measure of MutD in association detection reaches 81.5%. Our quantitative analysis reveals that MutD can effectively extract protein mutation disease associations when benchmarking based on curated database records. The analysis also demonstrates that incorporating

  14. High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

    Directory of Open Access Journals (Sweden)

    R. Rozenberg

    2006-09-01

    Full Text Available Gaucher disease (GD, the most prevalent lysosome storage disorder, presents an autosomal recessive mode of inheritance. It is a paradigm for therapeutic intervention in medical genetics due to the existence of effective enzyme replacement therapy. We report here the analysis of GD in 262 unrelated Brazilian patients, carried out in order to establish the frequency of the most common mutations and to provide prognostic information based on genotype-phenotype correlations. Among 247 type 1 GD patients, mutation N370S was detected in 47% of all the alleles, but N370S/N370S homozygosity was found in only 10% of the patients, a much lower frequency than expected, suggesting that most individuals presenting this genotype may not receive medical attention. Recombinant alleles were detected at a high frequency: 44% of the chromosomes bearing mutation L444P had other mutations derived from the pseudogene sequence, present in 25% of patients. Three neuronopathic type 2 patients were homozygous for L444P, all presenting additional mutations (E326K or recombinant alleles that probably lead to the more severe phenotypes. Six children, classified as type 1 GD patients, had a L444P/L444P genotype, showing that neuronopathic symptoms may only manifest later in life. This would indicate the need for a higher treatment dose during enzyme replacement therapy. Finally, mutation G377S was present in 4 homozygous type 1 patients and also in compound heterozygosity in 5 (42% type 3 patients. These findings indicate that G377S cannot be unambiguously classified as mild and suggest an allele-dose effect for this mutation.

  15. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

    Science.gov (United States)

    Choi, Soo-Kyung; Yoon, Song-Ro; Calabrese, Peter; Arnheim, Norman

    2008-07-22

    Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100-1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible Luria-Delbruck "mutation jackpots." An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another.

  16. Minireview: Human Obesity—Lessons from Monogenic Disorders

    National Research Council Canada - National Science Library

    O’Rahilly, Stephen; Farooqi, I. Sadaf; Yeo, Giles S. H; Challis, Benjamin G

    2003-01-01

    .... However, in the last 6 yr, a number of human genes have been identified in which major missense or nonsense mutations are sufficient in themselves to result in severe early-onset obesity, usually...

  17. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations

    Directory of Open Access Journals (Sweden)

    De-Min Yu

    2011-01-01

    Full Text Available Abstract Background Wilson's disease (WND is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China. Methods The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old. Results Neurologic manifestations were associated with older age at diagnosis (p Conclusions We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16 and two mutations (p.Arg778Leu, p.Pro992Leu should be considered high priority for cost-effective testing in China.

  18. G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

    Science.gov (United States)

    Pchelina, Sofya N; Yakimovskii, Andrei F; Ivanova, Olga N; Emelianov, Anton K; Zakharchuk, Andrei H; Schwarzman, Alexander L

    2006-12-01

    Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.

  19. Mitochondrial impairment observed in fibroblasts from South African Parkinson's disease patients with parkin mutations.

    Science.gov (United States)

    van der Merwe, Celia; Loos, Ben; Swart, Chrisna; Kinnear, Craig; Henning, Franclo; van der Merwe, Lize; Pillay, Komala; Muller, Nolan; Zaharie, Dan; Engelbrecht, Lize; Carr, Jonathan; Bardien, Soraya

    2014-05-01

    Parkinson's disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients' fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies.

  20. A nonsense mutation in the acid α-glucosidase gene causes Pompe disease in Finnish and Swedish Lapphunds.

    Science.gov (United States)

    Seppälä, Eija H; Reuser, Arnold J J; Lohi, Hannes

    2013-01-01

    Pompe disease is a recessively inherited and often fatal disorder caused by the deficiency of acid α-glucosidase, an enzyme encoded by the GAA gene and needed to break down glycogen in lysosomes. This glycogen storage disease type II has been reported also in Swedish Lapphund dogs. Here we describe the genetic defect in canine Pompe disease and show that three related breeds from Scandinavia carry the same mutation. The affected dogs are homozygous for the GAA c.2237G>A mutation leading to a premature stop codon at amino acid position 746. The corresponding mutation has previously been reported in humans and causes infantile Pompe disease in combination with a second fully deleterious mutation. The affected dogs from both the Finnish as well as the Swedish breed mimic infantile-onset Pompe disease genetically, but also clinico-pathologically. Therefore this canine model provides a valuable tool for preclinical studies aimed at the development of gene therapy in Pompe disease.

  1. Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

    Science.gov (United States)

    Oftedal, Bergithe E; Hellesen, Alexander; Erichsen, Martina M; Bratland, Eirik; Vardi, Ayelet; Perheentupa, Jaakko; Kemp, E Helen; Fiskerstrand, Torunn; Viken, Marte K; Weetman, Anthony P; Fleishman, Sarel J; Banka, Siddharth; Newman, William G; Sewell, W A C; Sozaeva, Leila S; Zayats, Tetyana; Haugarvoll, Kristoffer; Orlova, Elizaveta M; Haavik, Jan; Johansson, Stefan; Knappskog, Per M; Løvås, Kristian; Wolff, Anette S B; Abramson, Jakub; Husebye, Eystein S

    2015-06-16

    The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.

    Science.gov (United States)

    Goriely, Anne; Wilkie, Andrew O M

    2012-02-10

    Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.

  3. Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.

    Science.gov (United States)

    Giaccone, Giorgio; Morbin, Michela; Moda, Fabio; Botta, Mario; Mazzoleni, Giulia; Uggetti, Andrea; Catania, Marcella; Moro, Maria Luisa; Redaelli, Veronica; Spagnoli, Alberto; Rossi, Roberta Simona; Salmona, Mario; Di Fede, Giuseppe; Tagliavini, Fabrizio

    2010-12-01

    Mutations of three different genes, encoding β-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Aβ accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Aβ deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Aβ40 or Aβ42. Moreover, Aβ deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Aβ deposits as well as their topographic distribution in the brain.

  4. Polymorphism analysis of PARK2 gene mutations in Han Chinese patients with early-onset Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Yuancheng Bao; Ting Guan; Yuanxun Yu; Huaizhou Jiang; Changshui Fang; Lijuan Chen

    2010-01-01

    The PARK2 gene is a common disease gene in Han Chinese patients with Parkinson's disease.The detection of mutations in the PARK2 gene remains low.To investigate the role PARK2 gene mutations play in the pathogenesis of Parkinson's disease,30 Han Chinese patients with early-onset Parkinson's disease and 38 normal controls were studied to determine the sequence changes of 1,4,6 and 7 exon sections.In the 30 patients with Parkinson's disease,a heterozygous intron mutation(nt 119,G→G/A)in exon 1 was detected in one case;a homozygous intron mutation(nt 526500,T→C)between intron 3 and exon 4 in fourteen cases was found;a heterozygous intron mutation(nt 526607,G→G/A)between intron 3 and exon 4 was observed in eight cases;an exon 6missense mutation(nt 754317,C→C/T;codon 193,CGG→CGG/TGG;aa 193,Arg→Arg/Trp)in three cases was seen;and an exon 7 missense mutation(nt 941943,C→A/C;codon 272,CTC→CTC/ATC;aa 272,Leu→Leu/lle)was found in one case.These changes were not found in the normal population.The results indicated that the PARK2 exons 6 and 7 mutations are possibly pathogenic mutations,along with the intron 3-exert 4 and exon 1 mutations.PARK2 gene mutations are possible factors leading to the onset of Parkinson's disease.

  5. A novel biallelic splice site mutation of TECTA causes moderate to severe hearing impairment in an Algerian family.

    Science.gov (United States)

    Behlouli, Asma; Bonnet, Crystel; Abdi, Samia; Hasbellaoui, Mokhtar; Boudjenah, Farid; Hardelin, Jean-Pierre; Louha, Malek; Makrelouf, Mohamed; Ammar-Khodja, Fatima; Zenati, Akila; Petit, Christine

    2016-08-01

    Congenital deafness is certainly one of the most common monogenic diseases in humans, but it is also one of the most genetically heterogeneous, which makes molecular diagnosis challenging in most cases. Whole-exome sequencing in two out of three Algerian siblings affected by recessively-inherited, moderate to severe sensorineural deafness allowed us to identify a novel splice donor site mutation (c.5272+1G > A) in the gene encoding α-tectorin, a major component of the cochlear tectorial membrane. The mutation was present at the homozygous state in the three affected siblings, and at the heterozygous state in their unaffected, consanguineous parents. To our knowledge, this is the first reported TECTA mutation leading to the DFNB21 form of hearing impairment among Maghrebian individuals suffering from congenital hearing impairment, which further illustrates the diversity of the genes involved in congenital deafness in the Maghreb.

  6. Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

    Science.gov (United States)

    Bingham, Coralie; Bulman, Michael P.; Ellard, Sian; Allen, Lisa I. S.; Lipkin, Graham W.; Hoff, William G. van't; Woolf, Adrian S.; Rizzoni, Gianfranco; Novelli, Giuseppe; Nicholls, Anthony J.; Hattersley, Andrew T.

    2001-01-01

    Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)–1β have been associated with early-onset diabetes and nondiabetic renal disease—particularly renal cystic disease. We investigated a possible role for the HNF-1β gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1β gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1β mutations. PMID:11085914

  7. Diagnostic Genetics at a Distance: Von Hippel-Lindau Disease and a Novel Mutation

    Directory of Open Access Journals (Sweden)

    Clare Brookes

    2013-01-01

    Full Text Available Genetic testing at a distance is commonplace where members of a family with a segregating germline mutation are geographically separated. For the most part, this challenge is addressed through the intervention of health professionals in taking and/or processing blood samples for subsequent couriering of DNA to a referral laboratory. In some circumstances, however, the collecting of pivotal clinical material may involve direct patient involvement. We describe such a situation where noninvasive saliva samples were provided by members of a family manifesting Von Hippel-Lindau (VHL disease. The analysis identified a novel mutation in the VHL gene that was used to exclude other family members as being at risk of VHL disease.

  8. Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

    Science.gov (United States)

    Ranganath, Prajnya; Matta, Divya; Bhavani, Gandham SriLakshmi; Wangnekar, Savita; Jain, Jamal Mohammed Nurul; Verma, Ishwar C; Kabra, Madhulika; Puri, Ratna Dua; Danda, Sumita; Gupta, Neerja; Girisha, Katta M; Sankar, Vaikom H; Patil, Siddaramappa J; Ramadevi, Akella Radha; Bhat, Meenakshi; Gowrishankar, Kalpana; Mandal, Kausik; Aggarwal, Shagun; Tamhankar, Parag Mohan; Tilak, Preetha; Phadke, Shubha R; Dalal, Ashwin

    2016-10-01

    Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc.

  9. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a

    Energy Technology Data Exchange (ETDEWEB)

    Chou, J.Y.; Lei, K.J.; Shelly, L.L. [National Institutes of Health, Bethesda, MD (United States)

    1994-09-01

    Glycogen storage disease (GSD) type la (von Gierke disease) is caused by the deficiency of glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. The disease presents with clinical manifestations of severe hypoglycemia, hepatomegaly, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. We have succeeded in isolating a murine G6Pase cDNA from a normal mouse liver cDNA library by differentially screening method. We then isolated the human G6Pase cDNA and gene. To date, we have characterized the G6Pase genes of twelve GSD type la patients and uncovered a total of six different mutations. The mutations are comprised of R83C (an Arg at codon 83 to a Cys), Q347X (a Gly at codon 347 to a stop codon), 459insTA (a two basepair insertion at nucleotide 459 yielding a truncated G6Pase of 129 residues), R295C (an Arg at codon 295 to a Cys), G222R (a Gly at codon 222 to an Arg) and {delta}F327 (a codon deletion for Phe-327 at nucleotides 1058 to 1060). The relative incidences of these mutations are 37.5% (R83C), 33.3% (Q347X), 16.6% (459insTA), 4.2% (G222R), 4.2% (R295C) and 4.2% ({delta}F327). Site-directed mutagenesis and transient expression assays demonstrated that the R83C, Q347X, R295C, and {delta}F327 mutations abolished whereas the G222R mutation greatly reduced G6Pase activity. We further characterized the structure-function requirements of amino acids 83, 222, and 295 in G6Pase catalysis. The identification of mutations in GSD type la patients has unequivocally established the molecular basis of the type la disorder. Knowledge of the mutations may be applied to prenatal diagnosis and opens the way for developing and evaluating new therapeutic approaches.

  10. Selection and mutation in X-linked recessive diseases epidemiological model.

    Science.gov (United States)

    Verrilli, Francesca; Kebriaei, Hamed; Glielmo, Luigi; Corless, Martin; Del Vecchio, Carmen

    2015-01-01

    To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive.

  11. Disease Mutations in Rab7 Result in Unregulated Nucleotide Exchange and Inappropriate Activation

    Energy Technology Data Exchange (ETDEWEB)

    B McCray; E Skordalakes; J Taylor

    2011-12-31

    Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism. We present the 2.8 A crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Through extensive biochemical analysis, we demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that the increased activation of mutant Rab7 is counterbalanced by unregulated, GTP hydrolysis-independent membrane cycling. Notably, disease mutations are able to rescue the membrane cycling of a GTPase-deficient mutant. Thus, we demonstrate that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease not by a gain of novel toxic function, but by misregulation of native Rab7 activity.

  12. A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation.

    Science.gov (United States)

    Hornig, Nadine C; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

    2016-01-01

    A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general.

  13. A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation.

    Directory of Open Access Journals (Sweden)

    Nadine C Hornig

    Full Text Available A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS generating an upstream open reading frame (uORF in the 5' untranslated region (5'-UTR of the androgen receptor (AR gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general.

