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  1. Alport syndrome. Molecular genetic aspects

    DEFF Research Database (Denmark)

    Hertz, Jens Michael

    2009-01-01

    a highly efficient and sensitive molecular diagnostic approach for analysing the COL4A5 gene in putative AS cases. Based on the present results and the litterature, an algorithm for molecular genetic analysis of the COL4A5 gene is suggested. The overall mutation detection rate was found to be 53......Alport syndrome (AS) is a progressive renal disease that is characterised by hematuria and progressive renal failure, and often accompanied by progressive high-tone sensorineural hearing loss and ocular changes in form of macular flecks and lenticonus. AS is a genetic heterogenous disease, and X...... practice for carrier detection and prenatal diagnosis, in order to be able to offer a better genetic counselling to the families. Knowledge of a possible correlation between genotype and phenotype can be of help in predicting the prognosis. Samples from 135 probands suspected of AS and 359...

  2. Alport syndrome

    Science.gov (United States)

    ... have equally severe disease. Autosomal dominant Alport syndrome (ADAS) -- This is the rarest type. Males and females ... and girls have hearing loss during childhood. With ADAS, it occurs later in life. Hearing loss usually ...

  3. Alport Syndrome

    Science.gov (United States)

    ... signs and symptoms may differ, based on age, gender and inherited type of Alport syndrome. For example, ... prevention and treatment of kidney disease. The Better Business Bureau Wise Giving Alliance Charity Seal provides the ...

  4. Alport Syndrome Diagnosis

    Science.gov (United States)

    ... Groups Hear From the Experts Follow us on Facebook! Alport Syndrome Foundation of USA 2 days ago ... BIRTHDAY! ... See More See Less Photo View on Facebook · Share View on Facebook The Alport syndrome Foundation ...

  5. Alport's Syndrome in Pregnancy

    Directory of Open Access Journals (Sweden)

    Suchita Mehta

    2013-01-01

    Full Text Available Background. Alport's syndrome is an X-linked hereditary disorder affecting the glomerular basement membrane associated with ocular and hearing defects. In women, the disease is much less severe compared to that in men. However, women with Alport's syndrome can have an accelerated form of their disease during pregnancy with worsening of kidney function and can also develop preeclampsia. There are only four described cases of Alport's syndrome in pregnancy. Case Presentation. 20-year-old woman with a history of Alport's syndrome, which during pregnancy worsened resulting in hypertension, proteinuria, and acute kidney injury. Fortunately, there was complete resolution of the proteinuria and kidney injury with delivery, and the patient did not require any renal replacement therapy. Conclusion. One of the four reported cases had an accelerated form of the disease during pregnancy with rapid progression of kidney injury and end-stage renal disease. There are no definite guidelines to monitor these patients during pregnancy. Further studies are required to understand the exact pathophysiology of kidney damage that occurs in pregnant women with Alport's syndrome. This may give us some insight into the prognostic predictors, so that we can monitor these women more thoroughly and prevent adverse outcomes.

  6. X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Jais, Jean Philippe; Knebelmann, Bertrand; Giatras, Iannis

    2003-01-01

    Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease...... in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X...... to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified...

  7. Alport syndrome in southern Sweden

    DEFF Research Database (Denmark)

    Persson, U; Hertz, Jens Michael; Wieslander, J

    2005-01-01

    The aim of the present investigation is to study the epidemiology of Alport syndrome in southern Sweden, to search for mutations in the COL4A5 gene and to estimate the mutation frequency.......The aim of the present investigation is to study the epidemiology of Alport syndrome in southern Sweden, to search for mutations in the COL4A5 gene and to estimate the mutation frequency....

  8. X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Jais, J P; Knebelmann, B; Giatras, I

    2000-01-01

    Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease....... Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X...

  9. Does Alport syndrome affect the basement membrane of peritoneal vessels?

    NARCIS (Netherlands)

    Sampimon, Denise E.; Vlijm, Anniek; Struijk, Dirk G.; Krediet, Raymond T.

    2010-01-01

    Alport syndrome and encapsulating peritoneal sclerosis (EPS) are both rare diseases. Their joint occurrence is highly unlikely. Two patients at our center with Alport syndrome developed EPS. We therefore hypothesized that Alport syndrome might predispose to the development of EPS and that this

  10. Alport Syndrome in Women and Girls

    Science.gov (United States)

    Colville, Deb; Rheault, Michelle; Gear, Susie; Lennon, Rachel; Lagas, Sharon; Finlay, Moira; Flinter, Frances

    2016-01-01

    Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%–30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport syndrome should be tested at least annually for albuminuria and hypertension. The “Expert guidelines for the diagnosis and management of Alport syndrome” recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic

  11. OBSERVATION OF ALPORT SYNDROME IN OBSTETRIC PRACTICE

    Directory of Open Access Journals (Sweden)

    Ольга Сергеевна Тышкевич

    2016-06-01

    Full Text Available The relevance of Alport syndrome as a manifestation of differentiated forms of connective tissue dysplasia is caused by the difficulty of diagnosis, the severity of clinical manifestations and high risk of complications as the underlying disease, since pregnancy and childbirth. Supervision of the pregnant woman with the differentiated form of a displaziya of connecting tissue – Alport's syndrome is presented in original article. Interference of two states – pregnancy and Alport's syndrome is shown. Conclusion. The practicing doctor of any specialty needs to possess full information on a clinical picture and the principles of diagnostics of the DCT forms, on features of influence on the process of a gestation. As importance underestimation the changes of connecting fabric conducts to untimely verification of the diagnosis, inferiority of in due time effective preventive actions, an incorrect choice of tactics of maintaining patients.

  12. Alport syndrome in a Kazakh family: a case study

    Indian Academy of Sciences (India)

    Alport syndrome is a type-IV collagen inherited disorder caused by mutations in COL4A3 and COL4A4 (autosomal recessive) or COL4A5 (X-linked). In our study, we describe the case of Alport syndrome in a Kazakh family. The 20- year-old male, born in 1993, was diagnosed with chronic nephritic syndrome when he was ...

  13. [Clinical and pathological features of Alport syndrome in children].

    Science.gov (United States)

    Zhu, Chun-Hua; Huang, Song-Ming; Wu, Hong-Mei; Bao, Hua-Ying; Chen, Ying; Han, Yuan; Zhao, Fei; Zhang, Ai-Hua; Zhang, Wei-Zhen

    2010-03-01

    To study the clinical and pathological features of Alport syndrome in children. The clinical and histopathological data of 10 hospitalized children with Alport syndrome from February 2007 to February 2009 were retrospectively reviewed. There were 7 males and 3 females, with the age ranging from 2 years to 6 years and 7 months (mean 3 years and 2 months). Five of 10 cases had positive family history. X-linked dominant inheritance Alport syndrome was diagnosed in 8 cases, and autosomal recessive inheritance Alport syndrome in 2 cases. Recurrent gross hematuria was found in 5 cases, hematuria and proteinuria in 3 cases, massive proteinuria in 1 case, and nephritic syndrome in 1 case. Under the light microscope, 8 cases presented with mesangial proliferation glomerulonephritis, and 2 cases with focal segmental glomerulosclerosis. Immunofluorescence assay showed that all cases had IgM deposition in glomerulus. Only 1 case showed typical glomerular basement membrane (GBM) pathological changes. All cases showed abnormal alpha-chain distribution in renal collagen IV. The children with Alport syndrome have diverse clinical manifestations. Characteristic histopathological presentations could not be found under a light microscope, mesangial proliferation glomerulonephritis is the dominant pathological change, and IgM deposition in glomerulus is common. The GBM pathological change in children is not common. Immunofluorescence assay of alpha-chain in collagen IV is needed for the diagnosis of Alport syndrome.

  14. Association of Alport's syndrome with HLA-DR2 antigen in a group of unrelated patients

    Directory of Open Access Journals (Sweden)

    E.A. Donadi

    1998-04-01

    Full Text Available A few family studies have evaluated HLA antigens in Alport's syndrome; however, there are no large population studies. In the present report, we studied 40 unrelated white patients with Alport's syndrome seen at the Unit of Renal Transplantation, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil. HLA-A, -B, -DR and -DQ antigens were typed using a complement-dependent microlymphocytotoxicity assay. A control white population (N = 403 from the same geographical area was also typed for HLA antigens. Although the frequencies of HLA-A and -B antigens of patients were not statistically different from controls, the frequency of HLA-DR2 antigen observed in patients (65% was significantly increased in relation to controls (26%; P<0.001. The relative risk and etiologic fraction for HLA-DR2 antigen were 5.2 and 0.525, respectively. Although few immunological abnormalities have been shown in Alport's syndrome, in this report we emphasize the association of HLA molecules and Alport's syndrome. Besides the well-known inherited molecular defects encoded by type IV collagen genes in Alport's syndrome, the major histocompatibility alleles may be in linkage disequilibrium with these defective collagen genes

  15. Alport syndrome in a Kazakh family: a case study

    Indian Academy of Sciences (India)

    2National Research Center for Maternal and Child Health, 32 Turan Prospect, Astana 010000, Kazakhstan ... In our study, we describe the case of Alport syndrome in a Kazakh family. The 20-year-old male, born in 1993, was diagnosed with chronic nephritic syndrome, when he was 16 years old. ... Journal of Genetics, Vol.

  16. X-Linked and Autosomal Recessive Alport Syndrome

    DEFF Research Database (Denmark)

    Savige, Judith; Storey, Helen; Il Cheong, Hae

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published...... COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss...

  17. Type VII collagen in Alport syndrome.

    Science.gov (United States)

    Giannakakis, Konstantinos; Massella, Laura; Grassetti, Daniele; Dotta, Francesco; Perez, Marie; Muda, Andrea Onetti

    2007-12-01

    Absence or segmental distribution of the alpha5(IV) collagen chain along the epidermal basement membrane (EBM) is diagnostic of X-linked Alport syndrome (X-AS), but the typical morphologic alterations usually observed along the glomerular basement membrane (GBM) are lacking. However, several differences in protein composition exist between GBM and EBM, and such differences could account for a different phenotype with the same genetic defect. Type VII collagen is one of the major collagenous components of the EBM; the purpose of this study was to investigate the modifications of protein synthesis and expression of type VII collagen in the skin of patients with X-AS. The distribution of type VII collagen has been studied in 15 skin biopsies (10 from X-AS patients and 5 controls) by means of electron microscopy, immunofluorescence and confocal microscopy; type VII collagen mRNA expression was also measured by RT-PCR on the same skin fragments. Protein and mRNA amounts for type VII collagen were significantly higher in skin samples from X-AS patients than in controls (P < 0.001); highest values were in cases in which alpha5(IV) was completely absent. Our results indicate that lack of alpha5(IV) molecule significantly alters the assembly of extracellular matrix molecules other than alphax(IV) chains also at the EBM level. We suggest that the increased synthesis and deposition of type VII collagen is likely to balance the absence of stabilizing activity normally exerted by alpha5(IV).

  18. Diffuse esophageal leiomyomatosis in a child with alport syndrome: case report

    International Nuclear Information System (INIS)

    Ko, Hong Seok; Goo, Hyun Woo; Yoon, Chong Hyun

    2004-01-01

    Diffuse esophageal leiomyomatosis is an exceedingly rare, benign, neoplastic condition occurring predominantly in children and young adults. This condition may occur as an isolated finding, or it may be associated with Alport syndrome. We report a case of diffuse esophageal leiomyomatosis with Alport syndrome in a 5-year-old girl who had presented with recurrent pneumonia, and present a review of the literature. We suspected Alport syndrome in the patient because she had a clinical history of congenital cataracts and hematuria, as well as imaging findings of diffuse esophageal leiomyomatosis. Alport syndrome was subsequently confirmed by electron microscopy of the kidney

  19. Two Pregnancies with a Different Outcome in a Patient with Alport Syndrome

    Directory of Open Access Journals (Sweden)

    Biljana Gerasimovska Kitanovska

    2016-07-01

    CONCLUSIONS: Pre-pregnancy counselling and frequent controls during pregnancy are necessary for women with Alport syndrome, as well as regular monitoring after delivery. Recent reports are more in favour of good pregnancy and nephrological outcomes in women with Alport syndrome when renal disease is not advanced.

  20. Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome.

    Science.gov (United States)

    Gross, Oliver; Kashtan, Clifford E; Rheault, Michelle N; Flinter, Frances; Savige, Judith; Miner, Jeffrey H; Torra, Roser; Ars, Elisabet; Deltas, Constantinos; Savva, Isavella; Perin, Laura; Renieri, Alessandra; Ariani, Francesca; Mari, Francesca; Baigent, Colin; Judge, Parminder; Knebelman, Bertrand; Heidet, Laurence; Lagas, Sharon; Blatt, Dave; Ding, Jie; Zhang, Yanqin; Gale, Daniel P; Prunotto, Marco; Xue, Yong; Schachter, Asher D; Morton, Lori C G; Blem, Jacqui; Huang, Michael; Liu, Shiguang; Vallee, Sebastien; Renault, Daniel; Schifter, Julia; Skelding, Jules; Gear, Susie; Friede, Tim; Turner, A Neil; Lennon, Rachel

    2017-06-01

    Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis. © The Author 2016. Published by Oxford University Press on behalf of ERAEDTA.

  1. Alport syndrome. Molecular genetic aspects

    DEFF Research Database (Denmark)

    Hertz, Jens Michael

    2009-01-01

    with a proximal breakpoint in COL4A5 intron 8 at Xq22.3, and a distal breakpoint in the RAB33A gene at Xq26.1. This rearrangement was exclusively ascertained by the Southern blotting analysis. Three deletions of >or= 2 exons were detected by MLPA. One of these was detected in a female proband. A deletion...... in heterozygous form will not be detected by PCR-SSCP or direct sequencing. A method based on the PCR-SSCP technique was set up for screening of the COL4A5 gene exon-by-exon for mutation. All 51 COL4A5 exons with flanking intronic sequences were screened by this technique. The two alternatively transcribed exons...... mutations, frame-shifts, and larger structural rearrangements, were found to cause a juvenile form of the disease with a mean age at ESRD of 21.6 years, compared to 33.1 years in patients with a non-truncating mutation. The effect of non-truncating mutations is, however, less clear-cut. Glycine...