  14. A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation

    Science.gov (United States)

    Hornig, Nadine C.; de Beaufort, Carine; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra E.; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audi, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul-Martin

    2016-01-01

    A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5’ untranslated region (5’-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5′UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5′UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general. PMID:27110943

  15. Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities.

    Science.gov (United States)

    Zhang, Jian; Lieu, Yen K; Ali, Abdullah M; Penson, Alex; Reggio, Kathryn S; Rabadan, Raul; Raza, Azra; Mukherjee, Siddhartha; Manley, James L

    2015-08-25

    Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun to be examined. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease to introduce the P95H mutation to SRSF2 in K562 leukemia cells, generating an isogenic model so that splicing alterations can be attributed solely to mutant SRSF2. We found that SRSF2 (P95H) misregulates 548 splicing events (RNA gel shift assays showed that a mutant SRSF2 derivative bound more tightly than its wild-type counterpart to RNA sites containing UCCAG but bound less tightly to UGGAG sites. Thus in most cases the pattern of exon inclusion or exclusion correlated with stronger or weaker RNA binding, respectively. We further show that the P95H mutation does not affect other functions of SRSF2, i.e., protein-protein interactions with key splicing factors. Our results thus demonstrate that the P95H mutation positively or negatively alters the binding affinity of SRSF2 for cognate RNA sites in target transcripts, leading to misregulation of exon inclusion. Our findings shed light on the mechanism of the disease-associated SRSF2 mutation in splicing regulation and also reveal a group of misspliced mRNA isoforms for potential therapeutic targeting.

  16. LRRK2 G2019S mutation: frequency and haplotype data in South African Parkinson's disease patients.

    Science.gov (United States)

    Bardien, Soraya; Marsberg, Angelica; Keyser, Rowena; Lombard, Debbie; Lesage, Suzanne; Brice, Alexis; Carr, Jonathan

    2010-07-01

    Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most significant genetic cause of Parkinson's disease (PD). The exact function of LRRK2 is currently unknown but the presence of multiple protein interaction domains including WD40 and ankyrin indicates that it may act a scaffold for assembly of a multi-protein signaling complex. The G2019S mutation in LRRK2 represents the most clinically relevant PD-causing mutation and has been found in both familial and sporadic forms of the disorder. This mutation is situated in the highly conserved kinase MAPKKK domain, and has been found in up to 40% of PD patients from North African Arabic, 30% of Ashkenazi Jewish and approximately 10% of Portuguese and Spanish populations. Although extensively investigated in numerous European and North American populations, studies on the frequency of G2019S in African countries have been rare. The present study is the first on the South African population. High-resolution melt analysis was used to identify the G2019S mutation and it was found in 2% (4/205) of the patients studied. G2019S was not found in any of the Black PD patients screened. In all four G2019S-positive probands the mutation was shown to be present on the common haplotype referred to as haplotype 1. This reveals that the four South African G2019S-positive probands (three Caucasian and one of mixed ancestry) share a common ancestor with the other haplotype 1-associated families reported worldwide.

  17. 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.

  18. Proteolipid protein 1 gene mutation in nine patients with Pelizaeus-Merzbacher disease

    Institute of Scientific and Technical Information of China (English)

    WANG Jing-min; WU Ye; WANG Hui-fang; DENG Yan-hua; YANG Yan-ling; QIN Jiong; LI Xin-yi; WU Xi-ru; JIANG Yu-wu

    2008-01-01

    Background Pelizaeus-Merzbacher disease(PMD)is a rare X-linked recessive disorder with svmptoms including nystagmus,impaired motor development,ataxia,and progressive spasticity.The proteolipid protein 1(PLPl)gene is the only pathogenic gene of PMD.Duplication of the PLP1 gene is the most frequent gene defect.accounting for 500%-70%of PMD cases.whereas point mutations in the coding sequence or the splice sites account for 10%-25%of PMD cases.This study aimed to identify PLP1 mutations in nine unrelated Chinese patients(P1-9)with PMD,and 14 subjects from the family of patient 2 were also described.Methods Genomic DNA was extracted from peripheral blood samples.Gene dosage was determined using the multiplex ligation-dependent probe amplification (MLPA).All 7 exons and exon-intron boundanes of the PLP1 gene were amplified and analyzed using direct DNA sequencing.Reaults Of these nine patients,there were four transitional.four classical,and one connatal PMD according to their clinical and radiological presentations.PLP1 duplications were identified in patients 1-7 with PMD.Their mothers were PLP1 duplications carriers as well.Both duplication carders and normal genotypes of PLP1 were identified in the family members of patient 2.A c.51 7C>T(p.P173S)hemizygous missense mutation in exon 4 was found in patient 8 with PMD,and his mother was shown to be a heterozygote of this mutation.Conclusions We identified seven genomic duplications and one missense mutation(p.P173S)of the PLP1 gene in eight Chinese patients with PMD.This is the report about PLP1 mutations in PMD patients from the mainland of China.

  19. Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

    Energy Technology Data Exchange (ETDEWEB)

    Merwe, Celia van der, E-mail: celiavdm@sun.ac.za [Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Loos, Ben [Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch (South Africa); Swart, Chrisna [Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Kinnear, Craig [Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); MRC Centre for Molecular and Cellular Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Cape Town (South Africa); Henning, Franclo [Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Merwe, Lize van der [Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Department of Statistics, University of the Western Cape, Cape Town (South Africa); Pillay, Komala [National Health Laboratory Services (NHLS) Histopathology Laboratory, Red Cross Children’s Hospital, Cape Town (South Africa); Muller, Nolan [Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Zaharie, Dan [Neuropathology Unit, Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); Engelbrecht, Lize [Cell Imaging Unit, Central Analytical Facility, Stellenbosch University, Cape Town (South Africa); Carr, Jonathan [Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa); and others

    2014-05-02

    Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD

  20. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease.

    Science.gov (United States)

    Clark, L N; Ross, B M; Wang, Y; Mejia-Santana, H; Harris, J; Louis, E D; Cote, L J; Andrews, H; Fahn, S; Waters, C; Ford, B; Frucht, S; Ottman, R; Marder, K

    2007-09-18

    To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.

  1. Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation.

    Science.gov (United States)

    Goldstein, D S; Imrich, R; Peckham, E; Holmes, C; Lopez, G; Crews, C; Hardy, J; Singleton, A; Hallett, M

    2007-10-16

    Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.

  2. Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders

    Directory of Open Access Journals (Sweden)

    Cai Y

    2015-07-01

    Full Text Available Yan Cai,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, 2Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea Abstract: Alzheimer’s disease (AD is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1, presenilin 2 (PSEN2, and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson’s disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders. Keywords: mutations in presenilin 2, Alzheimer’s disease

  3. Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer’s disease mutations

    Science.gov (United States)

    Lee, Grace J; Lu, Po H; Medina, Luis D; Rodriguez-Agudelo, Yaneth; Melchor, Stephanie; Coppola, Giovanni; Braskie, Meredith N; Hua, Xue; Apostolova, Liana G; Leow, Alex D; Thompson, Paul M; Ringman, John M

    2013-01-01

    Background Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer’s disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer’s disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. Methods Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. Results MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. Conclusions Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD. PMID:23085935

  4. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

    Science.gov (United States)

    Lucarelli, Marco; Bruno, Sabina Maria; Pierandrei, Silvia; Ferraguti, Giampiero; Stamato, Antonella; Narzi, Fabiana; Amato, Annalisa; Cimino, Giuseppe; Bertasi, Serenella; Quattrucci, Serena; Strom, Roberto

    2015-01-01

    Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype–phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype–phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype–phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway. PMID:25910067

  5. Hemolytic anemia as first presentation of Wilson's disease with uncommon ATP7B mutation.

    Science.gov (United States)

    Ye, Xing-Nong; Mao, Li-Ping; Lou, Yin-Jun; Tong, Hong-Yan

    2015-01-01

    Wilson's disease (WD) is a rare inherited disorder of copper metabolism and the main manifestations are liver and brain disorders. Hemolytic anemia is an unusual complication of WD. We describe a 15-year-old girl who developed hemolytic anemia as the first manifestation of Wilson's disease. An Arg952Lys mutation was found in exon 12 of the ATP7B gene, which is uncommon among Chinese Han individuals. From this case and reviews, we can achieve a better understanding of WD. Besides, we may conclude that the probable diagnosis of WD should be considered in young patients with unexplained hemolytic anemia, especially in patients with hepatic and/or neurologic disorder.

  6. Genetics of Parkinson's disease

    National Research Council Canada - National Science Library

    Klein, Christine; Westenberger, Ana

    2012-01-01

    Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD...

  7. A mutation in SCARB2 is a modifier in Gaucher disease.

    Science.gov (United States)

    Velayati, Arash; DePaolo, John; Gupta, Nidhi; Choi, Jae H; Moaven, Nima; Westbroek, Wendy; Goker-Alpan, Ozlem; Goldin, Ehud; Stubblefield, Barbara K; Kolodny, Edwin; Tayebi, Nahid; Sidransky, Ellen

    2011-11-01

    Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD.

  8. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

    Science.gov (United States)

    Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel; Orcel, Philippe; Brown, Jacques P; Nuti, Ranuccio; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, Luigi; Gianfrancesco, Fernando

    2016-02-04

    Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

  9. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

    Science.gov (United States)

    Haapaniemi, Emma M; Kaustio, Meri; Rajala, Hanna L M; van Adrichem, Arjan J; Kainulainen, Leena; Glumoff, Virpi; Doffinger, Rainer; Kuusanmäki, Heikki; Heiskanen-Kosma, Tarja; Trotta, Luca; Chiang, Samuel; Kulmala, Petri; Eldfors, Samuli; Katainen, Riku; Siitonen, Sanna; Karjalainen-Lindsberg, Marja-Liisa; Kovanen, Panu E; Otonkoski, Timo; Porkka, Kimmo; Heiskanen, Kaarina; Hänninen, Arno; Bryceson, Yenan T; Uusitalo-Seppälä, Raija; Saarela, Janna; Seppänen, Mikko; Mustjoki, Satu; Kere, Juha

    2015-01-22

    The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

  10. Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome.

    Science.gov (United States)

    Polfus, Linda M; Boerwinkle, Eric; Gibbs, Richard A; Metcalf, Ginger; Muzny, Donna; Veeraraghavan, Narayanan; Grove, Megan; Shete, Sanjay; Wallace, Stephanie; Milewicz, Dianna; Hanchard, Neil; Lupski, James R; Hashmi, Syed Shahrukh; Gupta-Malhotra, Monesha

    2016-11-01

    To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), SCNN1B, an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, SCNN1A, possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.

  11. Incidence of Crohn's disease and CARD15 mutation in a small township in Sicily.

    Science.gov (United States)

    Cottone, M; Renda, M C; Mattaliano, A; Oliva, L; Fries, W; Criscuoli, V; Modesto, I; Scimeca, D; Maggio, A; Casà, A; Maisano, S; Mocciaro, F; Sferrazza, A; Orlando, A

    2006-01-01

    The incidence of Crohn's disease (CD) has been shown to be lower in Southern than in Northern Europe. Data on the frequency of the NOD2/CARD15 mutations for Mediterranean area are very scant. To determine the incidence of CD from 1979 to 2002 in a township in Sicily together with the allele frequency of NOD2/CARD15 mutations in patients, family members and controls, and to determine the allele frequency of these mutations in sporadic CD from other areas of Sicily in comparison with a control population. Casteltermini is a small town close to Agrigento (Sicily) with a population of 9,130 inhabitants. All the diagnoses of inflammatory bowel disease (IBD) made from 1979 to 2002 were obtained through the local health authority. NOD2/CARD15 mutations were studied in 23 out of the 29 patients with CD in Casteltermini, in 60 family members and in 64 controls. NOD2/CARD15 was also studied in 80 sporadic cases of CD disease among Sicilians outside Casteltermini and 118 healthy controls. From 1979 to 2002, 29 patients with CD and 13 patients with ulcerative colitis (UC) were registered. The 6-year mean incidence of CD ranged from 8.0 to 17 new cases for every 100,000 inhabitants, whereas the mean incidence of UC ranged from five new cases to 7.8 for every 100,000 inhabitants. The allele frequencies of NOD2/CARD15 mutations (L1007finsC, G908R, R702W) were 8.7, 4.3 and 8.7%, respectively, in CD cases; 5.0, 4.2 and 3.1% in family members; 1.6, 2.3 and 3.1% in controls. In sporadic Sicilian CD patients outside Casteltermini the allele frequency was 7.5, 8.1, 6.2% whereas in control population it was 3.3, 1.6, 1.6%. A high incidence of CD compared with UC was observed in this small town in Southern Italy. The frequency of NOD2/CARD15 mutations in CD is similar to other Caucasian population studied so far.

  12. DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish-Polish-Russian descent

    Energy Technology Data Exchange (ETDEWEB)

    Choy, F.Y.M.; Wei, C.; Applegarth, D.A.; McGillivray, B.C. [Univ. of British Columbia, Vancouver (Canada)

    1994-06-01

    Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genoma DNA nucleotide position 6683) from a Gaucher disease patient of Jewish-Polish-Russian descent with type 1 Gaucher disease. It is a G{yields}A transition in exon 11 that results in {sup 496}Arg{yields}{sup 496}His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A{yields}G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease. Since it was also postulated that mutation 1226 in the homozygous form will usually result in a good prognosis, we speculate that the orthopedic complications and the unusual presence of glomerulosclerosis in this patient may be attributable to the mutation at nucleotide 1604. This speculation will require a description of more patients with this mutation for confirmation. 32 refs., 5 figs.

  13. Identification of a SIRT1 mutation in a family with type 1 diabetes

    DEFF Research Database (Denmark)

    Biason-Lauber, Anna; Böni-Schnetzler, Marianne; Hubbard, Basil P

    2013-01-01

    Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members....... Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations...... identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes....

  14. Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes

    Directory of Open Access Journals (Sweden)

    Isanova Bella

    2009-07-01

    Full Text Available Abstract Background In von Hippel-Lindau (VHL disease, germline mutations in the VHL tumor suppressor gene cause clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product is part of an ubiquitin E3 ligase complex and hypoxia-inducible factor alpha (HIF-α is a key substrate, although additional VHL functions have been described. A genotype-phenotype relationship exists in VHL disease such that specific VHL mutations elicit certain subsets of these tumors. Here, we examine VHL genotype-phenotype correlations at the cellular level, focusing on the regulation of tight junctions and cell morphology. Methods Wild-type and various mutant VHL proteins representing VHL disease subtypes were stably expressed in 3 VHL-negative renal carcinoma cell lines. Using these cell lines, the roles of various VHL-associated cellular functions in regulation of cell morphology were investigated. Results As a whole, type 1 mutants varied greatly from type 2 mutants, demonstrating high levels of HIF-2α, cyclin D1 and α5 integrin, lower p27 levels, and a spindly, fibroblastic cellular appearance. Type 2 mutations demonstrated an epithelial morphology similar to wild-type VHL in the majority of the renal cell lines used. Knockdown of p27 in cells with wild-type VHL led to perturbations of both epithelial morphology and ZO-1 localization to tight junctions. ZO-1 localization correlated well with VHL disease subtypes, with greater mislocalization observed for genotypes associated with a higher risk of renal carcinoma. HIF-2α knockdown in 786-O partially restored ZO-1 localization, but did not restore an epithelial morphology. Conclusion VHL has both HIF-α dependent and HIF-α independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease.

  15. Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population.

    Science.gov (United States)

    Haghighi, Alireza; Rezazadeh, Jamileh; Shadmehri, Azam Ahmadi; Haghighi, Amirreza; Kornreich, Ruth; Desnick, Robert J

    2011-09-01

    The β-hexosaminidase A (HEXA) mutations in the first reported cases of infantile Tay-Sachs disease in the Persian population were identified in two unrelated consanguineous families. The clinical diagnoses of the affected infants were confirmed by their markedly deficient levels of HEXA activity in plasma or peripheral leukocytes. The specific causative mutation in each family was determined by sequencing the HEXA alleles in both sets of related parents. Two mutations were identified: c.1A>G (p.MIV), which obliterated the initiating methionine in codon 1, and c.1177C>T (p.R393X), which predicted a termination codon or nonsense mutation.

  16. Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

    DEFF Research Database (Denmark)

    Storr, Helen L; Metherell, Louise A; Dias, Renuka

    2010-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PP...... PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals....

  17. A novel SMPD1 mutation in two Chinese sibling patients with type B Niemann-Pick disease

    Institute of Scientific and Technical Information of China (English)

    HUA Rong; WU Hui; CUI Zhe; CHEN Jin-xian; WANG Zheng

    2012-01-01

    Type B Niemann-Pick disease is an autosomal recessive sphingolipidosis due to mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1).Here we present molecular findings for two sibling patients.One mutation V36A due to c.107T>C in exon 1 is a single nucleotide polymorphism and the other N522S due to c.1565 A>G in exon 6 is a novel missense mutation.This non-fatal missense mutation leads to -20% residual lysosomal acid sphingomyelinase activity in vitro and only results in hepatosplenomegaly without neurologic involvement.

  18. Multi-vector Spherical Monogenics, Spherical Means and Distributions in Clifford Analysis

    Institute of Scientific and Technical Information of China (English)

    Fred BRACKX; Bram De KNOCK Hennie; De SCHEPPER

    2005-01-01

    New higher-dimensional distributions have been introduced in the framework of Clifford analysis in previous papers by Brackx, Delanghe and Sommen. Those distributions were defined using spherical co-ordinates, the "finite part" distribution Fp xμ+ on the real line and the generalized spherical means involving vector-valued spherical monogenics. In this paper, we make a second generalization,leading to new families of distributions, based on the generalized spherical means involving a multivector-valued spherical monogenic. At the same time, as a result of our attempt at keeping the paper self-contained, it offers an overview of the results found so far.

  19. Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1.

    Science.gov (United States)

    Hildebrand, Michael S; Sorensen, Jessica L; Jensen, Maren; Kimberling, William J; Smith, Richard J H

    2008-09-01

    Most familial cases of autosomal dominant low frequency sensorineural hearing loss (LFSNHL) are attributable to mutations in the wolframin syndrome 1 (WFS1) gene at the DFNA6/14/38 locus. WFS1 mutations at this locus were first described in 2001 in six families segregating LFSNHL that was non-progressive below 2,000 Hz; the causative mutations all clustered in the C-terminal domain of the wolframin protein. Mutations in WFS1 also cause Wolfram syndrome (WS), an autosomal recessive neurodegenerative disorder defined by diabetes mellitus, optic atrophy and often deafness, while numerous single nucleotide polymorphisms (SNPs) in WFS1 have been associated with increased risk for diabetes mellitus, psychiatric illnesses and Parkinson disease. This study was conducted in an American family segregating autosomal dominant LFSNHL. Two hearing impaired family members also had autoimmune diseases-Graves disease (GD) and Crohn disease (CD). Based on the low frequency audioprofile, mutation screening of WFS1 was completed and a novel missense mutation (c.2576G --> A) that results in an arginine-to-glutamine substitution (p.R859Q) was identified in the C-terminal domain of the wolframin protein where most LFSNHL-causing mutations cluster. The family member with GD also carried polymorphisms in WFS1 that have been associated with other autoimmune diseases.

  20. Glycogen storage disease type Ia : recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flowchart

    NARCIS (Netherlands)

    Rake, JP; ten Berge, AM; Visser, G; Verlind, E; Niezen-Koning, KE; Buys, CHCM; Smit, GPA; Scheffer, H

    2000-01-01

    We studied the glucose-6-phosphatase (G6Pase) gene of 30 unrelated glycogen storage disease type Ia (GSD Ia) patients using single strand conformation, polymorphism (SSCP) prior to automated sequencing of exons revealing an aberrant SSCP pattern. In all patients we could identify mutations on both a

  1. Hepatic fibrinogen storage disease due to the fibrinogen γ375 Arg → Trp mutation "fibrinogen aguadilla" is present in Arabs

    Directory of Open Access Journals (Sweden)

    Abdulrahman Al-Hussaini

    2014-01-01

    Full Text Available The mutation γ375Arg → Trp (fibrinogen Aguadilla is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.

  2. Homozygous N396T mutation in Gaucher disease: Portuguese sisters with markedly different phenotypes

    Directory of Open Access Journals (Sweden)

    Samantha Kimball

    2011-03-01

    Full Text Available Samantha Kimball1,2, Francis Choy4, Agnes Zay5, Dominick Amato31Department of Nutritional Sciences, University of Toronto, Canada; 2Department of Laboratory Medicine and Pathology, 3Department of Medicine, Division of Hematology, Mt Sinai Hospital, Toronto, Canada; 4Department of Biology, University of Victoria, Victoria, Canada; 5MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, ScotlandAbstract: Gaucher disease (GD is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV infection. Enzyme replacement therapy (ERT improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV.Keywords: Gaucher disease, N396T mutation, glucocerebrosidase, HIV

  3. A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy.

    Science.gov (United States)

    Wuttke, Matthias; Seidl, Maximilian; Malinoc, Angelica; Prischl, Friedrich C; Kuehn, E Wolfgang; Walz, Gerd; Köttgen, Anna

    2015-12-01

    COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year-old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy. Targeted sequencing of candidate genes for steroid-resistant nephrotic syndrome and congenital thrombotic microangiopathy was negative. Despite all therapeutic efforts, including angiotensin-converting enzyme inhibition, immunosuppressive therapy, plasma exchanges and rituximab, the patient progressed to end-stage renal disease. When a male cousin presented with nephrotic syndrome years later, whole-exome sequencing identified a shared disruptive COL4A5 mutation (p.F222C) that showed X-linked segregation. Thus, mutations in COL4A5 give rise to a broader spectrum of clinical presentation than commonly suspected, highlighting the benefits of comprehensive rather than candidate genetic testing in young patients with otherwise unexplained glomerular disease. Our results are in line with an increasing number of atypical presentations of single-gene disorders identified through genome-wide sequencing.

  4. A Classic Case of Maple Syrup Urine Disease and a Novel Mutation in the BCKDHA Gene

    Directory of Open Access Journals (Sweden)

    Alieh Mirzaee

    2017-09-01

    Full Text Available Background: Maple syrup urine disease (MSUD is an inherited branched-chain amino acid metabolic disorder caused by the deficiency in the branched-chain alpha-keto acid dehydrogenase (BCKD complex. In MSUD, elevation of the branched-chain amino acids, such as alpha-keto acid and alpha-hydroxy acid, occurs due to the BCKDC gene deficiency, appearing in the blood, urine, and cerebrospinal fluid, which leads to neurological damage and mental retardation. MSUD phenotypically penetrates due to the mutations in the coding genes of four subunits of the BCKD complex, including the BCKDHA, BCKDHB, DBT, and DLD genes.Case report: We aimed to report the cases of three families whose children were affected by MSUD and presented with symptomatic features during the first week of birth, which were identified by mass spectrometry. DNA study was performed as a diagnosis panel containing four encoded BCKDC subunit genes.Conclusion: In the current study, DNA analysis and phenotypic manifestations indicated a novel mutation of c.143delT, p.L48Rfs*15 in the BCKDHA gene in a homozygous state, which is a causative mutation for the classic MSUD phenotype. Early diagnosis and neonatal screening are recommended for the accurate and effective treatment of this disease

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

    Directory of Open Access Journals (Sweden)

    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. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation

    DEFF Research Database (Denmark)

    Lindquist, S.G.; Holm, I.E.; Schwartz, M.

    2008-01-01

    We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre-symptomatic an......We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre...

  7. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.

    Science.gov (United States)

    Jansen, G A; Ofman, R; Ferdinandusse, S; Ijlst, L; Muijsers, A O; Skjeldal, O H; Stokke, O; Jakobs, C; Besley, G T; Wraith, J E; Wanders, R J

    1997-10-01

    Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid. We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation. This analysis confirms our finding that Refsum disease is caused by a deficiency of PhyH.

  8. Structural Insight into Processive Human Mitochondrial DNA Synthesis and Disease-Related Polymerase Mutations

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young-Sam; Kennedy, W. Dexter; Yin, Y. Whitney; (Texas)

    2010-09-07

    Human mitochondrial DNA polymerase (Pol {gamma}) is the sole replicase in mitochondria. Pol {gamma} is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol {gamma} holoenzyme and, separately, a variant of its processivity factor, Pol {gamma}B. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol {gamma}A interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol {gamma} structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.

  9. A new mutation for Huntington disease following maternal transmission of an intermediate allele.

    Science.gov (United States)

    Semaka, Alicia; Kay, Chris; Belfroid, René D M; Bijlsma, Emilia K; Losekoot, Monique; van Langen, Irene M; van Maarle, Merel C; Oosterloo, Mayke; Hayden, Michael R; van Belzen, Martine J

    2015-01-01

    New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (≥ 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeats. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPas

    DEFF Research Database (Denmark)

    Poulsen, Hanne; Khandelia, Himanshu; Morth, Jens Preben

    2010-01-01

    The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume...... potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause...... severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely...

  11. Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase

    DEFF Research Database (Denmark)

    Poulsen, Hanne; Khandelia, Himanshu; Morth, J Preben

    2010-01-01

    The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume...... potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause...... severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely...

  12. N370S-GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson's disease.

    Science.gov (United States)

    García-Sanz, Patricia; Orgaz, Lorena; Bueno-Gil, Guillermo; Espadas, Isabel; Rodríguez-Traver, Eva; Kulisevsky, Jaime; Gutierrez, Antonia; Dávila, José C; González-Polo, Rosa A; Fuentes, José M; Mir, Pablo; Vicario, Carlos; Moratalla, Rosario

    2017-08-05

    Heterozygous mutations in the GBA1 gene, which encodes the lysosomal enzyme β-glucocerebrosidase-1, increase the risk of developing Parkinson's disease, although the underlying mechanisms remain unclear. The aim of this study was to explore the impact of the N370S-GBA1 mutation on cellular homeostasis and vulnerability in a patient-specific cellular model of PD. We isolated fibroblasts from 4 PD patients carrying the N370S/wild type GBA1 mutation and 6 controls to study the autophagy-lysosome pathway, endoplasmic reticulum stress, and Golgi apparatus structure by Western blot, immunofluorescence, LysoTracker and Filipin stainings, mRNA analysis, and electron microscopy. We evaluated cell vulnerability by apoptosis, reactive oxygen species and mitochondrial membrane potential with flow cytometry. The N370S mutation produced a significant reduction in β-glucocerebrosidase-1 protein and enzyme activity and β-glucocerebrosidase-1 retention within the endoplasmic reticulum, which interrupted its traffic to the lysosome. This led to endoplasmic reticulum stress activation and triggered unfolded protein response and Golgi apparatus fragmentation. Furthermore, these alterations resulted in autophagosome and p62/SQSTM1 accumulation. This impaired autophagy was a result of dysfunctional lysosomes, indicated by multilamellar body accumulation probably caused by increased cholesterol, enlarged lysosomal mass, and reduced enzyme activity. This phenotype impaired the removal of damaged mitochondria and reactive oxygen species production and enhanced cell death. Our results support a connection between the loss of β-glucocerebrosidase-1 function, cholesterol accumulation, and the disruption of cellular homeostasis in GBA1-PD. Our work reveals new insights into the cellular pathways underlying PD pathogenesis, providing evidence that GBA1-PD shares common features with lipid-storage diseases. © 2017 International Parkinson and Movement Disorder Society. © 2017 International

  13. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

    Science.gov (United States)

    Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre; Plaisier, Emmanuelle

    2016-04-01

    Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.