  2. Spontaneous Coronary Artery Dissection: A Rare Manifestation of Alport Syndrome

    Science.gov (United States)

    Sethi, Prince; Steffen, Kelly; Jonsson, Orvar; Petrasko, Marian

    2017-01-01

    Alport syndrome (AS) is a genetic disorder due to inheritance of genetic mutations which lead to production of abnormal type IV collagen. AS has been associated with renal, auditory, and ocular diseases due to the presence of abnormal alpha chains of type IV collagen in the glomerulus, cochlea, cornea, lens, and retina. The resulting disorder includes hereditary nephritis, corneal opacities, anterior lenticonus, fleck retinopathy, temporal retinal thinning, and sensorineural deafness. Aortic and aortic valve pathologies have been described as extrarenal manifestations of AS in multiple case reports. One case report described intramural hematoma of the coronary artery. We report the first case of true spontaneous coronary artery dissection (SCAD) with an intimal flap as a very rare manifestation of AS. The patient is a 36-year-old female with history of AS with chronic kidney disease, hypertension, and obesity who presented to the emergency room with acute onset of substernal chest pain radiating to her neck and arms. Troponin was elevated, and ECG showed transient 1 mm ST-segment elevation in the inferior leads. Subsequent coronary angiography revealed localized dissection of the left circumflex artery. Percutaneous coronary angioplasty was performed and her symptoms improved. This case illustrates that SCAD may be a manifestation of AS patients with chest pain. PMID:28884028

  3. Spontaneous Coronary Artery Dissection: A Rare Manifestation of Alport Syndrome

    Directory of Open Access Journals (Sweden)

    Amornpol Anuwatworn

    2017-01-01

    Full Text Available Alport syndrome (AS is a genetic disorder due to inheritance of genetic mutations which lead to production of abnormal type IV collagen. AS has been associated with renal, auditory, and ocular diseases due to the presence of abnormal alpha chains of type IV collagen in the glomerulus, cochlea, cornea, lens, and retina. The resulting disorder includes hereditary nephritis, corneal opacities, anterior lenticonus, fleck retinopathy, temporal retinal thinning, and sensorineural deafness. Aortic and aortic valve pathologies have been described as extrarenal manifestations of AS in multiple case reports. One case report described intramural hematoma of the coronary artery. We report the first case of true spontaneous coronary artery dissection (SCAD with an intimal flap as a very rare manifestation of AS. The patient is a 36-year-old female with history of AS with chronic kidney disease, hypertension, and obesity who presented to the emergency room with acute onset of substernal chest pain radiating to her neck and arms. Troponin was elevated, and ECG showed transient 1 mm ST-segment elevation in the inferior leads. Subsequent coronary angiography revealed localized dissection of the left circumflex artery. Percutaneous coronary angioplasty was performed and her symptoms improved. This case illustrates that SCAD may be a manifestation of AS patients with chest pain.

  4. Cataract in a patient with the Alport syndrome and diffuse Leiomyomatosis Catarata em paciente com sindrome de alport e leiomiomatose difusa

    Directory of Open Access Journals (Sweden)

    Luis Santiago - Cabán

    2008-12-01

    Full Text Available We describe a case of painless progressive loss of vision in a 15 years old male patient with Alport syndrome and diffuse Leiomyomatosis. After a comprehensive history and ocular examination, a diagnosis of bilateral posterior subcapsular cataracts was given. Patient underwent cataract extraction. His best corrected post-operative visual acuity was 20/25 in both eyes. We conclude that posterior subcapsular cataracts may lead to painless and progressive loss of vision in patients with Alport syndrome and Diffuse Leiomyomatosis.Nós descrevemos o caso de perda visual progressiva indolor em um paciente de 15 anos, sexo masculino, com Síndrome de Alport e Leiomiomatose difusa. Após história completa e exame oftalmológico, foi feito o diagnóstico de catarata subcapsular posterior bilateral. O paciente foi submetido à cirurgia de catarata. Nós concluímos que cataratas subcapsulares posteriores podem levar a perda visual progressiva e indolor em pacientes com Síndrome de Alport e Leiomiomatose Difusa.

  5. Clear lens phacoemulsification in the anterior lenticonus due to Alport Syndrome: two case reports

    OpenAIRE

    Aslanzadeh, Ghassem Amir; Gharabaghi, Davoud; Naderi, Niloofar

    2008-01-01

    Abstract Introduction Alport Syndrome has a prevalence of 1 case per 5,000 people and 85% of patients have the X-linked form, where affected males develop renal failure and usually have high-tone sensorineural deafness by age 20. The main abnormality is deficient synthesis of type IV collagen, the main component of basement membranes. Common ocular abnormalities of this syndrome consist of dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, and anterior lenticonus, but other ...

  6. Generation of induced pluripotent stem cells from renal tubular cells of a patient with Alport syndrome

    Directory of Open Access Journals (Sweden)

    Chen WB

    2015-08-01

    Full Text Available Wenbiao Chen,1,* Jianrong Huang,2,* Xiangqi Yu,1 Xiaocong Lin,1 Yong Dai11The Clinical Medical Research Center, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, 2Department of Hemodialysis, The Third People's Hospital of Shenzhen, Shenzhen, Guangdong, 3Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Zhanjiang, People's Republic of China *These authors contributed equally to this workAbstract: Alport syndrome (AS is a hereditary disease that leads to kidney failure and is caused by mutations in the COL4A3, COL4A4, and COL4A5 genes that lead to the absence of collagen α3α4α5 (IV networks in the mature kidney glomerular basement membrane. Approximately 80% of AS is X-linked because of mutations in COL4A5, the gene encoding the alpha 5 chain of type IV collagen. To investigate the pathogenesis of AS at the genetic level, we generated induced pluripotent stem cells (iPSCs from renal tubular cells of a patient with AS. The successful iPSC generation laid the foundation to master the repair of the COL4A5 gene and to evaluate the differentiation of iPSC into Sertoli cells and the accompanying epigenetic changes at each stage. The generation of iPSCs from AS patients not only confirms that iPSCs could be generated from renal tubular cells, but also provides a novel type of genetic therapy for AS patients. In this study, we generated iPSCs from renal tubular cells via ectopic expression of four transcription factors (Oct4, Sox2, c-myc, and Klf4. According to the human embryonic stem cell (hESC charter, iPSC formation was confirmed by comparatively analyzing hESC markers via colony morphology, immunohistochemistry, qRT-PCR, flow cytometry, gene expression profiling of the three germ layers, and karyotyping. Our results demonstrated that iPSCs were similar to hESCs with regard to morphology, proliferation, hESC-specific surface marker expression, and differentiation into the cell types of the

  7. Clear lens phacoemulsification in the anterior lenticonus due to Alport Syndrome: two case reports.

    Science.gov (United States)

    Aslanzadeh, Ghassem Amir; Gharabaghi, Davoud; Naderi, Niloofar

    2008-05-27

    Alport Syndrome has a prevalence of 1 case per 5,000 people and 85% of patients have the X-linked form, where affected males develop renal failure and usually have high-tone sensorineural deafness by age 20. The main abnormality is deficient synthesis of type IV collagen, the main component of basement membranes. Common ocular abnormalities of this syndrome consist of dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, and anterior lenticonus, but other ocular defects such as cataracts, posterior lenticonus, and retinal detachments have also been reported. We report two cases of anterior lenticonus due to Alport Syndrome and describe clear lens phacoemulsification and foldable intraocular lens implantation as an effective and safe refractive procedure in the four eyes of these two patients. All four eyes of the two patients were in good condition after surgery and achieved satisfactory optical and visual results and had no remarkable complications at six-months follow-up. Clear lens phacoemulsification with foldable intraocular lens implantation can be used as an efficient and safe procedure for vision disorders in these patients.

  8. Clear lens phacoemulsification in the anterior lenticonus due to Alport Syndrome: two case reports

    Directory of Open Access Journals (Sweden)

    Aslanzadeh Ghassem

    2008-05-01

    Full Text Available Abstract Introduction Alport Syndrome has a prevalence of 1 case per 5,000 people and 85% of patients have the X-linked form, where affected males develop renal failure and usually have high-tone sensorineural deafness by age 20. The main abnormality is deficient synthesis of type IV collagen, the main component of basement membranes. Common ocular abnormalities of this syndrome consist of dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, and anterior lenticonus, but other ocular defects such as cataracts, posterior lenticonus, and retinal detachments have also been reported. Case presentation We report two cases of anterior lenticonus due to Alport Syndrome and describe clear lens phacoemulsification and foldable intraocular lens implantation as an effective and safe refractive procedure in the four eyes of these two patients. Conclusion All four eyes of the two patients were in good condition after surgery and achieved satisfactory optical and visual results and had no remarkable complications at six-months follow-up. Clear lens phacoemulsification with foldable intraocular lens implantation can be used as an efficient and safe procedure for vision disorders in these patients.

  9. Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Juncker, I; Persson, U

    2001-01-01

    of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X...

  10. Speech, language, and hearing function in twins with Alport syndrome: A seven-year retrospective case report

    Directory of Open Access Journals (Sweden)

    Ramesh Kaipa

    2017-06-01

    Full Text Available Alport syndrome is an X-linked syndrome that results in nephritis, renal failure, sensorineural hearing loss, and eye deficits. As a result of sensorineural hearing loss, these individuals are likely to experience difficulties in the area of speech and language. While studies in the past have examined the speech and language characteristics of children with syndromic sensorineural hearing loss, to our knowledge there are no previous studies to have documented the speech and language characteristics of these children on a long-term basis. The current study addresses this limitation by reporting speech, language, hearing, and function of twin brothers with X-linked Alport syndrome across a seven-year period. Information was collected by examining the medical records of the participants as well as through a verbal interview with the participants' guardian. Results revealed that the participants' hearing abilities gradually deteriorated over the seven-year period which affected their speech and language development as well. The kidney function tests revealed significant presence of hematuria (blood in the urine as well as proteinuria (protein in the urine suggesting chronic kidney dysfunction. This longitudinal study demonstrates the functional relationship between the kidneys and the cochlea, although they appear to be independent of one another. As individuals with Alport syndrome exhibit systemic complications, interdisciplinary collaboration is essential among health care providers including audiologists, speech-language pathologists, nephrologists, and ophthalmologist to promote evidence-based practice.

  11. Angiotensin converting enzyme inhibitor therapy in children with Alport syndrome: effect on urinary albumin, TGF-β, and nitrite excretion

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    Kashtan Clifford E

    2002-02-01

    Full Text Available Abstract Background Angiotensin converting enzyme inhibitors are routinely prescribed to patients with chronic kidney disease because of their known renoprotective effects. We evaluated the effect of short-term therapy with the angiotensin converting enzyme inhibitor, enalapril, in early Alport syndrome, defined as disease duration less than 10 years and a normal glomerular filtration rate. Methods 11 children with early Alport syndrome were investigated. Two consecutive early morning urine specimens were collected at the start of the study for measurement of urinary creatinine, total protein, albumin, TGF-β, and nitrite excretion. Patients were treated with enalapril, ≅ 0.2 mg/kg/day, once a day for 14 days. Two early morning urine specimens were collected on days 13 and 14 of enalapril treatment and two weeks later for measurement of urinary creatinine, total protein, albumin, TGF-β, and nitrite excretion. Results Prior to treatment, urinary excretion of transforming growth factor-β and nitrite, the major metabolite of nitric oxide, was within normal limits in all patients. Administration of enalapril for 2 weeks did not alter urinary albumin, transforming growth factor-β, or nitrite excretion. Conclusion These findings suggest that early Alport syndrome represents a disease involving exclusively intrinsic glomerular barrier dysfunction. At this stage of the illness, there is no evidence of angiotensin II-mediated proteinuria or increased production of transforming growth factor-β and, therefore, routine treatment with an angiotensin converting enzyme inhibitor may not be warranted.

  12. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing

    DEFF Research Database (Denmark)

    Martin, P; Heiskari, N; Zhou, J

    1998-01-01

    -amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining...... seven cases (14%) were autosomal or X chromosome-linked, it is likely that some of them were autosomal. It is concluded that PCR amplification and direct DNA sequencing of the promoter and exons is currently the best procedure to detect mutations in COL4A5 in Alport syndrome.......Approximately 85% of patients with Alport syndrome (hereditary nephritis) have been estimated to have mutations in the X chromosomal COL4A5 collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2. In the present work, the promoter...

  13. Morphological diagnosis of Alport syndrome and thin basement membrane nephropathy by low vacuum scanning electron microscopy.

    Science.gov (United States)

    Okada, Shinichi; Inaga, Sumire; Kitamoto, Koichi; Kawaba, Yasuo; Nakane, Hironobu; Naguro, Tomonori; Kaidoh, Toshiyuki; Kanzaki, Susumu

    2014-01-01

    Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetic disorders caused by mutations of the type IV collagen genes COL4A3, COL4A4, and/or COL4A5. We here aimed to investigate the three-dimensional ultrastructure of the glomerular basement membrane (GBM) in order to introduce a novel method of diagnosing AS and TBMN. The subjects were 4 patients with AS and 6 patients with TBMN. Conventional renal biopsy paraffin sections from AS and TBMN patients were stained with periodic acid methenamine silver (PAM) and observed directly under low vacuum scanning electron microscopy (LVSEM). The PAM-positive GBMs were clearly visible under LVSEM through the overlying cellular components. The GBMs showed characteristic coarse meshwork appearances in AS, and thin and sheet-like appearances in TBMN. At the cut side view of the capillary wall, the GBMs in AS appeared as fibrous inclusions between a podocyte and an endothelial cell, while the GBMs in TBMN showed thin linear appearances. These different findings of GBMs between AS and TBMN were easily observed under LVSEM. Thus, we conclude that three-dimensional morphological evaluation by LVSEM using conventional renal biopsy paraffin sections will likely be useful for the diagnosis of AS and TBMN, including for retrospective investigations.

  14. An unusual cause of pseudoachalasia: the Alport syndrome-diffuse leiomyomatosis association.

    Science.gov (United States)

    Sousa, Rita G; Figueiredo, Pedro C; Pinto-Marques, Pedro; Meira, Tânia; Novais, Luís A; Vieira, Ana I; Luz, Carlos; Borralho, Paula; Freitas, João

    2013-11-01

    Alport syndrome (AS) is a hereditary disease characterized by glomerular nephropathy progressing to end-stage renal disease, frequently associated with sensorineural deafness and ocular abnormalities. Rarely, AS coexists with diffuse leiomyomatosis, a benign proliferation of smooth muscle in the gastrointestinal tract, mostly of the oesophagus, but also of the tracheobronchial tree and the female genital tract. Patients with this association have been shown to have contiguous gene deletion involving both COL4A5 and COL4A6 genes. The authors report the case of a 25-year-old man with AS and long-standing dysphagia. The patient received a renal transplant at the age of 23 because of end-stage renal disease. Clinical assessment as well as endoscopic, manometric and radiologic studies suggested the diagnosis of achalasia, which was treated by Heller's myotomy with Dor fundoplication. Postprocedure dysphagia led to an endoscopic ultrasound that showed diffuse thickening of the second layer, resulting in the hypothesis of oesophageal leiomyomatosis. The diagnosis was confirmed through histological study of endoscopic biopsies and genetic analysis.

  15. Immunohistochemical diagnosis of Alport's syndrome in paraffin-embedded renal sections: antigen retrieval with autoclave heating.