  14. Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

    Directory of Open Access Journals (Sweden)

    Tianle Chen

    2012-01-01

    work, we use the expectation-maximization (EM algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

  15. Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations.

    Science.gov (United States)

    Zhai, Liting; Feng, Lingling; Xia, Lin; Yin, Huiyong; Xiang, Song

    2016-04-18

    Glycogen is a branched glucose polymer and serves as an important energy store. Its debranching is a critical step in its mobilization. In animals and fungi, the 170 kDa glycogen debranching enzyme (GDE) catalyses this reaction. GDE deficiencies in humans are associated with severe diseases collectively termed glycogen storage disease type III (GSDIII). We report crystal structures of GDE and its complex with oligosaccharides, and structure-guided mutagenesis and biochemical studies to assess the structural observations. These studies reveal that distinct domains in GDE catalyse sequential reactions in glycogen debranching, the mechanism of their catalysis and highly specific substrate recognition. The unique tertiary structure of GDE provides additional contacts to glycogen besides its active sites, and our biochemical experiments indicate that they mediate its recruitment to glycogen and regulate its activity. Combining the understanding of the GDE catalysis and functional characterizations of its disease-causing mutations provides molecular insights into GSDIII.

  16. Familial Mediterranean fever in two Bedouin families: mutation analysis and disease severity.

    Science.gov (United States)

    Press, J; Shinar, Y; Langevitz, P; Livneh, A; Pras, M; Buskila, D

    2000-06-05

    Familial Mediterranean fever (FMF) is an autosomal recessive disease prevalent among non-Ashkenazi Jews, Armenians, Arabs, and Turks. The Bedouin are nomad Arab tribes residing in desert margins of the Middle East and Arabia. FMF is quite rare in Bedouins, and here we report on two Bedouin families from southern Israel suffering from this disorder. The MEFV mutations found in the Bedouin patients M694I, V726A, and E148Q are consistent with their Arab origin. The disease severity score showed a mild to moderate severity disease in six patients. The Bedouins, leading a unique nomadic life, may prove instrumental in unraveling the role of environmental factors in the course and severity of FMF.

  17. Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation

    DEFF Research Database (Denmark)

    Lindquist, S.G.; Nielsen, J.E.; Stokholm, J.

    2008-01-01

    BACKGROUND: Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic...... features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features. METHODS AND RESULTS: We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer......'s disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense...

  18. Utilization of Gene Mapping and Candidate Gene Mutation Screening for Diagnosing Clinically Equivocal Conditions:A Norrie Disease Case Study

    Institute of Scientific and Technical Information of China (English)

    Vasiliki Chini; Danai Stambouli; Florina Mihaela Nedelea; George Alexandru Filipescu; Diana Mina; Marios Kambouris; Hatem El-Shanti

    2014-01-01

    Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members..Mapping of the X chromosome and candidate gene mutation screening i-dentified a c.C267A[p.F89L] mutation in NPD previously de-scribed as possibly causing Norrie disease..The detection of the c.C267A[p.F89L] variant in another unrelated family con-firms the pathogenic nature of the mutation for the Norrie dis-ease phenotype. Gene mapping, haplotype analysis, and can-didate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information..The clinical diagnosis and mutation identification were critical for provid-ing proper genetic counseling and prenatal diagnosis for this family.

  19. Short Tandem Repeats in Human Exons: A Target for Disease Mutations

    Directory of Open Access Journals (Sweden)

    Villesen Palle

    2008-09-01

    Full Text Available Abstract Background In recent years it has been demonstrated that structural variations, such as indels (insertions and deletions, are common throughout the genome, but the implications of structural variations are still not clearly understood. Long tandem repeats (e.g. microsatellites or simple repeats are known to be hypermutable (indel-rich, but are rare in exons and only occasionally associated with diseases. Here we focus on short (imperfect tandem repeats (STRs which fall below the radar of conventional tandem repeat detection, and investigate whether STRs are targets for disease-related mutations in human exons. In particular, we test whether they share the hypermutability of the longer tandem repeats and whether disease-related genes have a higher STR content than non-disease-related genes. Results We show that validated human indels are extremely common in STR regions compared to non-STR regions. In contrast to longer tandem repeats, our definition of STRs found them to be present in exons of most known human genes (92%, 99% of all STR sequences in exons are shorter than 33 base pairs and 62% of all STR sequences are imperfect repeats. We also demonstrate that STRs are significantly overrepresented in disease-related genes in both human and mouse. These results are preserved when we limit the analysis to STRs outside known longer tandem repeats. Conclusion Based on our findings we conclude that STRs represent hypermutable regions in the human genome that are linked to human disease. In addition, STRs constitute an obvious target when screening for rare mutations, because of the relatively low amount of STRs in exons (1,973,844 bp and the limited length of STR regions.

  20. Characterization of rice blast resistance genes in rice germplasm with monogenic lines and pathogenicity assays

    Science.gov (United States)

    Resistance (R) genes have been effectively deployed in preventing rice crop losses due to the fungus Magnaporthe oryzae. In the present study, we studied the interaction between 24 monogenic lines carrying at least one major R gene, Pia, Pib, Pii, Pik, Pik-h, Pik-m, Pik-p, Pik-s, Pish, Pit, Pita, Pi...

  1. Prevalence of S and Z alpha 1-antitrypsin mutations in patients with pancreatic diseases in Serbian population

    Directory of Open Access Journals (Sweden)

    Nikolić Aleksandra

    2010-01-01

    Full Text Available One of the key points in research of pancreatic disease pathology is further elucidation of the role of proteases and antiproteases, since their imbalance can lead to pancreatic injury. Alpha 1-antitrypsin (AAT is one of the most important serum inhibitors of proteolytic enzymes, including pancreatic enzymes trypsin, chymotrypsin and elastase. It is speculated that mutations in the AAT gene may influence the onset and the development of pancreatic disease. The presence of the most common AAT mutations Z and S was analyzed in 160 patients with pancreatic diseases (50 patients with pancreatic cancer, 50 patients with chronic pancreatitis and 60 patients with type 2 diabetes mellitus and 129 healthy individuals by PCR-mediated site-directed mutagenesis (PSM method. One patient with pancreatic cancer was found to be a carrier of Z mutation, as well as one patient with type 2 diabetes mellitus. One patient with chronic pancreatitis was found to be a carrier of S mutation. The common AAT mutations were statistically significantly over-represented in patients with pancreatic diseases (3 of 160 patients, allelic frequency 0.9% than in the control group (1 of 129 individuals, allelic frequency 0.4%. The results of this study, requiring confirmation, suggest that common AAT mutations Z and S may be associated with a modest increase in susceptibility to the development of pancreatic disease.

  2. Functional analysis of a promoter variant identified in the CFTR gene in cis of a frameshift mutation.

    Science.gov (United States)

    Viart, Victoria; Des Georges, Marie; Claustres, Mireille; Taulan, Magali

    2012-02-01

    In monogenic diseases, the presence of several sequence variations in the same allele may complicate our understanding of genotype-phenotype relationships. We described new alterations identified in a cystic fibrosis (CF) patient harboring a 48C>G promoter sequence variation associated in cis of a 3532AC>GTA mutation and in trans with the F508del mutation. Functional analyses including in vitro experiments confirmed the deleterious effect of the 3532GTA frameshift mutation through the creation of a premature termination codon. The analyses also revealed that the 48G promoter variant has a negative effect on both transcription and mRNA level, thus demonstrating the importance of analyzing all mutations or sequence variations with potential impact on CF transmembrane conductance regulator processing, even when the two known disease-causing mutations have already been detected. Our results emphasize the need to perform, wherever possible, functional studies that may greatly assist the interpretation of the disease-causing potential of rare mutation-associated sequence variations.

  3. 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.

  4. Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

    DEFF Research Database (Denmark)

    Vissing, John; Duno, Morten; Schwartz, Marianne

    2009-01-01

    and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A...... features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate......>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients...

  5. In utero copper treatment for Menkes disease associated with a severe ATP7A mutation.

    Science.gov (United States)

    Haddad, Marie Reine; Macri, Charles J; Holmes, Courtney S; Goldstein, David S; Jacobson, Beryl E; Centeno, Jose A; Popek, Edwina J; Gahl, Willam A; Kaler, Stephen G

    2012-09-01

    Menkes disease is a lethal X-linked recessive neurodegenerative disorder of copper transport caused by mutations in ATP7A, which encodes a copper-transporting ATPase. Early postnatal treatment with copper injections often improves clinical outcomes in affected infants. While Menkes disease newborns appear normal neurologically, analyses of fetal tissues including placenta indicate abnormal copper distribution and suggest a prenatal onset of the metal transport defect. In an affected fetus whose parents found termination unacceptable and who understood the associated risks, we began in utero copper histidine treatment at 31.5 weeks gestational age. Copper histidine (900 μg per dose) was administered directly to the fetus by intramuscular injection (fetal quadriceps or gluteus) under ultrasound guidance. Percutaneous umbilical blood sampling enabled serial measurement of fetal copper and ceruloplasmin levels that were used to guide therapy over a four-week period. Fetal copper levels rose from 17 μg/dL prior to treatment to 45 μg/dL, and ceruloplasmin levels from 39 mg/L to 122 mg/L. After pulmonary maturity was confirmed biochemically, the baby was delivered at 35.5 weeks and daily copper histidine therapy (250 μg sc b.i.d.) was begun. Despite this very early intervention with copper, the infant showed hypotonia, developmental delay, and electroencephalographic abnormalities and died of respiratory failure at 5.5 months of age. The patient's ATP7A mutation (Q724H), which severely disrupted mRNA splicing, resulted in complete absence of ATP7A protein on Western blots. These investigations suggest that prenatally initiated copper replacement is inadequate to correct Menkes disease caused by severe loss-of-function mutations, and that postnatal ATP7A gene addition represents a rational approach in such circumstances.

  6. Genetic Screening of Mutations Associated with Fabry Disease in a Nationwide Cohort of Juvenile Idiopathic Arthritis Patients

    Science.gov (United States)

    Gonçalves, Maria J.; Mourão, Ana F.; Martinho, António; Simões, Olívia; Melo-Gomes, José; Salgado, Manuel; Estanqueiro, Paula; Ribeiro, Célia; Brito, Iva; Fonseca, João E.; Canhão, Helena

    2017-01-01

    Fabry’s disease (FD) is a lysosomal storage disorder associated with an alpha-galactosidase A deficiency. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients with established diagnosis is unknown, but as musculoskeletal pain may be an important complaint at presentation, misdiagnosed cases are anticipated. With this study, we aim to calculate the frequency of FD-associated mutations in a cohort of JIA patients. Children with JIA from a national cohort were selected. Clinical and laboratorial information was recorded in the Portuguese rheumatic diseases register (http://Reuma.pt). Molecular genetic testing to detect GLA gene mutations was performed. After the multiplex polymerase chain reactions technique for DNA amplification, direct sequencing of the complete sequence of GLA gene was completed. From a cohort of 292 patients with JIA (188 females, 104 males), mutations were identified in 5 patients (all female). Four patients had the mutation D313Y, a rare GLA variant, which is associated with low enzymatic levels in plasma, but normal lysosomal levels. One patient presented the missense mutation R118C, which was previously described in Mediterranean patients with FD. This is the first screening of FD mutations in a cohort of JIA patients. No “classic” pathogenic FD mutations were reported. The late-onset FD-associated mutation, R118C, was found in a frequency of 0.34% (1/292). PMID:28299312

  7. Positive Selection during the Evolution of the Blood Coagulation Factors in the Context of Their Disease-Causing Mutations

    Science.gov (United States)

    Rallapalli, Pavithra M.; Orengo, Christine A.; Studer, Romain A.; Perkins, Stephen J.

    2014-01-01

    Blood coagulation occurs through a cascade of enzymes and cofactors that produces a fibrin clot, while otherwise maintaining hemostasis. The 11 human coagulation factors (FG, FII–FXIII) have been identified across all vertebrates, suggesting that they emerged with the first vertebrates around 500 Ma. Human FVIII, FIX, and FXI are associated with thousands of disease-causing mutations. Here, we evaluated the strength of selective pressures on the 14 genes coding for the 11 factors during vertebrate evolution, and compared these with human mutations in FVIII, FIX, and FXI. Positive selection was identified for fibrinogen (FG), FIII, FVIII, FIX, and FX in the mammalian Primates and Laurasiatheria and the Sauropsida (reptiles and birds). This showed that the coagulation system in vertebrates was under strong selective pressures, perhaps to adapt against blood-invading pathogens. The comparison of these results with disease-causing mutations reported in FVIII, FIX, and FXI showed that the number of disease-causing mutations, and the probability of positive selection were inversely related to each other. It was concluded that when a site was under positive selection, it was less likely to be associated with disease-causing mutations. In contrast, sites under negative selection were more likely to be associated with disease-causing mutations and be destabilizing. A residue-by-residue comparison of the FVIII, FIX, and FXI sequence alignments confirmed this. This improved understanding of evolutionary changes in FVIII, FIX, and FXI provided greater insight into disease-causing mutations, and better assessments of the codon sites that may be mutated in applications of gene therapy. PMID:25158795

  8. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

    OpenAIRE

    1998-01-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. L...

  9. Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC

    DEFF Research Database (Denmark)

    Tingaud-Sequeira, Angèle; Raldúa, Demetrio; Lavie, Julie

    2017-01-01

    ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid...... knockdown morphants were consistent with human PHARC hallmarks. High abhd12 transcript levels were found in the optic tectum and tract, colocalized with myelin basic protein, and in the spinal cord. Morphants have myelination defects and concomitant functional deficits, characterized by progressive ataxia...

  10. Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions

    OpenAIRE

    Elisa Greggio; Cookson, Mark R

    2009-01-01

    Mutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein–protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we disc...

  11. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells

    Science.gov (United States)

    Hoban, Megan D.; Cost, Gregory J.; Mendel, Matthew C.; Romero, Zulema; Kaufman, Michael L.; Joglekar, Alok V.; Ho, Michelle; Lumaquin, Dianne; Gray, David; Lill, Georgia R.; Cooper, Aaron R.; Urbinati, Fabrizia; Senadheera, Shantha; Zhu, Allen; Liu, Pei-Qi; Paschon, David E.; Zhang, Lei; Rebar, Edward J.; Wilber, Andrew; Wang, Xiaoyan; Gregory, Philip D.; Holmes, Michael C.; Reik, Andreas; Hollis, Roger P.

    2015-01-01

    Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the β-globin locus with minimal off-target modification. By codelivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34+ hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγnull mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34+ cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers. PMID:25733580

  12. RAB39B gene mutations are not linked to familial Parkinson’s disease in China

    Science.gov (United States)

    Kang, Ji-feng; Luo, Yang; Tang, Bei-sha; Wan, Chang-min; Yang, Yang; Li, Kai; Liu, Zhen-hua; Sun, Qi-ying; Xu, Qian; Yan, Xin-xiang; Guo, Ji-feng

    2016-01-01

    Recently, RAB39B mutations were reported to be a causative factor in patients with Parkinson’s disease (PD). To validate the role of RAB39B in familial PD, a total of 195 subjects consisting of 108 PD families with autosomal-dominant (AD) inheritance and 87 PD families with autosomal-recessive (AR) inheritance in the Chinese Han population from mainland China were included in this study. We did not identify any variants in the coding region or the exon-intron boundaries of the gene by Sanger sequencing method in the DNA samples of 180 patients (100 with AD and 80 with AR). Furthermore, we did not find any variants in the RAB39B gene when Whole-exome sequencing (WES) was applied to DNA samples from 15 patients (8 with AD and 7 with AR) for further genetic analysis. Additionally, when quantitative real-time PCR was used to exclude large rearrangement variants in these patients, we found no dosage mutations in RAB39B gene. Our results suggest that RAB39B mutation is very rare in familial PD and may not be a major cause of familial PD in the Chinese Han Population. PMID:27694831

  13. Machado-Joseph disease in a Nigerian family: mutational origin and review of the literature.

    Science.gov (United States)

    Ogun, Shamsideen Abayomi; Martins, Sandra; Adebayo, Philip B; Dawodu, Clara O; Sequeiros, Jorge; Finkel, Michael F

    2015-02-01

    Machado-Joseph disease (MJD) has been described in Africans, but no cases have been reported from Nigeria. Current MJD global distribution results from both the ancestral populations-of-origin and the founder effects of mutations, some as a consequence of the Portuguese sea travels in the 15th to 16th century. Two main ancestral haplotypes have been identified: the Machado lineage, which is more recent, predominant in families of Portuguese extraction, and the Joseph lineage, which is much older and worldwide spread, postulated to have an Asian origin. We report a Nigerian family with MJD from Calabar, once settled by Portuguese slave traders, and assessed its mutational origin. The proband was a 33-year-old man with progressive unsteady gait, weakness of all limbs, dysphagia, dysarthria, urinary frequency and diaphoresis. He had end-of-gaze nystagmus, spastic quadriparesis and atrophic small muscles of the hand. He showed fibrillation potentials on EMG, and nerve conduction studies suggested a central axonopathy without demyelination. This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around 7000 years.

  14. Identification a novel mononucleotide deletion mutation in GAA in pompe disease patients

    Directory of Open Access Journals (Sweden)

    Milad Ebrahimi

    2017-01-01

    Full Text Available Background: Mutations in the acid alpha-glucosidase (GAA gene usually lead to reduced GAA activity. In this study, we analyzed the mutations of GAA and GAA enzyme activity from one sibling suspected Pompe disease and their first-degree relatives. Materials and Methods: In this cross-sectional study, GAA enzyme activity assay was assessed using tandem mass spectrometry. Polymerase chain reaction and Sanger sequencing were performed for GAA analysis. Results: GAA enzyme activity was significantly decreased in patients compared to the normal range (P = 0.02. Two individuals showed ten alterations in the GAA sequence, in which one of them (c. 1650del G has not been previously described in the literature. A single Guanine deletion (del-G was detected at codon 551 in exon 12. Conclusion: According to the literature, the detected change is a novel mutation. We hypothesized that the discovered deletion in the GAA might lead to a reduced activity of the gene product.

  15. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    Science.gov (United States)

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Novel ATPase Cu(2+ transporting beta polypeptide mutations in Chinese families with Wilson's disease.

    Directory of Open Access Journals (Sweden)

    Shaojuan Gu

    Full Text Available Wilson's disease (WD is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu(2+ transporting beta polypeptide gene (ATP7B. The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA-treated human liver carcinoma (HepG2 cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2, BCL2-associated X protein (BAX, sterol regulatory element binding protein 1 (SREBP1, and minichromosome maintenance protein 7 (MCM7 of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01. In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.

  17. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease.

    Science.gov (United States)

    Gu, Shaojuan; Yang, Huarong; Qi, Yong; Deng, Xiong; Zhang, Le; Guo, Yi; Huang, Qing; Li, Jing; Shi, Xiaoliu; Song, Zhi; Deng, Hao

    2013-01-01

    Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu(2+) transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All Pmechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.

  18. An unusual presentation of Gaucher's disease: aortic valve fibrosis in a patient homozygous for a rare G377S mutation.

    Science.gov (United States)

    Perić, Zinaida; Kardum-Skelin, Ika; Puskarić, Biljana Jelić; Letilović, Tomislav; Vrhovac, Radovan; Jaksić, Branimir

    2010-03-01

    Gaucher's disease (GD) has variable presentations, but cardiac involvement is a generally uncommon clinical manifestation of the disease. In the past 25 years, the underlying genetic disorder in GD has been well characterized, with almost 300 mutations identified in the glucocerebrosidase gene (GBA). Nevertheless, clear genotype-phenotype correlations have been confirmed only for the most frequent mutations. We present a female patient, who was known to have aortic valve pathology from the age of 30. Despite medical follow up, at the age of 60 she presented with heart failure (NYHA III). At that time echocardiography showed severe fibrosed aortic valve stenosis. Valvuloplasty was planned, when thrombocytopenia, previously considered to be autoimmune, became severe. Anemia and leukopenia were also noted. Moderate splenomegaly and severe bone marrow infiltration were found on MRI. Bone marrow aspiration revealed typical Gaucher cells and the enzyme activity assay confirmed the diagnosis. DNA investigation showed that the patient is homozygous for the G377S mutation. To our knowledge, of all mutations identified so far, only homozygosity for the D409H mutation has been associated with cardiovascular valvular disease in patients with a rare type 3c GD. G377S, found in our patient, is a rare mutation, previously reported as a 'mild' mutation, because of the finding that homoallelic patients were essentialy asymptomatic or had mild disease. Our patient, also homozygous for G377S mutation, had a severe form of type 1 GD, with rare cardiac valve involvement, which is a previously unreported clinical presentation for this mutation. This case further proves that patients with the same genotypes can have different phenotypes, emphasizing the influence of other genetic and/or environmental factors.

  19. Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a Colombian family.

    Science.gov (United States)

    Martin, Angela M; Maradei, Silvia J; Velasco, Harvy M

    2015-12-30

    Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated. We describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family. We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A. The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.

  20. Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease

    Directory of Open Access Journals (Sweden)

    Yunhui Peng

    2015-11-01

    Full Text Available Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G and three not-yet-classified missense mutations (R108W, N142S, and R179H. We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain, indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless.

  1. Chromatin deregulation in disease.

    Science.gov (United States)

    Mirabella, Anne C; Foster, Benjamin M; Bartke, Till

    2016-03-01

    The regulation of chromatin by epigenetic mechanisms plays a central role in gene expression and is essential for development and maintenance of cell identity and function. Aberrant chromatin regulation is observed in many diseases where it leads to defects in epigenetic gene regulation resulting in pathological gene expression programmes. These defects are caused by inherited or acquired mutations in genes encoding enzymes that deposit or remove DNA and histone modifications and that shape chromatin architecture. Chromatin deregulation often results in neurodevelopmental disorders and intellectual disabilities, frequently linked to physical and developmental abnormalities, but can also cause neurodegenerative diseases, immunodeficiency, or muscle wasting syndromes. Epigenetic diseases can either be of monogenic origin or manifest themselves as complex multifactorial diseases such as in congenital heart disease, autism spectrum disorders, or cancer in which mutations in chromatin regulators are contributing factors. The environment directly influences the epigenome and can induce changes that cause or predispose to diseases through risk factors such as stress, malnutrition or exposure to harmful chemicals. The plasticity of chromatin regulation makes targeting the enzymatic machinery an attractive strategy for therapeutic intervention and an increasing number of small molecule inhibitors against a variety of epigenetic regulators are in clinical use or under development. In this review, we will give an overview of the molecular lesions that underlie epigenetic diseases, and we will discuss the impact of the environment and prospects for epigenetic therapies.

  2. [Clinical features and acid alpha-glucosidase gene mutation in 7 Chinese patients with glycogen storage disease type II].

    Science.gov (United States)

    Liu, Qi; Zhao, Juan; Wang, Zhao-xia; Zhang, Wei; Yuan, Yun

    2013-07-02

    To explore the clinical features and acid alpha-glucosidase (GAA) gene mutations of Chinese patients with glycogen storage disease typeII(GSDII). Seven patients with GSDII were diagnosed by muscle pathology examination at Department of Neurology, Peking University First Hospital from 2003 to 2011. One patient with infant-onset presented development retardation, generalized muscle weakness, dyspnea, cardiomegaly and hepatomegaly. Six cases were of late-onset ranging from 1 to 29 years. Their main clinical features included progressive muscle weakness. Two patients developed respiratory insufficiency. Increased serum creatine kinase was detected in all of them. Electromyography studies showed myopathic (n = 5) and neuropathic (n = 1) changes. Muscle biopsies showed basophilic vacuoles in muscle fibers containing a large amounts of glycogen on electron microscopy. GAA gene mutation was detected by direct sequencing of polymerase chain reaction (PCR) product. Novel mutations were screened in 100 normal controls. GAA gene mutations were found in all of them, including 10 point mutations and 1 frameshift deletion. Six mutations (p. P361L, p. P266S, p.R437C, p.R600C, p.W746S and p.W746*) have been reported before. And five novel mutations (p.R168Q, p.R168P, p.E521V, p.R594H and c.827_845del) were found in this study. None of these novel mutations were found in 100 normal controls except for p.R168Q mutation in two normal controls. p. P361L and p.W746* were detected in two unrelated GSDII patients while other mutations were carried by only one patient. In our study, we found several novel GAA mutations in Chinese patients with GSDII. No hot spot mutation of GAA gene existed in our patient group. However, p. P266S, p. P361L and p.R437C might be associated with late-onset GSDII.

  3. Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.

    Science.gov (United States)

    Grünewald, Anne; Breedveld, Guido J; Lohmann-Hedrich, Katja; Rohé, Christan F; König, Inke R; Hagenah, Johann; Vanacore, Nicola; Meco, Giuseppe; Antonini, Angelo; Goldwurm, Stefano; Lesage, Suzanne; Dürr, Alexandra; Binkofski, Ferdinand; Siebner, Hartwig; Münchau, Alexander; Brice, Alexis; Oostra, Ben A; Klein, Christine; Bonifati, Vincenzo

    2007-04-01

    PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.

  4. AB096. Pharmaco-genetic guided personalized medicine: discovery of a maturity onset diabetes of the young (MODY2) novel mutation [S441W in glucose kinase (GCK) gene] by next generation sequencing (NGS)

    Science.gov (United States)

    Clara, Tan Si Hua; Fen, Ang Su; Jessie, Fong Choi Wan; Ester, Yeoh Chai Kheng; Subramaniam, Tavintharan; Fang, Sum Chee; Chi, Lim Su

    2015-01-01

    Background and objective Monogenic diabetes or maturity onset diabetes of the young (MODY) is characterized by young-onset (G, p.Ser441Trp) in the GCK gene, which was confirmed by bi-directional Sanger’s sequencing. The mutation is predicted to be functionally deleterious using multiple bioinformatics tools (e.g., SIFT and PolyPhen-2). In accordance with clinical practice guideline, insulin replacement was successfully discontinued with no deterioration of glycemic control. Conclusions The successful treatment-conversion based on genotype exemplifies how pharmaco-genetics can improve disease-stratify to inform diagnosis and treatment. This can translate into improved clinical outcome and quality of life.