    Science.gov (United States)

    Naito, Ichiro; Ninomiya, Yoshifumi; Nomura, Shinsuke

    2003-03-01

    Alport's syndrome (AS) is a hereditary renal disease caused by mutations in the genes encoding collagen type IV. Immunohistochemical analysis of the alpha chains of collagen type IV has been found to be useful for the diagnosis of this disease. The monoclonal antibodies (mAbs) generated by us recognize alpha 1(IV) through alpha 6(IV) chains of collagen type IV on fresh-frozen sections but not on paraffin-embedded sections. Antigen retrieval by autoclave heating has been found to restore the epitopes recognized by the mAbs; however the heating conditions had not been well established. In this study, the heating conditions were carefully examined using renal sections obtained from AS and non-AS patients. The heating was performed in an autoclave, at 105 degrees -127 degrees C for 6-8 min. During the heating, the sections were immersed in 0.2 N HCl solution (pH 0.9). Then, the mAbs were applied for 30 min, and the bound mAbs were detected using the LSAB kit. The optimal temperature for the antigen retrieval varied among specimens, and was dependent on the type of basement membrane examined. Thus, it was considered that heating at two or three different temperatures could be helpful for the precise diagnosis of AS. Adopting the antigen retrieval method could extend the possibility of immunohistochemical diagnosis of AS to cases without using fresh-frozen sections.

  16. Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions

    DEFF Research Database (Denmark)

    Zhou, J; Hertz, Jens Michael; Tryggvason, K

    1992-01-01

    A single base mutation was identified in the type IV collagen alpha 5 chain gene (COL4A5) of a Danish kindred with Alport syndrome. The 27-year-old male proband developed hematuria in childhood and terminal renal failure at the age of 25 years. He has no hearing loss or ocular lesions. Electron.......9-kb fragments present in control DNA but the presence of a 2.2-kb variant fragment, indicating the loss of an MspI restriction site in the 3' end of the gene. The mother had all three fragments, indicating heterozygosity. PCR amplification of exon 14 (counted from the 3' end) and subsequent denaturing...

  17. Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient

    DEFF Research Database (Denmark)

    Zhou, J; Hertz, Jens Michael; Leinonen, A

    1992-01-01

    We have generated and characterized cDNA clones providing the complete amino acid sequence of the human type IV collagen chain whose gene has been shown to be mutated in X chromosome-linked Alport syndrome. The entire translation product has 1,685 amino acid residues. There is a 26-residue signal...... peptide, a 1,430-residue collagenous domain starting with a 14-residue noncollagenous sequence, and a Gly-Xaa-Yaa-repeat sequence interrupted at 22 locations, and a 229-residue carboxyl-terminal noncollagenous domain. The calculated molecular weight of the mature alpha 5(IV) chain is 158,303. Analysis...

  18. High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing

    DEFF Research Database (Denmark)

    Martin, P; Heiskari, N; Zhou, J

    1998-01-01

    sequence and previously unknown intron sequences flanking exons 2 and 37 of COL4A5 were determined. Furthermore, intron sequences flanking the other 49 exons were expanded from 35 to 190 to facilitate mutation analysis of the gene. Using this information, all 51 exons and the promoter region were PCR......Approximately 85% of patients with Alport syndrome (hereditary nephritis) have been estimated to have mutations in the X chromosomal COL4A5 collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2. In the present work, the promoter......-amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining...

  19. Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.

    Science.gov (United States)

    Massella, Laura; Gangemi, Concetta; Giannakakis, Kostas; Crisafi, Antonella; Faraggiana, Tullio; Fallerini, Chiara; Renieri, Alessandra; Muda, Andrea Onetti; Emma, Francesco

    2013-05-01

    X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy. GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution. These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.

  20. A nonsense mutation in the COL4A5 collagen gene in a family with X-linked juvenile Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Heiskari, N; Zhou, J

    1995-01-01

    The X-linked form of Alport syndrome is associated with mutations in the COL4A5 gene encoding the alpha 5-chain of type IV collagen. By using PCR-amplification and direct sequencing we identified a novel mutation involving a deletion of the last two bases in the codon GGA for Glycine-1479 in exon...... 47 of the COL4A5 gene in a patient with a juvenile form of X-linked Alport syndrome with deafness. This two base deletion caused a shift in the reading frame and introduced a premature stop codon which resulted in an alpha 5(IV)-chain shortened by 202 residues and lacking almost the entire NC1 domain....... The mutation was found to co-segregate with the disease in the family. The information of the sequence variation in this family was used to perform carrier detection and prenatal diagnosis by allele-specific oligonucleotide hybridization analysis and direct sequencing of PCR amplified exon 47. Prenatal...

  1. Dados clínicos e da audição em indivíduos com Síndrome de Alport Clinical data and hearing of individuals with Alport syndrome

    Directory of Open Access Journals (Sweden)

    Fatima Regina Abreu Alves

    2008-12-01

    Full Text Available A Síndrome de Alport (SA é uma desordem hereditária, caracterizada por nefropatia, muitas vezes, com perda auditiva sensorioneural e com defeitos oculares. OBJETIVO: Analisar os dados clínicos e da audição em indivíduos com SA, com ênfase na correlação entre alteração renal e perda auditiva (PA. FORMA DE ESTUDO: clínico prospectivo com coorte transversal. CASUÍSTICA E MÉTODO: 37 indivíduos realizaram avaliação otorrinolaringológica e testes audiológicos. Foram considerados para a análise estatística da PA os resultados das audiometrias de tons puros. RESULTADOS: Nos 28 indivíduos que apresentavam alterações clínicas foram encontrados 46,4% de DLX e 53,6% de AD. A PA ocorreu em 46,1% dos avaliados. 12 pacientes tinham PA no exame audiométrico 11,5%, leve e 34,6%, moderada. Comparados os familiares normais aos que tinham alteração renal, todos os que apresentavam PA mostravam comprometimento renal. Em 30,8% a configuração era descendente suave em agudos e em 11,5% era plana. CONCLUSÕES: A distribuição dos padrões de herança não coincide com o descrito na literatura. A PA é um achado extra-renal freqüente. Existe associação entre acometimento renal e PA (p= 0,009. As configurações mais freqüentes foram: descendente suave em agudos e plana. Não há associação entre a PA e a idade. Não existe correlação entre PA e sexo neste grupo.Alport Syndrome (AS is a hereditary disease, characterized by nephropathy, often times with sensorineural hearing loss and ocular defects. AIM: to analyze the clinical and hearing information from individuals with AS, more specifically the correlation between renal disorder and hearing loss (HL. STUDY DESIGN: clinical prospective with cross-sectional cohort. MATERIALS AND METHODS: 37 individuals underwent otorhinolaryngological evaluation and were submitted to audiologic tests. For HL statistical analysis we considered only the results from the pure tone audiometries

  2. Alport Syndrome Foundation

    Science.gov (United States)

    ... Groups Support ASF Donate Fundraising & Events Team ASF Online Shopping Annual Campaign for Healthy Kidneys Annual Campaign Donors ... Groups Support ASF Donate Fundraising & Events Team ASF Online Shopping Annual Campaign for Healthy Kidneys Annual Campaign Donors ...

  3. Identification of a distinct type IV collagen α chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome

    International Nuclear Information System (INIS)

    Hostikka, S.L.; Hoeyhtyae, M.; Tryggvason, K.; Eddy, R.L.; Byers, M.G.; Shows, T.B.

    1990-01-01

    The authors have identified and extensively characterized a type IV collagen α chain, referred to as α5(IV). Four overlapping cDNA clones isolated contain an open reading frame for 543 amino acid residues of the carboxyl-terminal end of a collagenous domain, a 229-residue carboxyl-terminal noncollagenous domain, and 1201 base pairs coding for a 3' untranslated region. The collagenous Gly-Xaa-Yaa repeat sequence has five imperfections that coincide with those in the corresponding region of the α1(IV) chain. The noncollagenous domain has 12 conserved cysteine residues and 83% and 63% sequence identity with the noncollagenous domains of the α1(IV) and α2(IV) chains, respectively. The α5(IV) chain has less sequence identity with the putative bovine α3(IV) and α4(IV) chains. Antiserum against an α5(IV) synthetic peptide stained a polypeptide chain of about 185 kDa by immunoblot analysis and immunolocalization of the chain in human kidney was almost completely restricted to the glomerulus. The gene was assigned to the Xq22 locus by somatic cell hybrids and in situ hybridization. This may be identical or close to the locus of the X chromosome-linked Alport syndrome that is believed to be a type IV collagen disease

  4. Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria.

    Directory of Open Access Journals (Sweden)

    Rajshekhar Chatterjee

    Full Text Available We applied customized targeted next-generation exome sequencing (NGS to determine if mutations in genes associated with renal malformations, Alport syndrome (AS or nephrotic syndrome are a potential cause of renal abnormalities in patients with equivocal or atypical presentation. We first sequenced 4,041 exons representing 292 kidney disease genes in a Caucasian woman with a history of congenital vesicoureteral reflux (VUR, recurrent urinary tract infections and hydronephrosis who presented with nephrotic range proteinuria at the age of 45. Her biopsy was remarkable for focal segmental glomerulosclerosis (FSGS, a potential complication of longstanding VUR. She had no family history of renal disease. Her proteinuria improved initially, however, several years later she presented with worsening proteinuria and microhematuria. NGS analysis revealed two deleterious COL4A3 mutations, one novel and the other previously reported in AS, and a novel deleterious SALL2 mutation, a gene linked to renal malformations. Pedigree analysis confirmed that COL4A3 mutations were nonallelic and compound heterozygous. The genomic results in conjunction with subsequent abnormal electron microscopy, Collagen IV minor chain immunohistochemistry and progressive sensorineural hearing loss confirmed AS. We then modified our NGS approach to enable more efficient discovery of variants associated with AS or a subset of FSGS by multiplexing targeted exome sequencing of 19 genes associated with AS or FSGS in 14 patients. Using this approach, we found novel or known COL4A3 or COL4A5 mutations in a subset of patients with clinically diagnosed or suspected AS, APOL1 variants associated with FSGS in African Americans and novel mutations in genes associated with nephrotic syndrome. These studies demonstrate the successful application of targeted capture-based exome sequencing to simultaneously evaluate genetic variations in many genes in patients with complex renal phenotypes and

  5. Genetics Home Reference: Alport syndrome

    Science.gov (United States)

    ... Martin P, Hertz JM, Schröder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler ... P, Hertz JM, Schröder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler ...

  6. Hereditaire nefritis met perceptieve slechthorendheid (Alport-syndroom) en een familie met hereditaire idiopathische schrompelnieren

    NARCIS (Netherlands)

    Bokkel Huinink, Jan Adam ten

    1967-01-01

    The first part of this thesis deals with the syndrome of hereditary nephritis and perception deafness. In the first Chapter a historical review of the literature is presented. Guthrie (1902) gave a detailed description of the signs and symptoms in this condition; Alport (1927~ was the first author

  7. X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene.

    Science.gov (United States)

    Fu, Xue Jun; Nozu, Kandai; Eguchi, Aya; Nozu, Yoshimi; Morisada, Naoya; Shono, Akemi; Taniguchi-Ikeda, Mariko; Shima, Yuko; Nakanishi, Koichi; Vorechovsky, Igor; Iijima, Kazumoto

    2016-10-01

    X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described. A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites. Immunohistochemistry (IHC) of kidney biopsies was used to detect α2 and α5 chain expression. We identified a hemizygous point mutation, c.876A>T, in exon 15 of COL4A5 in the proband and his brother, which is predicted to result in a synonymous amino acid change, p.(Gly292Gly). Transcript analysis showed that this mutation potentially altered splicing because it disrupted the splicing factor binding site. The kidney biopsy of the proband showed lamellation of the glomerular basement membrane (GBM), while IHC revealed negative α5(IV) staining in the GBM and Bowman's capsule, which is typical of XLAS. This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations.

  8. Progression of Alport Kidney Disease in Col4a3 Knock Out Mice Is Independent of Sex or Macrophage Depletion by Clodronate Treatment.

    Directory of Open Access Journals (Sweden)

    Munkyung Kim

    Full Text Available Alport syndrome is a genetic disease of collagen IV (α3, 4, 5 resulting in renal failure. This study was designed to investigate sex-phenotype correlations and evaluate the contribution of macrophage infiltration to disease progression using Col4a3 knock out (Col4a3KO mice, an established genetic model of autosomal recessive Alport syndrome. No sex differences in the evolution of body mass loss, renal pathology, biomarkers of tubular damage KIM-1 and NGAL, or deterioration of kidney function were observed during the life span of Col4a3KO mice. These findings confirm that, similar to human autosomal recessive Alport syndrome, female and male Col4a3KO mice develop renal failure at the same age and with similar severity. The specific contribution of macrophage infiltration to Alport disease, one of the prominent features of the disease in human and Col4a3KO mice, remains unknown. This study shows that depletion of kidney macrophages in Col4a3KO male mice by administration of clodronate liposomes, prior to clinical onset of disease and throughout the study period, does not protect the mice from renal failure and interstitial fibrosis, nor delay disease progression. These results suggest that therapy targeting macrophage recruitment to kidney is unlikely to be effective as treatment of Alport syndrome.

  9. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis.

    OpenAIRE

    Kashtan, C; Fish, A J; Kleppel, M; Yoshioka, K; Michael, A F

    1986-01-01

    We probed epidermal basement membranes (EBM) of acid-urea denatured skin from members of kindreds with Alport-type familial nephritis (FN) for the presence of antigens reactive with Goodpasture sera (GPS) and serum (FNS) from an Alport patient who developed anti-glomerular basement membrane (GBM) nephritis in a renal allograft. By immunoblotting, GPS reacted primarily with the 28,000 molecular weight (mol wt) monomer but also the 24,000 mol wt and 26,000 mol wt monomers of the noncollagenous ...

  10. Quaternary epitopes of α345(IV) collagen initiate Alport post-transplant anti-GBM nephritis

    DEFF Research Database (Denmark)

    Olaru, Florina; Luo, Wentian; Wang, Xu-Ping

    2013-01-01

    Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of α5(IV) collagen, which occurs in normal kidneys, including...... of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within α5NC1 monomers, shared by α345NC1 and α1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of α345NC1 hexamers. In Col4a5-null mice, immunization...... with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary α345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared α5NC1 alloepitopes. These results imply that quaternary epitopes within α345NC1 hexamers may initiate...

  11. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis.

    Science.gov (United States)

    Kashtan, C; Fish, A J; Kleppel, M; Yoshioka, K; Michael, A F

    1986-10-01

    We probed epidermal basement membranes (EBM) of acid-urea denatured skin from members of kindreds with Alport-type familial nephritis (FN) for the presence of antigens reactive with Goodpasture sera (GPS) and serum (FNS) from an Alport patient who developed anti-glomerular basement membrane (GBM) nephritis in a renal allograft. By immunoblotting, GPS reacted primarily with the 28,000 molecular weight (mol wt) monomer but also the 24,000 mol wt and 26,000 mol wt monomers of the noncollagenous globular domain (NC1) of type IV collagen from normal human GBM, while FNS identified only the 26,000-mol wt monomer. FNS reacted with EBM of 12 controls and nine unaffected male kindred members but not EBM of eight affected males. Five affected females exhibited interrupted reactivity of FNS with EBM. GPS showed variable reactivity with EBM and was not discriminating with respect to Alport-type FN. FNS did not stain renal basement members of five affected males. However, the EBM, tubular basement membrane, and Bowman's capsules of affected males contained antigens reactive with GPS. These immunochemical studies suggest that the FNS antigen is distinct from Goodpasture antigen(s). The expression of FNS antigen located on the NC1 domain of type IV collagen is altered in basement membranes of patients with Alport-type FN, and the distribution of this antigenic anomaly within kindreds suggests X-linked dominant transmission of a defective gene.