  5. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  6. Subretinal Fibrosis in Stargardt’s Disease with Fundus Flavimaculatus and ABCA4 Gene Mutation

    Directory of Open Access Journals (Sweden)

    Settimio Rossi

    2012-12-01

    Full Text Available Purpose: To report on 4 patients affected by Stargardt’s disease (STGD with fundus flavimaculatus (FFM and ABCA4 gene mutation associated with subretinal fibrosis. Methods: Four patients with a diagnosis of STGD were clinically examined. All 4 cases underwent a full ophthalmologic evaluation, including best-corrected visual acuity measured by the Snellen visual chart, biomicroscopic examination, fundus examination, fundus photography, electroretinogram, microperimetry, optical coherence tomography and fundus autofluorescence. All patients were subsequently screened for ABCA4 gene mutations, identified by microarray genotyping and confirmed by conventional DNA sequencing of the relevant exons. Results: In all 4 patients, ophthalmologic exam showed areas of subretinal fibrosis in different retinal sectors. In only 1 case, these lesions were correlated to an ocular trauma as confirmed by biomicroscopic examination of the anterior segment that showed a nuclear cataract dislocated to the superior site and vitreous opacities along the lens capsule. The other patients reported a lifestyle characterized by competitive sport activities. The performed instrumental diagnostic investigations confirmed the diagnosis of STGD with FFM in all patients. Moreover, in all 4 affected individuals, mutations in the ABCA4 gene were found. Conclusions: Patients with the diagnosis of STGD associated with FFM can show atypical fundus findings. We report on 4 patients affected by STGD with ABCA4 gene mutation associated with subretinal fibrosis. Our findings suggest that this phenomenon can be accelerated by ocular trauma and also by ocular microtrauma caused by sport activities, highlighting that lifestyle can play a role in the onset of these lesions.

  7. Mosaicism: The embryo as a target for induction of mutations leading to cancer and genetic disease

    Energy Technology Data Exchange (ETDEWEB)

    Mohrenweiser, H.; Zingg, B. [Lawrence Livermore National Lab., CA (United States)

    1995-12-31

    Mosaicismhas been observed in both germinal and somatic tissues of several species, including humans. Mutational events occurring during early embryogenesis can give rise to an organism with a significant number of cells with the mutant genotype in one or more tissues. In the F{sub 1} generation, this event will usually be perceived as a de novo germinal mutation rather than a transmitted variant allele, unless significant effort is directed toward detecting the mosaicism. Similarly, mutations in oncogenes and tumor-suppressor genes in proliferating somatic cells can generate populations of cells that are at increased risk of transforming into tumor cells. The number of potential preneoplastic cells is larger when the mutagenic event occurs in early development than if it occurs in the mature adult. Experimental data confirm that treatment of the developing embryo or fetus with carcinogenic and mutagenic agents increases the cancer incidence in these animals and the frequency of mutations in the offspring of the animals that were exposed in utero. The available data are conclusive that the developing organism is at risk from exposure to mutagenic and carcinogenic agents. However, the data are insufficient to estimate the level of risk associated with similar exposures to the adult organism. The potential risk from exposure of the developing embryo is increased relative to the risk from adult exposure if the sensitivity of the individual cells to damage in the adult and the embryo are equivalent. It seems apparent that the potential risks of cancer and heritable disease following in utero exposure are sufficient to warrant additional attention. It is important to obtain data for estimating the relative contribution of in utero exposure to mutagenic and carcinogenic agents to the total health burden and for the subsequent development of appropriate regulations. 60 refs., 2 figs.

  8. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases.

    Directory of Open Access Journals (Sweden)

    Gavin Hudson

    2014-05-01

    Full Text Available Mitochondrial DNA (mtDNA is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.

  9. Fabry Disease: A Turkish Case with a Novel Mutation and Dermatological Manifestations

    Directory of Open Access Journals (Sweden)

    Neslihan Onenli Mungan

    2015-03-01

    Full Text Available Fabry disease is a rare, X-linked disease, caused by the deficiency of lysosomal and #945;-galactosidase. Clinical fetaures are; acroparesthesia, unexplained fever, hypohidrosis and angiokeratomas. Untreated cases die early from cardiac complications, renal insuffiency or stroke. Currently there is no cure for Fabry disease, enzyme replacement therapy is the only choice in this progressive disease. A 9-year-old boy admitted to the Dermatology Clinic with reddish papular skin lesions, joint pain and anhydrosis. Hystological examination of the skin biopsy revealed angiokeratoma. There was no renal dysfunction or proteinuria. Biochemical confirmation of Fabry disease was made by determining the deficient leukocyte and #945;-galactosidase activity. Subsequently, the patient's molecular analysis was identified a novel nonsense mutation c. 785G>T in the GLA gene. Enzyme replacement therapy with agalsidase beta was started. He is on enzyme replacement therapy for 8 years, significant improvement was obtained in severity and frequency of pain crisis and fatigue. We report this case to emphasize the importance of early diagnosis of Fabry disease restricted to dermatological findings, especially before renal and cardiac involvement occurs, while enzyme replacement therapy is now available. Also this patient is one of the first Fabry patients under enzyme replacement therapy in Turkey. [Cukurova Med J 2015; 40(Suppl 1: 156-160

  10. Glucokinase (GCK mutations and their characterization in MODY2 children of southern Italy.

    Directory of Open Access Journals (Sweden)

    Marina Capuano

    Full Text Available Type 2 Maturity Onset Diabetes of the Young (MODY2 is a monogenic autosomal disease characterized by a primary defect in insulin secretion and hyperglycemia. It results from GCK gene mutations that impair enzyme activity. Between 2006 and 2010, we investigated GCK mutations in 66 diabetic children from southern Italy with suspected MODY2. Denaturing High Performance Liquid Chromatography (DHPLC and sequence analysis revealed 19 GCK mutations in 28 children, six of which were novel: p.Glu40Asp, p.Val154Leu, p.Arg447Glyfs, p.Lys458_Cys461del, p.Glu395_Arg397del and c.580-2A>T. We evaluated the effect of these 19 mutations using bioinformatic tools such as Polymorphism Phenotyping (Polyphen, Sorting Intolerant From Tolerant (SIFT and in silico modelling. We also conducted a functional study to evaluate the pathogenic significance of seven mutations that are among the most severe mutations found in our population, and have never been characterized: p.Glu70Asp, p.His137Asp, p.Phe150Tyr, p.Val154Leu, p.Gly162Asp, p.Arg303Trp and p.Arg392Ser. These seven mutations, by altering one or more kinetic parameters, reduced enzyme catalytic activity by >40%. All mutations except p.Glu70Asp displayed thermal-instability, indeed >50% of enzyme activity was lost at 50°C/30 min. Thus, these seven mutations play a pathogenic role in MODY2 insurgence. In conclusion, this report revealed six novel GCK mutations and sheds some light on the structure-function relationship of human GCK mutations and MODY2.

  11. Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

    Science.gov (United States)

    Kroos, Marian; Pomponio, Robert J; van Vliet, Laura; Palmer, Rachel E; Phipps, Michael; Van der Helm, Robert; Halley, Dicky; Reuser, Arnold

    2008-06-01

    Pompe disease was named after the Dutch pathologist Dr JC Pompe who reported about a deceased infant with idiopathic hypertrophy of the heart. The clinical findings were failure to thrive, generalized muscle weakness and cardio-respiratory failure. The key pathologic finding was massive storage of glycogen in heart, skeletal muscle and many other tissues. The disease was classified as glycogen storage disease type II and decades later shown to be a lysosomal disorder caused by acid alpha-glucosidase deficiency. The clinical spectrum of Pompe disease appeared much broader than originally recognized. Adults with the same enzyme deficiency, alternatively named acid maltase deficiency, were reported to have slowly progressive skeletal muscle weakness and respiratory problems, but no cardiac involvement. The clinical heterogeneity is largely explained by the kind and severity of mutations in the acid alpha-glucosidase gene (GAA), but secondary factors, as yet unknown, have a substantial impact. The Pompe disease mutation database aims to list all GAA sequence variations and describe their effect. This update with 107 sequence variations (95 being novel) brings the number of published variations to 289, the number of non-pathogenic mutations to 67 and the number of proven pathogenic mutations to 197. Further, this article introduces a tool to rate the various mutations by severity, which will improve understanding of the genotype-phenotype correlation and facilitate the diagnosis and prognosis in Pompe disease.

  12. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  13. ERP generator anomalies in presymptomatic carriers of the Alzheimer's disease E280A PS-1 mutation.

    Science.gov (United States)

    Bobes, María A; García, Yuriem Fernández; Lopera, Francisco; Quiroz, Yakeel T; Galán, Lídice; Vega, Mayrim; Trujillo, Nelson; Valdes-Sosa, Mitchell; Valdes-Sosa, Pedro

    2010-02-01

    Although subtle anatomical anomalies long precede the onset of clinical symptoms in Alzheimer's disease, their impact on the reorganization of brain networks underlying cognitive functions has not been fully explored. A unique window into this reorganization is provided by presymptomatic cases of familial Alzheimer's disease (FAD). Here we studied neural circuitry related to semantic processing in presymptomatic FAD cases by estimating the intracranial sources of the N400 event-related potential (ERP). ERPs were obtained during a semantic-matching task from 24 presymptomatic carriers and 25 symptomatic carriers of the E280A presenilin-1 (PS-1) mutation, as well as 27 noncarriers (from the same families). As expected, the symptomatic-carrier group performed worse in the matching task and had lower N400 amplitudes than both asymptomatic groups, which did not differ from each other on these variables. However, N400 topography differed in mutation carrier groups with respect to the noncarriers. Intracranial source analysis evinced that the presymptomatic-carriers presented a decrease of N400 generator strength in right inferior-temporal and medial cingulate areas and increased generator strength in the left hippocampus and parahippocampus compared to the controls. This represents alterations in neural function without translation into behavioral impairments. Compared to controls, the symptomatic-carriers presented a similar anatomical shift in the distribution of N400 generators to that found in presymptomatic-carriers, albeit with a larger reduction in generator strength. The redistribution of N400 generators in presymptomatic-carriers indicates that early focal degeneration associated with the mutation induces neural reorganization, possibly contributing to a functional compensation that enables normal performance in the semantic task.

  14. Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation.

    Science.gov (United States)

    Van Gorp, Hanne; Saavedra, Pedro H V; de Vasconcelos, Nathalia M; Van Opdenbosch, Nina; Vande Walle, Lieselotte; Matusiak, Magdalena; Prencipe, Giusi; Insalaco, Antonella; Van Hauwermeiren, Filip; Demon, Dieter; Bogaert, Delfien J; Dullaers, Melissa; De Baere, Elfride; Hochepied, Tino; Dehoorne, Joke; Vermaelen, Karim Y; Haerynck, Filomeen; De Benedetti, Fabrizio; Lamkanfi, Mohamed

    2016-12-13

    Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

  15. AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant

    Science.gov (United States)

    Morton, Sarah U.; Prabhu, Sanjay P.; Lidov, Hart G.W.; Shi, Jiahai; Anselm, Irina; Brownstein, Catherine A.; Bainbridge, Matthew N.; Beggs, Alan H.; Vargas, Sara O.; Agrawal, Pankaj B.

    2017-01-01

    Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function. PMID:28299359

  16. Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model

    DEFF Research Database (Denmark)

    Gao, R.; Liu, Y. X.; Gjesing, A. P.;

    2014-01-01

    diabetes as a study-model. Results: The performance of the assay was evaluated in 70 patients carrying known disease causing mutations previously identified in HNF4A, GCK, HNF1A, HNF1B, INS, or KCNJ11. Target regions with a less than 20-fold sequencing depth were either introns or UTRs. When only...

  17. COMPUTER ASSISTED RETINAL VESSEL TORTUOSITY EVALUATION IN NOVEL MUTATION FABRY DISEASE: Towards New Prognostic Markers.

    Science.gov (United States)

    San Román, Irene; Rodríguez, María-Elena; Caporossi, Orsola; Zoppetti, Claudia; Sodi, Andrea; Mecocci, Alessandro; López, David; Rodríguez, Beatriz; Gimeno, Juan-Ramón

    2017-03-01

    Fabry disease is a rare lysosomal storage disorder with systemic involvement. The authors report on a large Fabry family with GLA p.M187R mutation and exhaustive ophthalmologic assessment. Comprehensive systemic evaluation and genetic diagnosis were performed. Ophthalmologic evaluation included intraocular pressure/visual acuity measurement, refractometry, slit lamp examination, retinography, and optical coherence tomography. Three parameters quantified retinal vessel tortuosity: sum of angle metrics, product of angle distance, and triangular index. Calculations were semiautomatized using dedicated software. Ten individuals (2 males and 8 females) were described. Seventy-five percent had retinal vessel tortuosity. One hundred percent had cornea verticillata. Perimacular vessels were predominantly involved. The correlation between the right and left eye tortuosity measurements was very tight. A significant correlation between retinal vessel tortuosity and systemic severity measured by general Mainz Severity Score Index (MSSI), renal MSSI, and neurological MSSI but no cardiac MSSI was observed. Right sum of angle metrics value was an independent statistical predictor of the general-MSSI score in presence of age. p.M187R mutation causes a severe systemic and ophthalmologic phenotype, in both male and female patients. Semiautomatic assessment of retinal vessel tortuosity is an objective and reproducible tool. All three parameters of tortuosity are closely associated with Fabry severity scores. Studies of larger series are being awaited to establish the role of retinal vessel tortuosity as a noninvasive marker of disease progression.

  18. Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene

    Science.gov (United States)

    Rodriguez, Rene; Lopera, Francisco; Alvarez, Alfredo; Fernandez, Yuriem; Galan, Lidice; Quiroz, Yakeel; Bobes, Maria Antonieta

    2014-01-01

    To evaluate the hypothesis that quantitative EEG (qEEG) analysis is susceptible to detect early functional changes in familial Alzheimer's disease (AD) preclinical stages. Three groups of subjects were selected from five extended families with hereditary AD: a Probable AD group (18 subjects), an asymptomatic carrier (ACr) group (21 subjects), with the mutation but without any clinical symptoms of dementia, and a normal group of 18 healthy subjects. In order to reveal significant differences in the spectral parameter, the Mahalanobis distance (D2) was calculated between groups. To evaluate the diagnostic efficiency of this statistic D2, the ROC models were used. The ROC curve was summarized by accuracy index and standard deviation. The D2 using the parameters of the energy in the fast frequency bands shows accurate discrimination between normal and ACr groups (area ROC = 0.89) and between AD probable and ACr groups (area ROC = 0.91). This is more significant in temporal regions. Theses parameters could be affected before the onset of the disease, even when cognitive disturbance is not clinically evident. Spectral EEG parameter could be firstly used to evaluate subjects with E280A Presenilin-1 mutation without impairment in cognitive function. PMID:24551475

  19. Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene.