  12. Molecular aspects of Down syndrome.

    Science.gov (United States)

    Dutta, Samikshan; Nandagopal, Krishnadas; Gangopadhyay, Prasanta Kumar; Mukhopadhyay, Kanchan

    2005-04-01

    Molecular aspects of Down syndrome (DS), a major genetic cause for mental retardation, commonly associated with trisomy 21 are discussed. Two different hypotheses have been speculated to better understand the disease. One believes that increased gene dosage contributes to the phenotypic abnormalities; the other correlates genetic imbalance with DS pathogenesis. To sustain these hypotheses, different murine models have been developed. Experimental models as well as sequencing of human chromosome 21 helped in speculating a few possible candidate genes for DS. However, the phenotypic changes involved with this neurological disorder vis-a-vis the enhanced number of genes, still remain unexplained. Improvement in screening pattern, model system, as well as better understanding of the disease etiology may help in developing efficacious therapeutic regimes for DS.

  13. Molecular Biology of Exfoliation Syndrome.

    Science.gov (United States)

    Schlötzer-Schrehardt, Ursula

    2018-02-06

    Exfoliation syndrome (XFS) is a common age-related matrix process resulting from excessive production and disordered assembly of elastic microfibrillar components into highly cross-linked fibrillary aggregates throughout the anterior eye segment and various organ systems. The underlying molecular pathophysiology involves a complex interplay of pro-fibrotic protagonists including growth factors, proteolytic enzymes and inhibitors, pro-inflammatory cytokines, chaperones, and dysregulated stress response pathways including insufficient autophagy. Interaction between individual genetic predisposition and stress factors is a plausible theory explaining the development of XFS in the aging individual. Genome-wide association studies have identified robust genetic associations with LOXL1, CACNA1A, and five additional genes including POMP and TMEM136, which provide new biological insights into the pathology of XFS and highlight a role for abnormal matrix cross-linking processes, Ca channel deficiency, blood-aqueous barrier dysfunction, and abnormal ubiquitin-proteasome signaling in XFS pathophysiology. However, the exact pathophysiological mechanisms, the functional role of genetic risk variants and gene-environmental interactions still remain to be characterized.

  14. Molecular changes in fetal Down syndrome brain.

    Science.gov (United States)

    Engidawork, Ephrem; Lubec, Gert

    2003-03-01

    Trisomy of human chromosome 21 is a major cause of mental retardation and other phenotypic abnormalities collectively known as Down syndrome. Down syndrome is associated with developmental failure followed by processes of neurodegeneration that are known to supervene later in life. Despite a widespread interest in Down syndrome, the cause of developmental failure is unclear. The brain of a child with Down syndrome develops differently from that of a normal one, although characteristic morphological differences have not been noted in prenatal life. On the other hand, a review of the existing literature indicates that there are a series of biochemical alterations occurring in fetal Down syndrome brain that could serve as substrate for morphological changes. We propose that these biochemical alterations represent and/or precede morphological changes. This review attempts to dissect these molecular changes and to explain how they may lead to mental retardation.

  15. Molecular and Clinical Aspects of Angelman Syndrome

    Science.gov (United States)

    Dagli, A.; Buiting, K.; Williams, C.A.

    2012-01-01

    The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5–10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity. PMID:22670133

  16. The pediatric nephrotic syndrome spectrum: Clinical homogeneity and molecular heterogeneity

    OpenAIRE

    Schachter, Asher D.

    2004-01-01

    Idiopathic nephrotic syndrome is the most common glomerular disorder of childhood. Recurrence of nephrotic syndrome immediately following renal transplantation is rapid, results in a high rate of graft loss, and represents the most severe form of nephrotic syndrome. This review discusses the molecular heterogeneity of pediatric nephrotic syndrome across the spectrum of disease activity. A schema is offered for a molecular approach to pediatric nephrotic syndrome, including immune-mediated and...

  17. Treacher Collins Syndrome; Anesthetic considerations and Molecular Findings

    Directory of Open Access Journals (Sweden)

    Shahram Sayyadi

    2018-01-01

    Full Text Available Treacher Collins Syndrome (TCS is a rare disease with mandibulofacial dysostosis. The deformities accompanied by this syndrome could cause especial challenges for anesthesiologist. On the other hand Treacher protein is well recognized in the pathogenesis of this syndrome. In this report we want to present a successful management of a patient with Treacher Collins syndrome and also describe new advances in the molecular aspect of this disease.

  18. Genes and Syndromic Hearing Loss.

    Science.gov (United States)

    Keats, Bronya J. B.

    2002-01-01

    This article provides a description of the human genome and patterns of inheritance and discusses genes that are associated with some of the syndromes for which hearing loss is a common finding, including: Waardenburg, Stickler, Jervell and Lange-Neilsen, Usher, Alport, mitochondrial encephalomyopathy, and sensorineural hearing loss. (Contains…

  19. Duplication 3q syndrome: Molecular delineation of the critical region

    Energy Technology Data Exchange (ETDEWEB)

    Aqua, M.S.; Rizzu, P.; Lindsay, E.A. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1995-01-02

    The phenotype of dup(3q) syndrome partially overlaps with Brachmann-de Lange phenotype. Convulsions and eye, palate renal, and cardiac anomalies are more frequent in dup(3q) syndrome, while limb deficiencies, hirsutism, and synophrys are more characteristic of Brachmann-de Lange syndrome. Whether the two syndromes have a biological relationship has yet to be demonstrated. Using two patient translocation cell lines, each involving distal 3q, we have narrowed the critical region of the dup(3q) syndrome to the interval 3q26.31-q27.3 and initiated its molecular characterization. We have mapped in this region 6 cosmid clones spanning approximately 3 - 5 Mb. The critical region appears to overlap with the region where a balanced translocation was found in a Brachmann-de Lange patient. This work provides the mapping framework for finer molecular analysis dup(3q) syndrome. 25 refs., 3 figs.

  20. [Wolfram syndrome: clinical features, molecular genetics of WFS1 gene].

    Science.gov (United States)

    Tanabe, Katsuya; Matsunaga, Kimie; Hatanaka, Masayuki; Akiyama, Masaru; Tanizawa, Yukio

    2015-02-01

    Wolfram syndrome(WFS: OMIM 222300) is a rare recessive neuro-endocrine degenerative disorder, known as DIDMOAD(Diabetes Insipidus, early-onset Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene(WFS1). The WFS1 protein is an endoplasmic reticulum(ER) embedded protein, which functions in ER calcium homeostasis and unfolded protein responses. Dysregulation of these cellular processes results in the development of ER stress, leading to apoptosis. In addition, abundantly present WFS1 protein in insulin secretory granules plays a role in the intra-granular acidification. However, the phenotypic pleiomorphism and molecular complexity of this disease limit the understanding of WFS. Here we review clinical features, molecular mechanisms and mutations of WFS1 gene that relate to this syndrome.

  1. Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis.

    Directory of Open Access Journals (Sweden)

    Duane Delimont

    Full Text Available It has been known for some time that laminins containing α1 and α2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM of Alport mice, dogs, and humans. We show that laminins containing the α2 chain, but not those containing the α1 chain activates focal adhesion kinase (FAK on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of α2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin α2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages.

  2. Clinicopathologic, Immunohistochemical, and Molecular Features of Histiocytoid Sweet Syndrome.

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    Alegría-Landa, Victoria; Rodríguez-Pinilla, Socorro María; Santos-Briz, Angel; Rodríguez-Peralto, José Luis; Alegre, Victor; Cerroni, Lorenzo; Kutzner, Heinz; Requena, Luis

    2017-07-01

    Histiocytoid Sweet syndrome is a rare histopathologic variant of Sweet syndrome. The nature of the histiocytoid infiltrate has generated considerable controversy in the literature. The main goal of this study was to conduct a comprehensive overview of the immunohistochemical phenotype of the infiltrate in histiocytoid Sweet syndrome. We also analyze whether this variant of Sweet syndrome is more frequently associated with hematologic malignancies than classic Sweet syndrome. This is a retrospective case series study of the clinicopathologic, immunohistochemical, and molecular features of 33 patients with a clinicopathologic diagnosis of histiocytoid Sweet syndrome was conducted in the dermatology departments of 5 university hospitals and a private laboratory of dermatopathology. The clinical, histopathological, immunohistochemical, and follow-up features of 33 patients with histiocytoid Sweet syndrome were analyzed. In some cases, cytogenetic studies of the dermal infiltrate were also performed. We compare our findings with those of the literature. The dermal infiltrate from the 33 study patients (20 female; median age, 49 years; age range, 5-93 years; and 13 male; median age, 42 years; age range, 4-76 years) was mainly composed of myeloperoxidase-positive immature myelomonocytic cells with histiocytoid morphology. No cytogenetic anomalies were found in the infiltrate except in 1 case in which neoplastic cells of chronic myelogenous leukemia were intermingled with the cells of histiocytoid Sweet syndrome. Authentic histiocytes were also found in most cases, with a mature immunoprofile, but they appeared to be a minor component of the infiltrate. Histiocytoid Sweet syndrome was not more frequently related with hematologic malignancies than classic neutrophilic Sweet syndrome. The dermal infiltrate of cutaneous lesions of histiocytoid Sweet syndrome is composed mostly of immature cells of myeloid lineage. This infiltrate should not be interpreted as leukemia cutis.

  3. Metabolic syndrome: clinical concept and molecular basis.

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    Funahashi, Tohru; Matsuzawa, Yuji

    2007-01-01

    The metabolic syndrome is a cluster of insulin resistance, elevated blood pressure, and atherogenic dyslipidemia and is a common basis of cardiovascular diseases (CVD). Although the precise mechanism remains to be elucidated, a practical definition is needed. A worldwide definition that considers increased waist circumference as an essential component has been settled. Visceral fat locates upstream of the liver. Free fatty acids and glycerol derived from visceral fat reach the liver and stimulate lipoprotein synthesis and gluconeogenesis, respectively. The adipose tissue produces a variety of bioactive substances conceptualized as 'adipocytokines'. Overproduction of plasminogen activator inhibitor-1 and tumor necrosis factor- seems to relate to the thrombotic and inflammatory tendency. On the other hand, adiponectin, which has antiatherogenic and antidiabetic activities, is reduced in subjects with metabolic syndrome. In Japan, the waist circumference criterion based on visceral fat accumulation has been adopted. The concept of this syndrome has been widely publicized, and health promotion programs based on the concept have commenced in various areas of the country. Such 'Adipo-Do-It' movement is an incentive to encourage physical exercise to reduce visceral fat and is a big challenge to prevent life-style-related diseases and CVD.

  4. The Molecular Genetics of Restless Legs Syndrome.

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    Rye, David B

    2015-09-01

    Restless legs syndrome (RLS) is a common sensorimotor trait defined by symptoms that interfere with sleep onset and maintenance in a clinically meaningful way. Nonvolitional myoclonus while awake and asleep is a sign of the disorder and an informative endophenotype. The genetic contributions to RLS/periodic leg movements are substantial, are among the most robust defined to date for a common disease, and account for much of the variance in disease expressivity. The disorder is polygenic, as revealed by recent genome-wide association studies. Experimental studies are revealing mechanistic details of how these common variants might influence RLS expressivity. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Molecular and cytogenetic characterization of del(9p) syndrome

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    Micale, M.A.; Haren, J.M.; Schwartz, S. [Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States)] [and others

    1994-09-01

    The del(9p) syndrome is characterized by mental retardation, trigonocephaly, midface hypoplasia, upward slanting palpebral fissures, a long philtrum, and is typically associated with a breakpoint at 9p22. Seventeen unrelated patients with del(9p) and their parents were analyzed by high resolution chromosome studies, molecular analysis using a series of highly polymorphic dinucleotide repeat markers for 9p, and fluorescence in situ hybridization (FISH) to characterize precisely the extent of chromosome loss. Eleven patients were found to have an interstitial deletion with breakpoints assigned to 9p22.1 and 9p24.3 in most cases. Two patients had familial unbalanced translocations of maternal origin and four had de novo complex rearrangements identified by high resolution analysis and FISH utilizing chromosome libraries. PCR analysis of eleven families with eight minisatellite markers determined paternal origin of the deletion in six cases and maternal origin in five. This suggests that the molecular event resulting in the deletion is equally prevalent in both male and female gametogenesis and that genomic imprinting does not play a role in the pathogenesis of del(9p) syndrome. Increased precision in mapping these minisatellite markers was also possible through this work. This study demonstrates the existence of molecular heterogeneity as six patients with a cytological breakpoint at 9p22.1 revealed three different molecular breakpoints. These findings suggest that genotype-phenotype correlations in deletion syndromes such as this should be based on high-resolution molecular analysis of the deleted chromosome segment. Work is in progress to map a series of cosmid probes by FISH relative to chromosomal breakpoints in these patients. These combined studies should provide a better understanding of the mechanisms involved in the pathogenesis of del(9p) syndrome and may identify loci where genes responsible for one or more aspects of the del(9p) phenotype may reside.

  6. Adrenogenital syndrome: molecular mechanisms of development

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    V.P. Pishak

    2017-03-01

    Full Text Available On the long multistage pathway of biosynthesis of steroid hormones from cholesterol to cortisol, testo­sterone and estradiol, due to mutations in genes, there is the deficiency of steroidogenesis enzymes in the adrenal glands: cholesterol desmolase, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, 21-hydroxylase, and enzymes of steroidogenesis in the testis: 17,20-desmolasis, 17β-hydroxystyrol dehydroreductase and others, as well as a complex of widespread congenital diseases of heterogeneous group with autosomal recessive type of inheritance — adrenogenital syndrome (AGS. Deficiency of any of these enzymes or transport proteins leads to partial or complete loss of their activity. Phenotypic manifestations of AGS are quite polymorphic: phenomenon of hypoadrenocorticism; violation of the nature and rates of sexual development; bilateral increasing of adrenal glands; hypercorticotropinemia sensitive to dexamethasone; oligo- or amenorrhea; anovulatory infertility, miscarriage in early pregnancy. Pathogenetic component of these signs is congenital disorder of steroidogenesis caused by 11β-hydroxylase deficiency and symptoms of androgen excess. In AGS, there are distinguished a phenotype and nonclassical forms of steroidogenesis enzyme deficiency. In most cases, both types of diseases occur in persons of both sexes with different course — from mild to severe forms of the disease.

  7. Molecular genetic analysis of Down syndrome.

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    Patterson, David

    2009-07-01

    Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

  8. [Molecular basis of Rett syndrome: A current look].

    Science.gov (United States)

    Pantaleón F, Gretta; Juvier R, Tamara

    2015-01-01

    Rett syndrome (RS) is a neurodevelopmental disorder that exclusively affects girls, and occurs along with autism. It is very uncommon, and has five distinct forms, one classic and the others atypical, which generally compromise manual skills, language, and mobility, and widely associated with the appearance of stereotypy and early epilepsy. With the aim of updating the information about RS, a search was performed in the computer data bases of PubMed, Hinari, SCIELO and Medline, as well as consulting other web sites including OMIM, ORPHANET, GeneMap, Genetests, Proteins and Gene, using the descriptors "Síndrome de Rett", "genes y Síndrome de Rett", "Rett Syndrome gene", "Rett Syndrome", "Rett Syndrome gene therapy", and "Rett Syndrome review". Of the 1,348 articles found, 42 articles were selected, which reported 3 genes causing the syndrome: MECP2, CDKL5 and FOXG. The MECP2 gene is mutated in 80% of patients with classic RS, as well as in 40% of those affected by any of its atypical forms. RS with early epilepsy and the congenital variant are mainly due to variations in the CDKL5 and FOXG1 genes, respectively. The diagnosis of RS is based on clinical criteria. However, the advances in molecular biology and genetics have opened a wide range of possibilities for diagnosing the different clinical forms that could not be classified before. Molecular analysis can help confirm the clinical criteria and provided information as regards the prognosis of the patient. Copyright © 2015. Publicado por Elsevier España, S.L.U.

  9. Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.

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    Moccia, Amanda; Srivastava, Anshika; Skidmore, Jennifer M; Bernat, John A; Wheeler, Marsha; Chong, Jessica X; Nickerson, Deborah; Bamshad, Michael; Hefner, Margaret A; Martin, Donna M; Bielas, Stephanie L

    2018-01-04

    PurposeCHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome.MethodsWe performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.ResultsPathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES.ConclusionThese results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.233.

  10. Molecular Pathogenesis of Familial Wolff-Parkinson-White Syndrome.

    Science.gov (United States)

    Licht, Miyamotoa

    2018-01-01

    Familial Wolff-Parkinson-White (WPW) syndrome is an autosomal dominant inherited disease and consists of a small percentage of WPW syndrome which exhibits ventricular pre-excitation by development of accessory atrioventricular pathway. A series of mutations in PRKAG2 gene encoding gamma2 subunit of 5'AMP-activated protein kinase (AMPK) has been identified as the cause of familial WPW syndrome. AMPK is one of the most important metabolic regulators of carbohydrates and lipids in many types of tissues including cardiac and skeletal muscles. Patients and animals with the mutation in PRKAG2 gene exhibit aberrant atrioventricular conduction associated with cardiac glycogen overload. Recent studies have revealed "novel" significance of canonical pathways leading to glycogen synthesis and provided us profound insights into molecular mechanism of the regulation of glycogen metabolism by AMPK. This review focuses on the molecular basis of the pathogenesis of cardiac abnormality due to PRKAG2 mutation and will provide current overviews of the mechanism of glycogen regulation by AMPK. J. Med. Invest. 65:1-8, February, 2018.

  11. Metabolic syndrome and Cancer: Do they share common molecular pathways?

    Directory of Open Access Journals (Sweden)

    Veniou E.

    2016-06-01

    Full Text Available Metabolic syndrome, a clustering of risk factors including obesity, has emerged as a global health plague. A lot of epidemiological and clinical evidence suggests that the metabolic syndrome is linked not only to cardiovascular diseases and diabetes mellitus type 2 but also to cancer development and progression. In this review the potential mechanisms tying the metabolic syndrome with cancer are presented. The role of insulin resistance and hyperinsulinemia, the activation of insulin-like growth factor-1 (IGF-1 pathway, and the induction of cytotoxic products are highlighted. Subsequent effects leading to oxidative stress, release of lipokines with signaling properties by adipocytes, development of a sustained systemic inflammation, production of inflammatory cytokines, and establishment of a tumorigenic environment are also discussed. The importance of the metabolic syndrome and obesity coupled with the deeper understanding of the underlying molecular mechanisms has trigger intensive clinical research with an aim to prevent the risk of cancer and improve outcomes. Moreover, the need for lifestyle changes with increased physical activity and improved dietary quality has been emerged as urgent health priority.

  12. Molecular and clinical study of 61 Angelman syndrome patients

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    Saitoh, Shinji; Harada, Naoki; Jinno, Yoshihiro; Niikawa, Norio [Nagasaki Univ. School of Medicine (Japan); Imaizumi, Kiyoshi; Kuroki, Yoshikazu; Fukushima; Yoshimitsu; Sugimoto, Tateo; Renedo, Monica

    1994-08-15

    We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted. 37 refs., 2 figs., 4 tabs.

  13. Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

    Science.gov (United States)

    Õunap, Katrin

    2016-01-01

    Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS. PMID:27587987

  14. Molecular pathogenesis of long QT syndrome type 1

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    Jie Wu, PhD

    2016-10-01

    Full Text Available Long QT syndrome type 1 (LQT1 is a subtype of a congenital cardiac syndrome caused by mutation in the KCNQ1 gene, which encodes the α-subunit of the slow component of delayed rectifier K+ current (IKs channel. Arrhythmias in LQT1 are characterized by prolongation of the QT interval on ECG, as well as the occurrence of life-threatening cardiac events, frequently triggered by adrenergic stimuli (e.g., physical or emotional stress. During the past two decades, much advancement has been made in understanding the molecular pathogenesis underlying LQT1. Uncovering the genotype-phenotype correlations in LQT1 is of clinical importance to better understand the gene-specific differences that may influence the propensity for developing life-threatening arrhythmias under specific conditions. Elucidation of these mechanisms will also help to improve the diagnosis and management of this cardiac disorder based on gene-specific considerations. This review describes the current medical consensus and recent developments regarding the molecular pathogenesis of LQT1 and provides a novel insight into the adrenergic regulation of this disease.

  15. Fishing the molecular bases of Treacher Collins syndrome.

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    Andrea M J Weiner

    Full Text Available Treacher Collins syndrome (TCS is an autosomal dominant disorder of craniofacial development, and mutations in the TCOF1 gene are responsible for over 90% of TCS cases. The knowledge about the molecular mechanisms responsible for this syndrome is relatively scant, probably due to the difficulty of reproducing the pathology in experimental animals. Zebrafish is an emerging model for human disease studies, and we therefore assessed it as a model for studying TCS. We identified in silico the putative zebrafish TCOF1 ortholog and cloned the corresponding cDNA. The derived polypeptide shares the main structural domains found in mammals and amphibians. Tcof1 expression is restricted to the anterior-most regions of zebrafish developing embryos, similar to what happens in mouse embryos. Tcof1 loss-of-function resulted in fish showing phenotypes similar to those observed in TCS patients, and enabled a further characterization of the mechanisms underlying craniofacial malformation. Besides, we initiated the identification of potential molecular targets of treacle in zebrafish. We found that Tcof1 loss-of-function led to a decrease in the expression of cellular proliferation and craniofacial development. Together, results presented here strongly suggest that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the TCOF1 ortholog in zebrafish. This experimental condition may facilitate the study of the disease etiology during embryonic development.

  16. Fishing the molecular bases of Treacher Collins syndrome.

    Science.gov (United States)

    Weiner, Andrea M J; Scampoli, Nadia L; Calcaterra, Nora B

    2012-01-01

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, and mutations in the TCOF1 gene are responsible for over 90% of TCS cases. The knowledge about the molecular mechanisms responsible for this syndrome is relatively scant, probably due to the difficulty of reproducing the pathology in experimental animals. Zebrafish is an emerging model for human disease studies, and we therefore assessed it as a model for studying TCS. We identified in silico the putative zebrafish TCOF1 ortholog and cloned the corresponding cDNA. The derived polypeptide shares the main structural domains found in mammals and amphibians. Tcof1 expression is restricted to the anterior-most regions of zebrafish developing embryos, similar to what happens in mouse embryos. Tcof1 loss-of-function resulted in fish showing phenotypes similar to those observed in TCS patients, and enabled a further characterization of the mechanisms underlying craniofacial malformation. Besides, we initiated the identification of potential molecular targets of treacle in zebrafish. We found that Tcof1 loss-of-function led to a decrease in the expression of cellular proliferation and craniofacial development. Together, results presented here strongly suggest that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the TCOF1 ortholog in zebrafish. This experimental condition may facilitate the study of the disease etiology during embryonic development.

  17. Fragile X syndrome: a review of clinical and molecular diagnoses.

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    Ciaccio, Claudia; Fontana, Laura; Milani, Donatella; Tabano, Silvia; Miozzo, Monica; Esposito, Susanna

    2017-04-19

    Fragile X Syndrome (FXS) is the second cause of intellectual disability after Down syndrome and the most prevalent cause of intellectual disability in males, affecting 1:5000-7000 men and 1:4000-6000 women. It is caused by an alteration of the FMR1 gene, which maps at the Xq27.3 band: more than 99% of individuals have a CGG expansion (>200 triplets) in the 5' UTR of the gene, and FMR1 mutations and duplication/deletion are responsible for the remaining (<1%) molecular diagnoses of FXS. The aim of this review was to gather the current clinical and molecular knowledge about FXS to provide clinicians with a tool to guide the initial assessment and follow-up of FXS and to offer to laboratory workers and researchers an update about the current diagnostic procedures. FXS is a well-known condition; however, most of the studies thus far have focused on neuropsychiatric features. Unfortunately, some of the available studies have limitations, such as the paucity of patients enrolled or bias due to the collection of the data in a single-country population, which may be not representative of the average global FXS population. In recent years, insight into the adult presentation of the disease has progressively increased. Pharmacological treatment of FXS is essentially symptom based, but the growing understanding of the molecular and biological mechanisms of the disease are paving the way to targeted therapy, which may reverse the effects of FMRP deficiency and be a real cure for the disease itself, not just its symptoms. The clinical spectrum of FXS is wide, presenting not only as an isolated intellectual disability but as a multi-systemic condition, involving predominantly the central nervous system but potentially affecting any apparatus. Given the relative high frequency of the condition and its complex clinical management, FXS appears to have an important economic and social burden.

  18. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.

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    Killoran, C E; Abbott, M; McKusick, V A; Biesecker, L G

    2000-07-01

    The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.

  19. Parent stress across molecular subtypes of children with Angelman syndrome.

    Science.gov (United States)

    Miodrag, N; Peters, S

    2015-09-01

    Parenting stress has been consistently reported among parents of children with developmental disabilities. However, to date, no studies have investigated the impact of a molecular subtype of Angelman syndrome (AS) on parent stress, despite distinct phenotypic differences among subtypes. Data for 124 families of children with three subtypes of AS: class I and II deletions (n = 99), imprinting centre defects (IC defects; n = 11) and paternal uniparental disomy (UPD; n = 14) were drawn from the AS Rare Diseases Clinical Research Network (RDCRN) database and collected from five research sites across the Unites States. The AS study at the RDCRN gathered health information to understand how the syndrome develops and how to treat it. Parents completed questionnaires on their perceived psychological stress, the severity of children's aberrant behaviour and children's sleep patterns. Children's adaptive functioning and developmental levels were clinically evaluated. Child-related stress reached clinical levels for 40% of parents of children with deletions, 100% for IC defects and 64.3% for UPD. Sleep difficulties were similar and elevated across subtypes. There were no differences between molecular subtypes for overall child and parent-related stress. However, results showed greater isolation and lack of perceived parenting skills for parents of children with UPD compared with deletions. Better overall cognition for children with deletions was significantly related to more child-related stress while their poorer adaptive functioning was associated with more child-related stress. For all three groups, the severity of children's inappropriate behaviour was positively related to different aspects of stress. How parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can

  20. Novel Implications in Molecular Diagnosis of Lynch Syndrome

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    Raffaella Liccardo

    2017-01-01

    Full Text Available About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP and Lynch syndrome (LS. In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

  1. Analysis of Downs syndrome with molecular techniques for future diagnoses

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    May Salem Al-Nbaheen

    2018-03-01

    Full Text Available Down syndrome (DS is a genetic disorder appeared due to the presence of trisomy in chromosome 21 in the G-group of the acrocentric region. DS is also known as non-Mendelian inheritance, due to the lack of Mendel’s laws. The disorder in children is identified through clinical symptoms and chromosomal analysis and till now there are no biochemical and molecular analyses. Presently, whole exome sequencing (WES has largely contributed in identifying the new disease-causing genes and represented a significant breakthrough in the field of human genetics and this technique uses high throughput sequencing technologies to determine the arrangement of DNA base pairs specifying the protein coding regions of an individual’s genome. Apart from this next generation sequencing and whole genome sequencing also contribute for identifying the disease marker. From this review, the suggestion was to perform the WES is DS children to identify the marker region. Keywords: Downs syndrome, Exome sequencing, Chromosomal analysis, Genes, Genetics

  2. The clinical and molecular spectrum of androgen insensitivity syndromes

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    Hiort, O.; Sinnecker, G.H.G.; Holterhus, P.M.; Nitsche, E.M.; Kruse, K. [Medical Univ. of Luebeck (Germany)

    1996-05-03

    Androgen insensitivity syndromes (AIS) are due to end-organ resistance to androgenic steroids in males leading to defective virilization of the external genitalia. The phenotype encompasses a wide array of genital ambiguity and may range from completely female to undervirilized but unequivocally male with infertility. This disorder is caused by mutations of the androgen receptor and is an X-linked recessive trait. We have studied 47 patients with AIS and have characterized the underlying molecular abnormality in the androgen receptor gene. Twenty patients had complete AIS and twenty-seven had partial AIS. Of the latter, 11 were of predominantly female phenotypic appearance and gender was assigned accordingly, while 16 were raised as males. Within the group of complete AIS, two patients had gross deletions within the gene, one had a small deletion, and one had an insertion. In the other patients with complete AIS, as well as all individuals with partial AIS, single nucleotide substitutions within the coding region were detected, each leading to an amino acid alteration. Seven codons were involved in more than one mutation in different cases. In addition, in one patient with spinal and bulbar muscular atrophy, an elongation of a glutamine-repeat was characterized. We conclude that mutations in the androgen receptor gene may be present throughout the whole coding region. However, our study provides evidence that several mutational hot spots exist. 18 refs., 2 figs.