    Science.gov (United States)

    Rodriguez, Rene; Lopera, Francisco; Alvarez, Alfredo; Fernandez, Yuriem; Galan, Lidice; Quiroz, Yakeel; Bobes, Maria Antonieta

    2014-01-01

    To evaluate the hypothesis that quantitative EEG (qEEG) analysis is susceptible to detect early functional changes in familial Alzheimer's disease (AD) preclinical stages. Three groups of subjects were selected from five extended families with hereditary AD: a Probable AD group (18 subjects), an asymptomatic carrier (ACr) group (21 subjects), with the mutation but without any clinical symptoms of dementia, and a normal group of 18 healthy subjects. In order to reveal significant differences in the spectral parameter, the Mahalanobis distance (D (2)) was calculated between groups. To evaluate the diagnostic efficiency of this statistic D (2), the ROC models were used. The ROC curve was summarized by accuracy index and standard deviation. The D (2) using the parameters of the energy in the fast frequency bands shows accurate discrimination between normal and ACr groups (area ROC = 0.89) and between AD probable and ACr groups (area ROC = 0.91). This is more significant in temporal regions. Theses parameters could be affected before the onset of the disease, even when cognitive disturbance is not clinically evident. Spectral EEG parameter could be firstly used to evaluate subjects with E280A Presenilin-1 mutation without impairment in cognitive function.

  20. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease.

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Ragazzon, Bruno; Renouf, Sylvie; Wils, Julien; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A; Bertherat, Jérôme; Lefebvre, Hervé

    2016-09-22

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.

  1. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

    Science.gov (United States)

    Tiranti, V; Hoertnagel, K; Carrozzo, R; Galimberti, C; Munaro, M; Granatiero, M; Zelante, L; Gasparini, P; Marzella, R; Rocchi, M; Bayona-Bafaluy, M P; Enriquez, J A; Uziel, G; Bertini, E; Dionisi-Vici, C; Franco, B; Meitinger, T; Zeviani, M

    1998-12-01

    Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.

  2. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

    Science.gov (United States)

    Bram, Zakariae; Louiset, Estelle; Renouf, Sylvie; Duparc, Céline; Boutelet, Isabelle; Rizk-Rabin, Marthe; Libé, Rossella; Young, Jacques; Carson, Dennis; Vantyghem, Marie-Christine; Szarek, Eva; Martinez, Antoine; Stratakis, Constantine A.; Bertherat, Jérôme

    2016-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD. PMID:27699247

  3. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.

    Science.gov (United States)

    Tchasovnikarova, Iva A; Timms, Richard T; Douse, Christopher H; Roberts, Rhys C; Dougan, Gordon; Kingston, Robert E; Modis, Yorgo; Lehner, Paul J

    2017-07-01

    Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.

  4. The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease.

    Science.gov (United States)

    Blot, S; Poirier, C; Dreyfus, P A

    1995-11-01

    Muscle deficient (mdf) is an autosomal-recessive mutation mapped to mouse chromosome 19. The clinical phenotype and the muscle histopathology, briefly described in 1980, and the nervous system histopathology are detailed in the present study. Homozygotes develop a posterior waddle at 4 to 8 weeks of age. Soon thereafter, the hindlimbs become paralyzed and weakness appears in forelimbs, leading to a serious disability. The disease progresses slowly and the mean lifespan is reduced to 8 months. Skeletal muscles exhibit a neurogenic atrophy with signs of reinnervation. Peripheral nerves display axonal degeneration. Neurons within the spinal cord ventral horn, and some motor nuclei of the brain stem, are affected by a cytoplasmic vacuolar degeneration. Ascending and descending spinal cord tracts appear normal. An astrogliosis, restricted to the ventral horn of the spinal cord, occurs in mdf/mdf mice of 10 weeks of age. These clinical and histological features are indicative of a progressive motor neuronopathy. Among the murine spinal muscular atrophies, the programmed cell death of the mdf motoneurons is morphologically similar to wobbler. Because of the long time course, the mdf mutation may represent a valuable tool for understanding juvenile motoneuron diseases with chronic evolution, even though the murine locus is not syntenic with the human ones.

  5. Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease.

    Science.gov (United States)

    Kimura, Fuyo; Ueda, Ai; Sato, Eiichi; Akimoto, Jiro; Kaise, Hiroshi; Yamada, Kimito; Hosonaga, Mari; Kawai, Yuko; Teraoka, Saeko; Okazaki, Miki; Ishikawa, Takashi

    2017-12-01

    Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

  6. Assessing the pathogenic potential of human Nephronophthisis disease-associated NPHP-4 missense mutations in C. elegans.

    Science.gov (United States)

    Masyukova, Svetlana V; Winkelbauer, Marlene E; Williams, Corey L; Pieczynski, Jay N; Yoder, Bradley K

    2011-08-01

    A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormalities, cystic kidneys and CNS malformation. Mutations in multiple genes have been identified in NPHP and MKS patients, and an unexpected finding has been that mutations within the same gene can cause either disorder. Further, there is minimal genotype-phenotype correlation and despite recessive inheritance, numerous patients were identified as having a single heterozygous mutation. This has made it difficult to determine the significance of these mutations on disease pathogenesis and led to the hypothesis that clinical presentation in an individual will be determined by genetic interactions between mutations in multiple cilia-related genes. Here we utilize Caenorhabditis elegans and cilia-associated behavioral and morphologic assays to evaluate the pathogenic potential of eight previously reported human NPHP4 missense mutations. We assess the impact of these mutations on C. elegans NPHP-4 function, localization and evaluate potential interactions with mutations in MKS complex genes, mksr-2 and mksr-1. Six out of eight nphp-4 mutations analyzed alter ciliary function, and three of these modify the severity of the phenotypes caused by disruption of mksr-2 and mksr-1. Collectively, our studies demonstrate the utility of C. elegans as a tool to assess the pathogenicity of mutations in ciliopathy genes and provide insights into the complex genetic interactions contributing to the diversity of phenotypes associated with cilia disorders.

  7. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

    NARCIS (Netherlands)

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen, Annet; Sibley, Cailin; Batu, Ezgi D; Gül, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

    2015-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflamma

  8. Mosaicism in segmental darier disease: an in-depth molecular analysis quantifying proportions of mutated alleles in various tissues

    DEFF Research Database (Denmark)

    Harboe, Theresa Larriba; Willems, Patrick; Jespersgaard, Cathrine;

    2011-01-01

    Darier disease is an autosomal dominant genodermatosis caused by germline mutations in the ATP2A2 gene. Clinical expression is variable, including rare segmental phenotypes thought to be caused by postzygotic mosaicism. Genetic counseling of segmental Darier patients is complex, as risk...... of transmitting a nonsegmental phenotype to offspring is of unknown magnitude. We present the first in-depth molecular analysis of a mosaic patient with segmental disease, quantifying proportions of mutated and normal alleles in various tissues. Pyrosequence analysis of DNA from semen, affected and normal skin......, peripheral leukocytes and hair revealed an uneven distribution of the mutated allele, from 14% in semen to 37% in affected skin. We suggest a model for segmental manifestation expression where a threshold number of mutated cells is needed for manifestation development. We further recommend molecular analysis...

  9. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  10. Computational study of missense mutations in phenylalanine hydroxylase.

    Science.gov (United States)

    Réblová, Kamila; Kulhánek, Petr; Fajkusová, Lenka

    2015-04-01

    Hyperphenylalaninemia (HPA) is one of the most common metabolic disorders. HPA, which is transmitted by an autosomal recessive mode of inheritance, is caused by mutations of the phenylalanine hydroxylase gene. Most mutations are missense and lead to reduced protein stability and/or impaired catalytic function. The impact of such mutations varies, ranging from classical phenylketonuria (PKU), mild PKU, to non-PKU HPA phenotypes. Despite the fact that HPA is a monogenic disease, clinical data show that one PKU genotype can be associated with more in vivo phenotypes, which indicates the role of other (still unknown) factors. To better understand the phenotype-genotype relationships, we analyzed computationally the impact of missense mutations in homozygotes stored in the BIOPKU database. A total of 34 selected homozygous genotypes was divided into two main groups according to their phenotypes: (A) genotypes leading to non-PKU HPA or combined phenotype non-PKU HPA/mild PKU and (B) genotypes leading to classical PKU, mild PKU or combined phenotype mild PKU/classical PKU. Combining in silico analysis and molecular dynamics simulations (in total 3 μs) we described the structural impact of the mutations, which allowed us to separate 32 out of 34 mutations between groups A and B. Testing the simulation conditions revealed that the outcome of mutant simulations can be modulated by the ionic strength. We also employed programs SNPs3D, Polyphen-2, and SIFT but based on the predictions performed we were not able to discriminate mutations with mild and severe PKU phenotypes.

  11. Rapid detection of the ACMG/ACOG-recommended 23 CFTR disease-causing mutations using ion torrent semiconductor sequencing.

    Science.gov (United States)

    Elliott, Aaron M; Radecki, Joy; Moghis, Bellal; Li, Xiang; Kammesheidt, Anja

    2012-04-01

    Cystic fibrosis (CF) is one of the most frequently diagnosed autosomal-recessive diseases in the Caucasian population. For general-population CF carrier screening, the American College of Medical Genetics (ACMG)/American College of Obstetricians and Gynecologists (ACOG) have recommended a core panel of 23 mutations that will identify 49-98% of carriers, depending on ethnic background. Using a genotyping technology that can rapidly identify disease-causing mutations is important for high-throughput general-population carrier screening, confirming clinical diagnosis, determining treatment options, and prenatal diagnosis. Here, we describe a proof-of-concept study to determine whether the Ion Torrent Personal Genome Machine (PGM) sequencer platform can reliably identify all ACMG/ACOG 23 CF transmembrane conductance regulator (CFTR) mutations. A WT CF specimen along with mutant DNA specimens representing all 23 CFTR mutations were sequenced bidirectionally on the Ion Torrent 314 chip to determine the accuracy of the PGM for CFTR variant detection. We were able to reliably identify all of the targeted mutations except for 2184delA, which lies in a difficult, 7-mer homopolymer tract. Based on our study, we believe PGM sequencing may be a suitable technology for identifying CFTR mutations in the future. However, as a result of the elevated rate of base-calling errors within homopolymer stretches, mutations within such regions currently need to be evaluated carefully using an alternative method.

  12. Disease-causing mutations in exon 11 of the medium-chain acyl-CoA dehydrogenase gene

    DEFF Research Database (Denmark)

    Andresen, B S; Jensen, T G; Bross, P

    1994-01-01

    spot. Here we describe the results from sequence analysis of exon 11 and part of the flanking introns from 36 compound heterozygous patients with MCAD deficiency. We have identified four previously unknown disease-causing mutations (M301T, S311R, R324X, and E359X) and two silent mutations in exon 11......Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of the mitochondrial beta-oxidation in humans. It is a potentially fatal, autosomal recessive inherited defect. Most patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985......), causing a change from lysine to glutamate at position 304 (K304E) in the mature MCAD. Only seven non-G985 mutations, all of which are rare, have been reported. Because the G985 mutation and three of the non-G985 mutations are located in exon 11, it has been suggested that this exon may be a mutational hot...

  13. Sick sinus syndrome, progressive cardiac conduction disease, atrial flutter and ventricular tachycardia caused by a novel SCN5A mutation

    DEFF Research Database (Denmark)

    Holst, Anders G; Liang, Bo; Jespersen, Thomas

    2010-01-01

    Mutations in the cardiac sodium channel encoded by the gene SCN5A can result in a wide array of phenotypes. We report a case of a young male with a novel SCN5A mutation (R121W) afflicted by sick sinus syndrome, progressive cardiac conduction disorder, atrial flutter and ventricular tachycardia. His...... the spectrum of SCN5A loss-of-function associated disease entities should be viewed as one syndrome....

  14. High frequency of beta-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management.

    Science.gov (United States)

    Dômont, J; Salas, S; Lacroix, L; Brouste, V; Saulnier, P; Terrier, P; Ranchère, D; Neuville, A; Leroux, A; Guillou, L; Sciot, R; Collin, F; Dufresne, A; Blay, J-Y; Le Cesne, A; Coindre, J-M; Bonvalot, S; Bénard, J

    2010-03-16

    Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for beta-catenin mutations in a European multicentre series of fibromatosis tumours to relate beta-catenin mutational status to disease outcome. Direct sequencing of exon 3 beta-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients). Mutations of beta-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with beta-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in beta-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02). A high frequency (87%) of beta-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type beta-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.

  15. Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease.

    Science.gov (United States)

    Rose-Zerilli, M J J; Gibson, J; Wang, J; Tapper, W; Davis, Z; Parker, H; Larrayoz, M; McCarthy, H; Walewska, R; Forster, J; Gardiner, A; Steele, A J; Chelala, C; Ennis, S; Collins, A; Oakes, C C; Oscier, D G; Strefford, J C

    2016-06-01

    The biological features of IGHV-M chronic lymphocytic leukemia responsible for disease progression are still poorly understood. We undertook a longitudinal study close to diagnosis, pre-treatment and post relapse in 13 patients presenting with cMBL or Stage A disease and good-risk biomarkers (IGHV-M genes, no del(17p) or del(11q) and low CD38 expression) who nevertheless developed progressive disease, of whom 10 have required therapy. Using cytogenetics, fluorescence in situ hybridisation, genome-wide DNA methylation and copy number analysis together with whole exome, targeted deep- and Sanger sequencing at diagnosis, we identified mutations in established chronic lymphocytic leukemia driver genes in nine patients (69%), non-coding mutations (PAX5 enhancer region) in three patients and genomic complexity in two patients. Branching evolutionary trajectories predominated (n=9/13), revealing intra-tumoural epi- and genetic heterogeneity and sub-clonal competition before therapy. Of the patients subsequently requiring treatment, two had sub-clonal TP53 mutations that would not be detected by standard methodologies, three qualified for the very-low-risk category defined by integrated mutational and cytogenetic analysis and yet had established or putative driver mutations and one patient developed progressive, therapy-refractory disease associated with the emergence of an IGHV-U clone. These data suggest that extended genomic and immunogenetic screening may have clinical utility in patients with apparent good-risk disease.