  3. Tcof1-Related Molecular Networks in Treacher Collins Syndrome.

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    Dai, Jiewen; Si, Jiawen; Wang, Minjiao; Huang, Li; Fang, Bing; Shi, Jun; Wang, Xudong; Shen, Guofang

    2016-09-01

    Treacher Collins syndrome (TCS) is a rare, autosomal-dominant disorder characterized by craniofacial deformities, and is primarily caused by mutations in the Tcof1 gene. This article was aimed to perform a comprehensive literature review and systematic bioinformatic analysis of Tcof1-related molecular networks in TCS. First, the up- and down-regulated genes in Tcof1 heterozygous haploinsufficient mutant mice embryos and Tcof1 knockdown and Tcof1 over-expressed neuroblastoma N1E-115 cells were obtained from the Gene Expression Omnibus database. The GeneDecks database was used to calculate the 500 genes most closely related to Tcof1. Then, the relationships between 4 gene sets (a predicted set and sets comparing the wildtype with the 3 Gene Expression Omnibus datasets) were analyzed using the DAVID, GeneMANIA and STRING databases. The analysis results showed that the Tcof1-related genes were enriched in various biological processes, including cell proliferation, apoptosis, cell cycle, differentiation, and migration. They were also enriched in several signaling pathways, such as the ribosome, p53, cell cycle, and WNT signaling pathways. Additionally, these genes clearly had direct or indirect interactions with Tcof1 and between each other. Literature review and bioinformatic analysis finds imply that special attention should be given to these pathways, as they may offer target points for TCS therapies.

  4. Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome

    Directory of Open Access Journals (Sweden)

    Maki Fukami

    2012-01-01

    Full Text Available Aromatase excess syndrome (AEXS is a rare autosomal dominant disorder characterized by gynecomastia. This condition is caused by overexpression of CYP19A1 encoding aromatase, and three types of cryptic genomic rearrangement around CYP19A1, that is, duplications, deletions, and inversions, have been identified in AEXS. Duplications appear to have caused CYP19A1 overexpression because of an increased number of physiological promoters, whereas deletions and inversions would have induced wide CYP19A1 expression due to the formation of chimeric genes consisting of a noncoding exon(s of a neighboring gene and CYP19A1 coding exons. Genotype-phenotype analysis implies that phenotypic severity of AEXS is primarily determined by the expression pattern of CYP19A1 and the chimeric genes and by the structural property of the fused exons with a promoter function (i.e., the presence or the absence of a natural translation start codon. These results provide novel information about molecular mechanisms of human genetic disorders and biological function of estrogens.

  5. Angelman syndrome: review of clinical and molecular aspects

    Directory of Open Access Journals (Sweden)

    Bird LM

    2014-05-01

    Full Text Available Lynne M Bird1Department of Pediatrics, University of California, Division of Genetics, Rady Children’s Hospital, San Diego, California, USAAbstract: “Angelman syndrome” (AS is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling.Keywords: Angelman syndrome, chromosome 15q11-13, UBE3A, imprinting

  6. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome.

    Science.gov (United States)

    Cooper, Wendy N; Luharia, Anita; Evans, Gail A; Raza, Hussain; Haire, Antonita C; Grundy, Richard; Bowdin, Sarah C; Riccio, Andrea; Sebastio, Gianfranco; Bliek, Jet; Schofield, Paul N; Reik, Wolf; Macdonald, Fiona; Maher, Eamonn R

    2005-09-01

    Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (Pmanagement and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.

  7. Molecular medicine of fragile X syndrome: based on known molecular mechanisms.

    Science.gov (United States)

    Luo, Shi-Yu; Wu, Ling-Qian; Duan, Ran-Hui

    2016-02-01

    Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included "fragile X syndrome", "FXS and medication", "FXS and therapeutics" and "FXS and treatment". Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.

  8. Nance-Horan syndrome: a contiguous gene syndrome involving deletion of the amelogenin gene? A case report and molecular analysis.

    Science.gov (United States)

    Franco, E; Hodgson, S; Lench, N; Roberts, G J

    1995-03-01

    A case of Nance-Horan syndrome in a male is presented, with some features of the condition in his carrier mother and her mother. It is proposed that Nance-Horan syndrome might be a contiguous gene syndrome mapping to chromosome Xp21.2-p22.3. The proband had congenital cataract microphthalmia and dental abnormalities including screwdriver shaped incisors and evidence of enamel pitting hypoplasia. The region Xp21.2-p22.3 also contains the tooth enamel protein gene, amelogenin (AMGX). Using molecular genetic techniques, we have shown that there is no evidence that the AMGX gene is deleted in this case of the Nance-Horan syndrome.

  9. Clinical and Molecular Genetic Features of Autoinflammatory Syndromes in Children

    Directory of Open Access Journals (Sweden)

    Е. I. Alexeeva

    2015-01-01

    Full Text Available Objective: Our aim was to study the prevalence and clinical features of autoinflammatory syndromes among patients with systemic juvenile idiopathic arthritis. Methods: A prospective nonrandomized study was conducted. All its members have been studied for mutations in TNFRSF1A and NLRP3 genes by the sequencing method. Results: 90 children (27 boys, 63 girls aged from 1 to 17 (average age 8.2 years, with a guide diagnosis: «Systemic juvenile idiopathic arthritis», were examined. As a result, 10 (14% patients showed mutations in TNFRSF1A gene, leading to the development of TRAPS-syndrome (8 had the most common mutation of R92Q; 3 — not previously described mutations in NLRP3 gene. 2 patients had the diagnosis of CINCA/NOMID Syndrome, 1 — Muckle–Wells Syndrome. In three cases, mutations leading to the development of TRAPS-syndromethe were identified in the first line of descent. Classical examples of autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS, and tumor necrosis factor receptor associated periodic syndrome (TRAPS. The data about their pathogenesis, clinical features, diagnosis and treatment is presented. Conclusion: It is shown that early detection and adequate treatment of patients with autoinflammatory syndromes, characterized by severe disease and serious prognosis, is difficult due to lack of awareness of pediatricians and unavailability of genetic diagnosis of these syndromes. The necessity of the development of a universal model of the diagnostic algorithm for identification of autoinflammatory syndromes using next-generation sequencing technologies is grounded. 

  10. Molecular characterization of WFS1 in patients with Wolfram syndrome.

    NARCIS (Netherlands)

    Ouweland, J.M.W. van den; Cryns, K.; Pennings, R.J.E.; Walraven, I.; Janssen, G.M.; Maassen, J.A.; Veldhuijzen, B.F.; Arntzenius, A.B.; Lindhout, D.; Cremers, C.W.R.J.; Camp, G. van; Dikkeschei, L.D.

    2003-01-01

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  11. Molecular characterization of WFS1 in patients with Wolfram syndrome

    NARCIS (Netherlands)

    Van den Ouweland, JMW; Cryns, K; Pennings, RJE; Walraven, [No Value; Janssen, GMC; Maassen, JA; Veldhuijzen, BFE; Arntzenius, AB; Lindhout, D; Cremers, CWRJ; Van Camp, G; Dikkeschei, LD

    Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for

  12. Síndrome de Alport: reporte de caso y revisión.

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    Jose Augusto Urrego Díaz

    2015-01-01

    Full Text Available Presentamos el caso de una paciente de 4 años de edad, con hermano gemelo dicigoto asintomático, hija de padres no consanguíneos y sin antecedentes familiares de enfermedad renal. Inicia su cuadro clínico con edemas y proteinuria severa como manifestación de un síndrome nefrótico primario de cambios mínimos, que fue diagnosticado por biopsia renal y manejado inicialmente con esteroides. Su evolución no fue adecuada debido a múltiples recaídas que lo clasificaron como síndrome nefrótico corticorresistente, requiriendo cambio en su tratamiento y una segunda biopsia renal, cuyo resultado histológico sorprendió al grupo médico tratante porque los cambios en la membrana basal glomerular confirmaban que se trataba de un Síndrome de Alport.

  13. Natural History and Genotype–Phenotype Correlation in Female X-Linked Alport Syndrome

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    Tomohiko Yamamura

    2017-09-01

    Discussion: This study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS.

  14. Lenticonus diagnosis in Alport's syndrome: Anterior capsule apical angle calculation using Scheimpflug imagery.

    Science.gov (United States)

    Jarrín, E; Jarrín, I; Arnalich-Montiel, F

    2015-08-01

    We describe a simplified method to detect anterior lenticonus. Three eyes of 2 patients with anterior lenticonus, plus 16 eyes from 16 healthy controls underwent Scheimpflug imaging of their anterior segment with Pentacam. The anterior capsule apex angle was manually identified and automatically measured by AutoCAD. The mean angle was 173.06° (SD: 1.91) in healthy subjects, and 158.33° (SD: 3.05) in anterior lenticonus eyes. The angle obtained from patients was more than 3 SD steeper than those from healthy subjects. The apical angle calculation method seems to discriminate well between normal eyes and eyes suspected of having anterior lenticonus. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  15. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    NARCIS (Netherlands)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha; Taylor, Claire F.; Aeby, Alec; Aicardi, Jean; Artuch, Rafael; Montalto, Simon Attard; Bacino, Carlos A.; Barroso, Bruno; Baxter, Peter; Benko, Willam S.; Bergmann, Carsten; Bertini, Enrico; Biancheri, Roberta; Blair, Edward M.; Blau, Nenad; Bonthron, David T.; Briggs, Tracy; Brueton, Louise A.; Brunner, Han G.; Burke, Christopher J.; Carr, Ian M.; Carvalho, Daniel R.; Chandler, Kate E.; Christen, Hans-Jurgen; Corry, Peter C.; Cowan, Frances M.; Cox, Helen; D'Arrigo, Stefano; Dean, John; de Laet, Corinne; de Praeter, Claudine; Dery, Catherine; Ferrie, Colin D.; Flintoff, Kim; Frints, Suzanna G. M.; Garcia-Cazorla, Angels; Gener, Blanca; Goizet, Cyril; Goutieres, Francoise; Green, Andrew J.; Guet, Agnes; Hamel, Ben C. J.; Hayward, Bruce E.; Heiberg, Arvid; Hennekam, Raoul C.; Husson, Marie; Jackson, Andrew P.; Jayatunga, Rasieka; Jiang, Yong-Hui; Kant, Sarina G.; Kao, Amy; King, Mary D.; Kingston, Helen M.; Klepper, Joerg; van der Knaap, Marjo S.; Kornberg, Andrew J.; Kotzot, Dieter; Kratzer, Wilfried; Lacombe, Didier; Lagae, Lieven; Landrieu, Pierre Georges; Lanzi, Giovanni; Leitch, Andrea; Lim, Ming J.; Livingston, John H.; Lourenco, Charles M.; Lyall, E. G. Hermione; Lynch, Sally A.; Lyons, Michael J.; Marom, Daphna; McClure, John P.; McWilliam, Robert; Melancon, Serge B.; Mewasingh, Leena D.; Moutard, Marie-Laure; Nischal, Ken K.; Ostergaard, John R.; Prendiville, Julie; Rasmussen, Magnhild; Rogers, R. Curtis; Roland, Dominique; Rosser, Elisabeth M.; Rostasy, Kevin; Roubertie, Agathe; Sanchis, Amparo; Schiffmann, Raphael; Scholl-Burgi, Sabine; Seal, Sunita; Shalev, Stavit A.; Corcoles, C. Sierra; Sinha, Gyan P.; Soler, Doriette; Spiegel, Ronen; Stephenson, John B. P.; Tacke, Uta; Tan, Tiong Yang; Till, Marianne; Tolmie, John L.; Tomlin, Pam; Vagnarelli, Federica; Valente, Enza Maria; van Coster, Rudy N. A.; van der Aa, Nathalie; Vanderver, Adeline; Vles, Johannes S. H.; Voit, Thomas; Wassmer, Evangeline; Weschke, Bernhard; Whiteford, Margo L.; Willemsen, Michel A. A.; Zankl, Andreas; Zuberi, Sameer M.; Orcesi, Simona; Fazzi, Elisa; Lebon, Pierre; Crow, Yanick J.

    2007-01-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease

  16. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome

    NARCIS (Netherlands)

    Cooper, Wendy N.; Luharia, Anita; Evans, Gail A.; Raza, Hussain; Haire, Antonita C.; Grundy, Richard; Bowdin, Sarah C.; Riccio, Andrea; Sebastio, Gianfranco; Bliek, Jet; Schofield, Paul N.; Reik, Wolf; Macdonald, Fiona; Maher, Eamonn R.

    2005-01-01

    Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into

  17. Churg-Strauss vasculitis and idiopathic hypereosinophyl syndrome: role of molecular biology in the differential diagnosis of hypereosinophyl syndrome

    Directory of Open Access Journals (Sweden)

    A. d'Ascanio

    2011-09-01

    Full Text Available Objective: Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations, often without an identifiable cause. Churg-Strauss syndrome is a systemic vasculitis characterized by prominent peripheral eosinophilia, asthma and systemic involvement. The presence of mild to severe eosinophilia and systemic involvement raise the search of many trigger factor that need to be ruled out. Distinguishing CSS from idiopathic hypereosinophilic syndrome may be particularly challenging, especially in ANCA negative patients. Methods: The aim of the present study was to present a small case series of patients referred to a Rheumatology Unit for mild to severe eosinophilia and signs and symptoms of systemic involvement and to outline the clinical significance of molecular biology in the work-up of hypereosinophilia. Results: Eleven patients with moderate to severe peripheral eosinophylia, were referred to our Unit from 1996 to 2007. Female to male ratio was 7/4, mean age 40.54 (range 22-75. Three out of eleven patients resulted positive for molecular biology. The diagnosis of idiopathic hypereosinophylia was confirmed in one out of three on the basis of the clinical picture and bone marrow biopsy. Conclusions: Molecular biology may be useful in the screening and in the follow-up of a new hypereosinophylic patient.

  18. Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

    OpenAIRE

    Burkhart, Keith K.; Abernethy, Darrell; Jackson, David

    2015-01-01

    Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was al...

  19. Cytogenetic and Molecular Investigation in Children with Possible Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Onur Ozer

    2012-04-01

    Full Text Available Objective: Fragile X syndrome (FXS is the most common cause of inherited mental retardation and is due to a mutation in the X-linked FMR1 gene. Molecular genetic testing and chromosome analysis are indicated for this disorder. In this context, we tried to determine the frequency of the FXS, and other chro¬mosomal abnormalities of Turkish pediatric neurology outpatients. Materials and Methods: Cytogenetic and molecular screenings were performed to esti-mate the prevalence of the fragile X in 107 patients with mental retardation, language disorders, hyperactivity, develop¬mental delay or fragile X syndrome phenotype. Only 26 out of 107 patients were screened, molecularly. Results: Cytogenetically fragile X-positive cells was found in 8 cases (7.5% of 107 patients; in 4.7% of males and in 2.8% of females. The autosomal fragile sites (FS was found in 14 (13.1% cases. One (0.9% patient had pericentric inversion of chromosome 9. Molecular analysis were performed for 26 patients and all patients showed normal CGG expansion. Conclusion: In diagnosis of fragile X syndrome, chromosome analysis must be run in conjunction with the molecular studies. It is recommended that all members of the fragile X family under risk should be screened both by cytogenetic and molecular methods. Genetic counseling can be useful to patients and families considering genetic testing. [Cukurova Med J 2012; 37(2.000: 76-83

  20. [Adipocytokines and metabolic syndrome--molecular mechanism and clinical implication].

    Science.gov (United States)

    Matsuda, Morihiro; Shimomura, Iichiro

    2004-06-01

    Recent progress in adipocyte-biology shows that adipocytes are not merely fat-storing cells but that they secrete a variety of hormones, cytekines, growth factors and other bioactive substabces, conceptualized as adipocytokines. These include plasminogen activator inhibitor 1(PAI-1), tumor necrosis factor(TNF-alpha), leptin and adiponectin. Dysregulated productions of these adipocytekines participate in the pathogenesis of obesity-associated metabolic syndrome such as insulin resistance, type 2 diabetes, hyperlipidemia, and vascular diseases. Increased productions of PAI-1 and TNF-alpha from accumulated fat contribute to the formation of thrombosis and insulin resistance in obesity, respectively. Lack of leptin causes metabolic syndrome. Adiponectin exerts insulin-sensitizing and anti-atherogenic effects, hence decrease of plasma adiponectin is causative for insulin resistance and atherosclerosis in obesity.

  1. Pearson marrow pancreas syndrome: a molecular study and clinical management.

    Science.gov (United States)

    Seneca, S; De Meirleir, L; De Schepper, J; Balduck, N; Jochmans, K; Liebaers, I; Lissens, W

    1997-05-01

    Human mitochondrial DNA (mt DNA) lesions can cause a heterogeneous group of mitochondrial degenerative disorders. We report on a 5-year-old patient suffering from the full-blown picture of Pearson syndrome. His symptoms started in the first year of life with failure to thrive, followed by chronic diarrhoea and lactic acidosis at 18 months of age. Analysis of mitochondrial DNA revealed large amounts of mt DNA molecules with a 2.7 kb deletion in all tissues examined. The diagnosis of Pearson syndrome was made initially in the absence of haematological disturbances. In the following months neutropenia, sideroblastic anaemia and hypoparathyroidism developed. Daily administration of dichloroacetate (DCA) and bicarbonate controls the lactic acidosis, while episodic treatments with filgastrim (Neupogen) reverse episodes of severe neutropenia. Calcium and vitamin D supplementation compensate for the hypoparathyroidism. Chronic administration of DCA and supportive treatment for a long period help to stabilize patients with multiorgan dysfunction.

  2. Phenotype, Cancer Risk, and Surveillance in Beckwith-Wiedemann Syndrome Depending on Molecular Genetic Subgroups

    NARCIS (Netherlands)

    Maas, Saskia M.; Vansenne, Fleur; Kadouch, Daniel J. M.; Ibrahim, Abdulla; Bliek, Jet; Hopman, Saskia; Mannens, Marcel M.; Merks, Johannes H. M.; Maher, Eamonn R.; Hennekam, Raoul C.

    Patients with Beckwith-Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences,

  3. Molecular characterization of a patient presumed to have prader-willi syndrome.

    Science.gov (United States)

    Falaleeva, Marina; Sulsona, Carlos R; Zielke, Horst R; Currey, Kathleen M; de la Grange, Pierre; Aslanzadeh, Vahid; Driscoll, Daniel J; Stamm, Stefan

    2013-01-01

    Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. Currently, there are no mouse models that faithfully reflect the human phenotype and investigations rely on human post-mortem material. During molecular characterization of tissue deposited in a public brain bank from a patient diagnosed with Prader-Willi syndrome, we found RNA expression from SNRPN, SNORD115, and SNORD116 which does not support a genetic diagnosis of Prader-Willi syndrome. The patient was a female, Caucasian nursing home resident with history of morbid obesity (BMI 56.3) and mental retardation. She died at age of 56 from pulmonary embolism. SNORD115 and SNORD116 are unexpectedly stable in post mortem tissue and can be used for post-mortem diagnosis. Molecular characterization of PWS tissue donors can confirm the diagnosis and identify those patients that have been misdiagnosed.

  4. Clinical and molecular phenotype of Aicardi-Goutieres syndrome

    DEFF Research Database (Denmark)

    Rice, Gillian; Patrick, Teresa; Parmar, Rekha

    2007-01-01

    Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease...... identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from...

  5. A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect

    Directory of Open Access Journals (Sweden)

    De Molfetta Greice Andreotti

    2002-01-01

    Full Text Available Angelman syndrome (AS and Prader-Willi syndrome (PWS are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity.

  6. Tetrasomy 21 pter {yields} q22.1 and Down syndrome: Molecular definition of the region

    Energy Technology Data Exchange (ETDEWEB)

    Daumer-Haas, C.; Schuffenhauer, S.; Walther, J.U. [Universitaet Muenchen (Germany); Portsmann, T. [Humboldt Universitaet, Berlin (Germany); Korenberg, J.R.; Schipper, R.D. [Univ. of California, Los Angeles, CA (United States)

    1994-12-01

    Down syndrome is usually caused by complete trisomy 21. Rarely, it is due to partial trisomy of the segment 21q22. We report on a 33-month-old girl with tetrasomy 21 pter {yields} q22.1 resulting from an extra chromosome idic(21)(q22.1). She has craniofacial traits typical of Down syndrome, including brachycephaly, third fontanel, upward slanting palpebral fissures, round face, and protruding tongue. Speech development is quite delayed whereas motor development is only mildly retarded. The molecular content of the extra isodicentric chromosome was defined by molecular genetic investigations using 13 single copy probes unique to chromosome 21, and SOD1 expression studies. The child was found to have 4 copies of the region defined by D21S16 (21cen) through D21S93 on 21q22.1 and two copies of the remaining region defined by SOD1 {yields} D21S55 {yields} D21S123. In view of the recent assignment of Down syndrome facial characters to the 21q22 region, defined in part by D21S55, it is significant that this child shows a subset of Down syndrome facial manifestations, without duplication of this region. These results suggest that genes contributing to the facial and some of the hand manifestations of Down syndrome also exist in the chromosomal region proximal to D21S55 in band 21q22.1. 34 refs., 6 figs., 3 tabs.

  7. Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome.

    Science.gov (United States)

    Hasumi, Hisashi; Baba, Masaya; Hasumi, Yukiko; Furuya, Mitsuko; Yao, Masahiro

    2016-03-01

    Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1-dependent cell proliferation. Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer. © 2015 The Japanese Urological Association.

  8. Proteus syndrome review: molecular, clinical, and pathologic features.

    Science.gov (United States)

    Cohen, M Michael

    2014-02-01

    Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Conventional and molecular cytogenetic features of myelodysplastic syndrome in China.

    Science.gov (United States)

    Chen, L- J; Li, J- Y; Zhu, Y; Qiu, H- R; Pan, J- L; Wang, R; Qian, S- X; Xu, W; Xue, Y- Q

    2007-12-01

    Myelodysplastic syndrome (MDS) constitutes a heterogeneous group of hematopoietic stem cell disorder characterized by peripheral blood cytopenia(s), in the presence of hypercellular bone marrow with features of ineffective hematopoiesis, and susceptibility to acute leukemia (AL). Although the precise pathogenesis of MDS remains to be clarified, cytogenetic abnormalities seem to be involved in its pathogenesis and are considered as an important factor in diagnosis and predicting clinical outcome. To explore the cytogenetic features of Chinese patients with myelodysplastic syndrome (MDS). Conventional cytogenetic analysis was performed in 88 MDS patients and among them, 34 cases were studied by interphase fluorescence in situ hybridization (I-FISH) with precisely chromosome 8 centromere specific DNA probe and DNA specific probes for 7q32 , 5q31. Of the 88 patients, 45 (51.1%) showed clonal karyotypic abnormalities by CC at diagnosis, including numerical changes (18 cases, 20.5%), structural changes (12 cases, 13.6%), and numerical and structural changes simultaneously(15 cases, 17.0%). Trisomy 8, -5/5q-, and -7/ 7q- account for 20.5%, 15.9%, and 5.7% respectively. Complex karyotypes were observed in 17 patients, the incidence being 19.3% in the whole series of cases. Among 34 MDS patients studied by I-FISH, -5/5q-, -7/7q- and trisomy 8 occurring in 4, 2 and 10 cases respectively for CC were confirmed by I-FISH. 5 cases in 30 cases who did not show -5/5q- by CC displayed this abnormality by I-FISH. 3 cases without -7/7q- by CC presented this aberration by I-FISH. 5 cases with trisomy 8 for I-FISH was not identified this change by CC. The frequent abnormalities are trisomy 8, -5/5q- and -7/ 7q-. FISH is very useful in detecting these alterations in MDS and it is an important complement to CC.

  10. Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: Estimated prevalence rate in a Danish country

    Energy Technology Data Exchange (ETDEWEB)

    Petersen, M.B.; Brondum-Nielsen, K.; Hansen, L.K.; Wulff, K.

    1995-06-19

    Angelman syndrome (AS) was initially considered a rather rare abnormality, but in later years, with the possibilities for cytogenetic and molecular diagnosis an increasing number of patients have been reported. The incidence is quoted to be around 1:20,000. The etiology of AS is associated with the lack of maternal allele(s) of one or more loci at 15q11-q13, and is considered an effect of parental imprinting of that region, since a similar deficiency of paternal alleles leads to Prader-Willi syndrome. 9 refs., 1 tab.

  11. Molecular Characterization of a Patient Presumed to Have Prader-Willi Syndrome

    OpenAIRE

    Falaleeva, Marina; Sulsona, Carlos R.; Zielke, Horst R.; Currey, Kathleen M.; de la Grange, Pierre; Aslanzadeh, Vahid; Driscoll, Daniel J.; Stamm, Stefan

    2013-01-01

    Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. Currently, there are no mouse models that faithfully reflect the human phenotype and investigations rely on human post-mortem material. During molecular characterization of tissue deposited in a public brain bank from a patient diagnosed with Prader-Willi syndrome, we found RNA expression from SNRPN, SNORD115, and SNORD116 which does not su...

  12. Testosterone deficiency syndrome: cellular and molecular mechanism of action.

    Science.gov (United States)

    Carruthers, Malcolm

    2013-02-01

    There is virtually no correlation between what are generally accepted to be the symptoms of deficient androgen in men and levels of androgens as measured in the laboratory. Now that androgen deficiency is being shown to play a part in conditions as diverse as metabolic syndrome, diabetes, and coronary heart disease, a hypothesis is needed to explain this apparent discrepancy between measured androgen levels and our understanding of the symptoms of androgen deficiency. When the possible mechanisms for androgen actions are considered, one explanation emerges that androgen may act much like insulin in persons with type 2 diabetes mellitus: the degree of androgen resistance may be variable depending on the organs or systems considered. Therefore, the symptoms can result from altered or damaged synthesis of androgen synthesis or regulation, elevated androgen binding, a reduction in tissue response, or decreased as a result of polymorphism and aging. Genomic transcription and translation may also be affected. As with diabetes, in adult male androgen deficiency, it is suggested that the definition of androgen deficiency should be based on individual physiology, with the requirements of the individual at a particular stage of life setting the baseline against which any deficiency of androgens or androgen metabolites, either absolute or relative, is determined. This approach will affect the terminology, etiology, diagnosis, and treatment of androgen deficiency.

  13. Molecular mechanisms of severe acute respiratory syndrome (SARS

    Directory of Open Access Journals (Sweden)

    Zabel Peter

    2005-01-01

    Full Text Available Abstract Severe acute respiratory syndrome (SARS is a new infectious disease caused by a novel coronavirus that leads to deleterious pulmonary pathological features. Due to its high morbidity and mortality and widespread occurrence, SARS has evolved as an important respiratory disease which may be encountered everywhere in the world. The virus was identified as the causative agent of SARS due to the efforts of a WHO-led laboratory network. The potential mutability of the SARS-CoV genome may lead to new SARS outbreaks and several regions of the viral genomes open reading frames have been identified which may contribute to the severe virulence of the virus. With regard to the pathogenesis of SARS, several mechanisms involving both direct effects on target cells and indirect effects via the immune system may exist. Vaccination would offer the most attractive approach to prevent new epidemics of SARS, but the development of vaccines is difficult due to missing data on the role of immune system-virus interactions and the potential mutability of the virus. Even in a situation of no new infections, SARS remains a major health hazard, as new epidemics may arise. Therefore, further experimental and clinical research is required to control the disease.

  14. The neurobehavioral and molecular phenotype of Angelman Syndrome.

    Science.gov (United States)

    Wink, Logan K; Fitzpatrick, Sarah; Shaffer, Rebecca; Melnyk, Sophia; Begtrup, Amber H; Fox, Emma; Schaefer, Tori L; Mathieu-Frasier, Lauren; Ray, Balmiki; Lahiri, Debomoy; Horn, Paul A; Erickson, Craig A

    2015-11-01

    Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research. © 2015 Wiley Periodicals, Inc.

  15. Freeman–Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa

    Directory of Open Access Journals (Sweden)

    A. M. Ali

    2017-01-01

    Full Text Available We report a case of a male baby who has characteristic signs of Freeman–Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman–Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman–Sheldon syndrome in sub-Saharan Africa.

  16. Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes.

    Science.gov (United States)

    Márquez, Manlio F; Cruz-Robles, David; Ines-Real, Selene; Vargas-Alarcón, Gilberto; Cárdenas, Manuel

    2015-01-01

    Hereditary sudden cardiac death syndromes comprise a wide range of diseases resulting from alteration in cardiac ion channels. Genes involved in these syndromes represent diverse mutations that cause the altered encoding of the diverse proteins constituting these channels, thus affecting directly the currents of the corresponding ions. In the present article we will briefly review how to arrive to a clinical diagnosis and we will present the results of molecular genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National Institute of Cardiology of Mexico City. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  17. Angelman syndrome: review of clinical and molecular aspects

    Science.gov (United States)

    Bird, Lynne M

    2014-01-01

    “Angelman syndrome” (AS) is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A) gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling. PMID:24876791

  18. Molecular genetic analysis of Prader-Willi and Angelman syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Kokkonen, H.M.; Kahkonen, T.M.; Leisti, J. [Oulu Univ. Central Hospital (Finland)

    1994-09-01

    Angelman (AS) and Prader-Willi (PWS) syndromes are caused by the loss of either maternal (AS) or paternal (PWS) contributions to chromosome 15q11-q13 region, which is subject to genomic imprinting. DNA methylation has been postulated to play a crucial role in genomic imprinting and the diagnostic test used is based on the differential parental methylation of 15q11-q13. We report here the DNA studies of 39 classical PWS and 12 AS patients. For DNA polymorphism and dosage studies we used nine genomic probes and five microsatellite markers specific for chromosome 15. To study the methylation patterns the probes DN34 (D15S9) and PW71 (D15S63), which show a parental-specific DNA methylation imprint, were used. Among the PWS patients, 29 (77%) cases with a deletion belonging to four different size classes and 9 (23%) with maternal uniparental disomy were found, respectively. Of the AS patients, 8 (67%) had a deletion, 1 (8%) paternal uniparental disomy and 3 (25%) biparental inheritance, respectively. Two sibs with biparental disomy showed a typical methylation pattern for AS, indicating that the maternal chromosome 15 carried a paternal methylation imprint. In the DNA methylation analysis the probe PW71 was useful: in our study it detected all deletions and uniparental disomy patients as well as potential imprinting mutations. The probe DN34 couldn`t identify patients which have a deletion outside the D15S9 locus. In the diagnosis of AS and PWS, the differential methylation of the parental 15q11-q13 offers a rapid diagnostic test but does not distinguish between a deletion and uniparental disomy. In our material the probe 4a.1, which detects DNA sequences from both the locus SNRPN (15q12) and SNRPNP1 (6pter-p21), proved to be reliable detecting all deletions. For detection of parental origin of deletion or uniparental disomy, microsatellite markers proved useful.