  16. Concise Review: Heteroplasmic Mitochondrial DNA Mutations and Mitochondrial Diseases: Toward iPSC-Based Disease Modeling, Drug Discovery, and Regenerative Therapeutics.

    Science.gov (United States)

    Hatakeyama, Hideyuki; Goto, Yu-Ichi

    2016-04-01

    Mitochondria contain multiple copies of their own genome (mitochondrial DNA; mtDNA). Once mitochondria are damaged by mutant mtDNA, mitochondrial dysfunction is strongly induced, followed by symptomatic appearance of mitochondrial diseases. Major genetic causes of mitochondrial diseases are defects in mtDNA, and the others are defects of mitochondria-associating genes that are encoded in nuclear DNA (nDNA). Numerous pathogenic mutations responsible for various types of mitochondrial diseases have been identified in mtDNA; however, it remains uncertain why mitochondrial diseases present a wide variety of clinical spectrum even among patients carrying the same mtDNA mutations (e.g., variations in age of onset, in affected tissues and organs, or in disease progression and phenotypic severity). Disease-relevant induced pluripotent stem cells (iPSCs) derived from mitochondrial disease patients have therefore opened new avenues for understanding the definitive genotype-phenotype relationship of affected tissues and organs in various types of mitochondrial diseases triggered by mtDNA mutations. In this concise review, we briefly summarize several recent approaches using patient-derived iPSCs and their derivatives carrying various mtDNA mutations for applications in human mitochondrial disease modeling, drug discovery, and future regenerative therapeutics.

  17. Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

    Directory of Open Access Journals (Sweden)

    Morgadinho Ana S

    2006-07-01

    Full Text Available Abstract Background Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD and Parkinson diseases (PD. Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886, and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. Methods Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. Results A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. Conclusion Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.

  18. Ionizing radiation and genetic risks. VIII. The concept of mutation component and its use in risk estimation for multifactorial diseases.

    Science.gov (United States)

    Denniston, C; Chakraborty, R; Sankaranarayanan, K

    1998-08-31

    Multifactorial diseases, which include the common congenital abnormalities (incidence: 6%) and chronic diseases with onset predominantly in adults (population prevalence: 65%), contribute substantially to human morbidity and mortality. Their transmission patterns do not conform to Mendelian expectations. The model most frequently used to explain their inheritance and to estimate risks to relatives is a Multifactorial Threshold Model (MTM) of disease liability. The MTM assumes that: (i) the disease is due to the joint action of a large number of genetic and environmental factors, each of which contributing a small amount of liability, (ii) the distribution of liability in the population is Gaussian and (iii) individuals whose liability exceeds a certain threshold value are affected by the disease. For most of these diseases, the number of genes involved or the environmental factors are not fully known. In the context of radiation exposures of the population, the question of the extent to which induced mutations will cause an increase in the frequencies of these diseases has remained unanswered. In this paper, we address this problem by using a modified version of MTM which incorporates mutation and selection as two additional parameters. The model assumes a finite number of gene loci and threshold of liability (hence, the designation, Finite-Locus Threshold Model or FLTM). The FLTM permits one to examine the relationship between broad-sense heritability of disease liability and mutation component (MC), the responsiveness of the disease to a change in mutation rate. Through the use of a computer program (in which mutation rate, selection, threshold, recombination rate and environmental variance are input parameters and MC and heritability of liability are output estimates), we studied the MC-heritability relationship for (i) a permanent increase in mutation rate (e.g., when the population sustains radiation exposure in every generation) and (ii) a one-time increase

  19. [A splicing mutation of EXT1 in a Chinese pedigree with hereditary multiple exostoses].

    Science.gov (United States)

    Wang, Wei; Qiu, Zheng-Qing; Song, Hong-Mei

    2014-02-01

    Hereditary multiple exostoses (HME) is an autosomal dominant monogenic disorder of paraplasia ossium. Mutations in EXT1 and EXT2 have been suggested to be responsible for over 70% of HME cases. This study aimed to analyze the clinical features and pathogenic mutations in a Chinese family with HME (6 patients in 24 members of 3 generations) and to review the relative literature regarding mutations in EXT1 and EXT2 in the Chinese population. Clinical pedigree dada from a Chinese family of HME were collected and analysed. EXT gene mutations in this pedigree assessed by PCR and sequencing. Pubmed and Wanfang (a Chinese database) were searched for the literature related to gene mutations in Chinese HME patients. In the pedigree analyzed, the age of onset of HME was becoming younger, the disease was becoming more severe, and the number of osteochondromas was increasing, in successive generations. A splicing mutation IVS5+1G>A, first identified in Chinese population, was found in all diseased members of this pedigree. According the currently available literature, EXT1 and EXT2 mutations have been detected in 29% (26/90) and 43% (39/90) Chinese families with HME. HME starts earlier and becomes more severe and extensive with each successive generation in members of the pedigree analyzed. A splicing mutation, IVS5+1G>A, of EXT1, first identified in Chinese population, may be responsible for HME in the studied pedigree. EXT1 and EXT2 mutation rates may be different between the Chinese and Western populations.

  20. No Association between Loss-of-Function Mutations in filaggrin and Diabetes, Cardiovascular Disease, and All-Cause Mortality

    Science.gov (United States)

    Husemoen, Lise Lotte N.; Skaaby, Tea; Jørgensen, Torben; Thyssen, Jacob P.; Meldgaard, Michael; Szecsi, Pal B.; Stender, Steen; Johansen, Jeanne Duus; Linneberg, Allan

    2013-01-01

    Background Common loss-of-function mutations in the filaggrin gene (FLG) are a major predisposing risk factor for atopic disease due to reduced epidermal filaggrin protein levels. We previously observed an association between these mutations and type 2 diabetes and hypothesized that an inherited impairment of skin barrier functions could facilitate low-grade inflammation and hence increase the risk of diabetes and cardiovascular disease. We examined the association between loss-of-function mutations in FLG and diabetes, stroke, ischemic heart disease (IHD), and all-cause mortality in the general population. Methods The R501X and 2282del4 loss-of function mutations in FLG were genotyped in four Danish study populations including a total of 13373 adults aged 15-77 years. Two of the studies also genotyped the R2447X mutation. By linkage to Danish national central registers we obtained information for all participants on dates of diagnoses of diabetes, stroke, and IHD, as well as all-cause mortality. Data were analyzed by Cox proportional hazard models and combined by fixed effect meta-analyses. Results In meta-analyses combining the results from the four individual studies, carriage of loss-of-function mutations in FLG was not associated with incident diabetes (hazard ratio (HR) (95% confidence intervals (CI)) = 0.95 (0.73, 1.23), stroke (HR (95% CI) = 1.27 (0.97, 1.65), ischemic heart disease (HR (95%CI) = 0.92 (0.71, 1.19), and all-cause mortality (HR (95%CI) = 1.02 (0.83, 1.25)). Similar results were obtained when including prevalent cases in logistic regression models. Conclusion Our results suggest that loss-of-function mutations in FLG are not associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. However, larger studies with longer follow-up are needed to exclude any associations. PMID:24367652

  1. No association between loss-of-function mutations in filaggrin and diabetes, cardiovascular disease, and all-cause mortality.

    Directory of Open Access Journals (Sweden)

    Lise Lotte N Husemoen

    Full Text Available BACKGROUND: Common loss-of-function mutations in the filaggrin gene (FLG are a major predisposing risk factor for atopic disease due to reduced epidermal filaggrin protein levels. We previously observed an association between these mutations and type 2 diabetes and hypothesized that an inherited impairment of skin barrier functions could facilitate low-grade inflammation and hence increase the risk of diabetes and cardiovascular disease. We examined the association between loss-of-function mutations in FLG and diabetes, stroke, ischemic heart disease (IHD, and all-cause mortality in the general population. METHODS: The R501X and 2282del4 loss-of function mutations in FLG were genotyped in four Danish study populations including a total of 13373 adults aged 15-77 years. Two of the studies also genotyped the R2447X mutation. By linkage to Danish national central registers we obtained information for all participants on dates of diagnoses of diabetes, stroke, and IHD, as well as all-cause mortality. Data were analyzed by Cox proportional hazard models and combined by fixed effect meta-analyses. RESULTS: In meta-analyses combining the results from the four individual studies, carriage of loss-of-function mutations in FLG was not associated with incident diabetes (hazard ratio (HR (95% confidence intervals (CI = 0.95 (0.73, 1.23, stroke (HR (95% CI = 1.27 (0.97, 1.65, ischemic heart disease (HR (95%CI = 0.92 (0.71, 1.19, and all-cause mortality (HR (95%CI = 1.02 (0.83, 1.25. Similar results were obtained when including prevalent cases in logistic regression models. CONCLUSION: Our results suggest that loss-of-function mutations in FLG are not associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. However, larger studies with longer follow-up are needed to exclude any associations.

  2. A Novel COL4A5 Mutation Identified in a Chinese Han Family Using Exome Sequencing

    Directory of Open Access Journals (Sweden)

    Xiaofei Xiu

    2014-01-01

    Full Text Available Alport syndrome (AS is a monogenic disease of the basement membrane (BM, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3, the collagen type IV alpha-4 gene (COL4A4, and the collagen type IV alpha-5 gene (COL4A5, which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36 in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD. Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

  3. Implications of genetics on the diagnosis and care of patients with Parkinson disease.

    Science.gov (United States)

    Klein, Christine

    2006-03-01

    The identification of several monogenic forms has established Parkinson disease (PD) as a movement disorder with a considerable genetic origin in at least a subset of patients. Four of the known forms, Parkin-, PINK1 (PTEN-induced putative kinase 1)-, DJ1-, and LRRK2 (leucine-rich repeat kinase 2)-linked PD, may present clinically as "idiopathic PD" and account for at least 1% of all cases of PD. However, all known monogenic forms combined explain about only 20% of early-onset PD and less than 3% of late-onset PD at best. Although the individual clinical course cannot be predicted, overall, many cases of genetic PD will progress more slowly and respond better to treatment than patients without mutations. Genetic testing frequently yields inconclusive results, is expensive, and should be used for diagnostic purposes only after careful consideration in selected cases at specialty centers. While genetic findings have greatly advanced our understanding of the pathophysiology of PD, we are faced with many novel challenges. These include the definition of the phenotypic and genotypic spectrum of the monogenic forms, a revised terminology and classification of parkinsonian syndromes, identification of genetic susceptibility factors, and development of guidelines for genetic testing and of new treatment options for PD.

  4. Minireview: human obesity-lessons from monogenic disorders.

    Science.gov (United States)

    O'Rahilly, Stephen; Farooqi, I Sadaf; Yeo, Giles S H; Challis, Benjamin G

    2003-09-01

    Genetic influences on the determination of human fat mass are profound and powerful, a statement that does not conflict with the obvious influence of environmental factors that drive recent changes in the prevalence of obesity. The assertion of the importance of genetic factors has, until recently, largely been based on twin and adoption studies. However, in the last 6 yr, a number of human genes have been identified in which major missense or nonsense mutations are sufficient in themselves to result in severe early-onset obesity, usually associated with disruption of normal appetite control mechanisms. Progress in the identification of more common, subtler genetic variants that influence fat mass in larger numbers of people has been slower, but discernible. Human genetics will continue to make an invaluable contribution to the study of human obesity by identifying critical molecular components of the human energy balance regulatory systems, pointing the way toward more targeted and effective therapies and assisting the prediction of individual responses to environmental manipulations.

  5. Point mutation in exon 4 of presenilin-1 gene and early-onset familial Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Yu Liao; Fan Zhao

    2006-01-01

    BACKGROUND:A total of 50 missense mutations of presenilin-1 (PS-1) have been found thus far in early-onset familial Alzheimer disease(EOFAD),PS-1 gene might be a causative gene for Chinese EOFAD.OBJECTIVE:To investigate mutation of PS-1 gene in the blood of Chinese patients with familial Alzheimer disease(FAD).DESIGN:A design with randomized control and repeated sequencing.SETTlNG:Department of Neurology,the Second People's Hospital of Wuxi.PARTICIPANTS:The experiment was carried out in Huaihua Hospital Affiliated to Nanhua University in September 1993.Eight FAD patients were graded as FAD group.There were 6 males and 2 females with the mean age of(36±16)years.The control group was composed of 42 persons,including 8 hospitalized SAD patients diagnosed according to the criteria of Practical Neuralgia and conformed to the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders(DCM-Ⅳ-TR),11 dementia patients caused by multipie cerebral infarction,13 normal persons in the FAD family mentioned above family,and 10 normal healthy adults provided by the health examination section of our hospital.METHODS:GeneAmp PCR System 2400 (Applied Biosystems,USA),DNA-Sequencer Model 310(Perkin Elmer,USA),Taq DNA Polymerase(Fermentas,Canada).All reagents used for DNA extraction were prepared with analytical reagents manufactured in China.The samples were stratified carefully,collected the leukocytic cream from the interface,added STMT to each sample and vortexed to suspend evenly.Then the samples were centrifugated.The nuclear pellet was resuspended in digestion solution with proteinase K and incubated under appropriate condit