  19. Molecular and clinical characterization of Angelman syndrome in Chinese patients.

    Science.gov (United States)

    Bai, J-L; Qu, Y-J; Jin, Y-W; Wang, H; Yang, Y-L; Jiang, Y-W; Yang, X-Y; Zou, L-P; Song, F

    2014-03-01

    Angelman syndrome (AS) is a neurobehavioral disorder caused by lack of function of the maternal copy of the ubiquitin-protein ligase E3A (UBE3A) gene. In our study, 49 unrelated patients with classic AS phenotypes were confirmed by methylation-specific PCR (MS-PCR) analysis, short tandem repeat linkage analysis, and mutation screening of the UBE3A gene. Among the Chinese AS patients, 83.7% (41/49) had deletions on maternal chromosome 15q11.2-13. Paternal uniparental disomy, imprinting defects, and UBE3A gene mutations each accounted for 4.1% (2/49). Two AS patients were confirmed by MS-PCR analysis, but the pathogenic mechanism was unknown because their parents' samples were unavailable. Of the two described UBE3A gene mutations, that is, p.Pro400His (c.1199C>A) and p.Asp563Gly (c.1688A>G), the latter has not been reported previously. Mutation transmission analysis showed that the p.Pro400His and p.Asp563Gly mutations originated from asymptomatic mothers. The patients with the maternal deletion showed AS clinical manifestations that were consistent with other studies. However, the incidence of microcephaly (36.7%, 11/30) was lower than that in the Caucasian population (approximately 80%), but similar to that of the Japanese population (34.5%). Our study demonstrated that the occurrence of microcephaly in AS may vary among different populations. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

    DEFF Research Database (Denmark)

    Nunn, Laurence M; Lopes, Luis R; Syrris, Petros

    2016-01-01

    AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility...... previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively...

  1. PPAR? population shift produces disease-related changes in molecular networks associated with metabolic syndrome

    OpenAIRE

    Jurkowski, W; Roomp, K; Crespo, I; Schneider, J G; del Sol, A

    2011-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network,...

  2. Ellis-Van Creveld Syndrome: Prenatal Diagnosis, Molecular Analysis and Genetic Counseling

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2010-12-01

    Conclusion: Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects.

  3. Evolutionary and molecular analysis of the emergent severe fever with thrombocytopenia syndrome virus

    OpenAIRE

    Lam, Tommy Tsan-Yuk; Liu, Wei; Bowden, Thomas A.; Cui, Ning; Zhuang, Lu; Liu, Kun; Zhang, Yao-Yun; Cao, Wu-Chun; Pybus, Oliver G.

    2013-01-01

    In 2009, a novel Bunyavirus, called severe fever with thrombocytopenia syndrome virus (SFTSV) was identified in the vicinity of Huaiyangshan, China. Clinical symptoms of this zoonotic virus included severe fever, thrombocytopenia, and leukocytopenia, with a mortality rate of ?10%. By the end of 2011 the disease associated with this pathogen had been reported from eleven Chinese provinces and human-to-human transmission suspected. However, current understanding of the evolution and molecular e...

  4. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement

    NARCIS (Netherlands)

    Brioude, Frédéric; Kalish, Jennifer M.; Mussa, Alessandro; Foster, Alison C.; Bliek, Jet; Ferrero, Giovanni Battista; Boonen, Susanne E.; Cole, Trevor; Baker, Robert; Bertoletti, Monica; Cocchi, Guido; Coze, Carole; de Pellegrin, Maurizio; Hussain, Khalid; Ibrahim, Abdulla; Kilby, Mark D.; Krajewska-Walasek, Malgorzata; Kratz, Christian P.; Ladusans, Edmund J.; Lapunzina, Pablo; Le Bouc, Yves; Maas, Saskia M.; Macdonald, Fiona; Õunap, Katrin; Peruzzi, Licia; Rossignol, Sylvie; Russo, Silvia; Shipster, Caroleen; Skórka, Agata; Tatton-Brown, Katrina; Tenorio, Jair; Tortora, Chiara; Grønskov, Karen; Netchine, Irène; Hennekam, Raoul C.; Prawitt, Dirk; Tümer, Zeynep; Eggermann, Thomas; Mackay, Deborah J. G.; Riccio, Andrea; Maher, Eamonn R.

    2018-01-01

    Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular

  5. Molecular and Cellular Mechanisms Elucidating Neurocognitive Basis of Functional Impairments Associated with Intellectual Disability in Down Syndrome

    Science.gov (United States)

    Rachidi, Mohammed; Lopes, Carmela

    2010-01-01

    Down syndrome, the most common genetic cause of intellectual disability, is associated with brain disorders due to chromosome 21 gene overdosage. Molecular and cellular mechanisms involved in the neuromorphological alterations and cognitive impairments are reported herein in a global model. Recent advances in Down syndrome research have lead to…

  6. Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

    Science.gov (United States)

    Popov, Dmitri

    Key Words: Aplastic Anemia (AA), Pluripotential Stem Cells (PSC) Introduction: Aplastic Anemia (AA) is a disorder of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. The etiology of AA include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-proliferative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodskyet al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation-Acquired Aplastic Anemia) is the acute toxic syndrome which usually occurs with a dose of irradiation between 0.7 and 10 Gy (70- 1000 rads), depending on the species irradiated. [Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of bone marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and other specific toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders, in cases such as the acute radiation-acquired form of AA. AA results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit{granulocyte-macrophage (CFU-GM) and burst forming unit {erythroid (BFU{E) are reduced markedly in patients with AA. [Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally

  7. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes

    Directory of Open Access Journals (Sweden)

    Birch Rachael

    2010-05-01

    Full Text Available Abstract Background Prader-Willi syndrome (PWS and Angelman syndrome (AS are clinically distinct neurodevelopmental genetic disorders that map to 15q11-q13. The primary phenotypes are attributable to loss of expression of imprinted genes within this region which can arise by means of a number of mechanisms. The most sensitive single approach to diagnosing both PWS and AS is to study methylation patterns within 15q11-q13; however many techniques exist for this purpose. Given the diversity of techniques available, there is a need for consensus testing and reporting guidelines. Methods Testing and reporting guidelines have been drawn up and agreed in accordance with the procedures of the UK Clinical Molecular Genetics Society and the European Molecular Genetics Quality Network. Results A practical set of molecular genetic testing and reporting guidelines has been developed for these two disorders. In addition, advice is given on appropriate reporting policies, including advice on test sensitivity and recurrence risks. In considering test sensitivity, the possibility of differential diagnoses is discussed. Conclusion An agreed set of practice guidelines has been developed for the diagnostic molecular genetic testing of PWS and AS.

  8. Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

    DEFF Research Database (Denmark)

    Krejsgaard, T; Gjerdrum, L M; Ralfkiaer, E

    2008-01-01

    Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3...... in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress...... the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF...

  9. Chemical and molecular factors in irritable bowel syndrome: current knowledge, challenges, and unanswered questions.

    Science.gov (United States)

    Camilleri, Michael; Oduyebo, Ibironke; Halawi, Houssam

    2016-11-01

    Several chemical and molecular factors in the intestine are reported to be altered and to have a potentially significant role in irritable bowel syndrome (IBS), particularly in IBS with diarrhea. These include bile acids; short-chain fatty acids; mucosal barrier proteins; mast cell products such as histamine, proteases, and tryptase; enteroendocrine cell products; and mucosal mRNAs, proteins, and microRNAs. This article reviews the current knowledge and unanswered questions in the pathobiology of the chemical and molecular factors in IBS. Evidence continues to point to significant roles in pathogenesis of these chemical and molecular mechanisms, which may therefore constitute potential targets for future research and therapy. However, it is still necessary to address the interaction between these factors in the gut and to appraise how they may influence hypervigilance in the central nervous system in patients with IBS. Copyright © 2016 the American Physiological Society.

  10. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome.

    Science.gov (United States)

    Schmidt, Laura S; Linehan, W Marston

    2015-10-01

    Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFβ signalling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease.

  11. Craniofacial development: current concepts in the molecular basis of Treacher Collins syndrome.

    Science.gov (United States)

    van Gijn, Daniel Richard; Tucker, Abigail S; Cobourne, Martyn T

    2013-07-01

    The human face and skull are an elegant example of the anatomical sophistication that results from the interplay between the molecular cascades and the tissue interactions that are necessary for the proper development of the craniofacial complex. When it fails to develop normally the consequences can have life-long implications for the biological, psychological, and aesthetic wellbeing of an affected person. Among the many syndromes that affect the region, understanding of the biology that underlies Treacher Collins syndrome has advanced in the last decade, particularly concerning the causative TCOF1 gene that encodes TREACLE protein, a serine/alanine-rich nucleolar phosphoprotein with an essential function during ribosome biogenesis in cranial neural crest cells. Abnormal growth and differentiation of these cells affect much of the craniofacial skeleton. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  12. [Molecular genetics of beta-galactosidase deficiency (GM1-gangliosidosis and Morquio syndrome type B)].

    Science.gov (United States)

    Yoshida, K; Yanagisawa, N

    1993-09-01

    Recent advances in the molecular study of beta-galactosidase deficiency (GM1-gangliosidosis and Morquio syndrome type B) are reviewed. Until now, 14 different mutations have been found in the beta-galactosidase gene in patients with this disorder. Gene mutations are heterogeneous, but common and specific mutations have been identified for three types of protracted clinical course; 51Ile-->Thr mutation for Japanese adult/chronic GM1-gangliosidosis, 201Arg-->Cys for Japanese late infantile/juvenile GM1-gangliosidosis and 273Trp-->Leu for Caucasian Morquio syndrome type B. These phenotype-specific mutant genes produce mutant proteins with significant residual enzyme activity, whereas mutant proteins associated with infantile GM1-gangliosidosis patients show complete loss of enzyme activity. The phenotypic variations of this disorder may be related to different mode of intracellular processing and turnover of mutant enzyme proteins.

  13. [Algorithm for the molecular analysis of Bardet-Biedl syndrome in Spain].

    Science.gov (United States)

    Castro-Sánchez, Sheila; Álvarez-Satta, María; Pereiro, Inés; Piñeiro-Gallego, M Teresa; Valverde, Diana

    2015-08-21

    Bardet-Biedl syndrome (BBS) is a multisystemic genetic disorder, which is not widespread among the Caucasian population, characterized by a highly variable phenotype and great genetic heterogeneity. BBS belongs to a group of diseases called ciliopathies, caused by defects in the structure and/or function of cilia. Due to the diagnostic complexity of the syndrome, the objective of this study was to analyse our whole group of patients in order to create an algorithm to facilitate the routine molecular diagnosis of BBS. We also calculated several epidemiological parameters in our cohort. We analysed 116 BBS patients belonging to 89 families from the whole Spanish geography. All probands fulfilled diagnosis criteria established for BBS. For this, we used: genotyping microarray, direct sequencing and homozygosis mapping (in consanguineous families). By means of the different approaches, it was possible to diagnose 47% of families (21% by genotyping microarray, 18% by direct sequencing of predominant BBS genes, and 8% by homozygosis mapping). With regard to epidemiological data, a prevalence value of 1:407,000 was obtained for BBS in Spain, and a sex ratio of 1.4:1 (men:women). The proposed algorithm, based on the analysis of predominant BBS genes combined with homozygosis mapping, allowed us to confirm the molecular diagnosis in a significant percentage of families with clinically suspected BBS. This diagnostic algorithm will be useful for the improvement of the efficiency of molecular analysis in BBS. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  14. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients

    Energy Technology Data Exchange (ETDEWEB)

    Juyal, R.C.; Figuera, L.E.; Hauge, X. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1996-05-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

  15. Molecular genetics of experimental hypertension and the metabolic syndrome: from gene pathways to new therapies

    Czech Academy of Sciences Publication Activity Database

    Pravenec, Michal; Kurtz, T. W.

    2007-01-01

    Roč. 49, č. 5 (2007), s. 941-952 ISSN 0194-911X R&D Projects: GA MZd(CZ) NR8545; GA ČR(CZ) GA301/04/0390; GA ČR(CZ) GA301/06/0028 Grant - others:The Howard Hughes Institute(US) HHMI55005624 Institutional research plan: CEZ:AV0Z50110509 Keywords : SHR * CD36 * metabolic syndrome Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.194, year: 2007

  16. Unraveling molecular pathways shared by Kabuki and Kabuki-like syndromes.

    Science.gov (United States)

    Lintas, C; Persico, A M

    2017-01-31

    Kabuki syndrome (KS) is a rare genetic syndrome characterized by a typical facial gestalt, variable degrees of intellectual disability, organ malformations, postnatal growth retardation and skeletal abnormalities. So far, KMT2D or KDM6A mutation has been identified as the main cause of KS, accounting for 56%-75% and 3%-8% of cases, respectively. Patients without mutations in 1 of the 2 causative KS genes are often referred to as affected by Kabuki-like syndrome. Overall, they represent approximately 30% of KS cases, pointing toward substantial genetic heterogeneity for this condition. Here, we review all currently available literature describing KS-like phenotypes (or phenocopies) associated with genetic variants located in loci different from KMT2D and KDM6A . We also report on a new KS phenocopy harboring a 5 Mb de novo deletion in chr10p11.22-11.21. An enrichment analysis aimed at identifying functional Gene Ontology classes shared by the 2 known KS causative genes and by new candidate genes currently associated with KS-like phenotypes primarily converges upon abnormal chromatin remodeling and transcriptional dysregulation as pivotal to the pathophysiology of KS phenotypic hallmarks. The identification of mutations in genes belonging to the same functional pathways of KMT2D and KDM6A can help design molecular screenings targeted to KS-like phenotypes. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Molecular biology of multiple organ dysfunction syndrome: injury, adaptation, and apoptosis.

    Science.gov (United States)

    Cobb, J P; Buchman, T G; Karl, I E; Hotchkiss, R S

    2000-01-01

    Injury will equal or surpass communicable disease in the year 2020 as the number one cause of lost disability-adjusted life-years worldwide. The major cause of "late death" after trauma is organ dysfunction, commonly as a complication of shock or sepsis. The pathophysiology of injury-induced organ dysfunction is poorly characterized but has been linked to systemic inflammation as a result of infection (either obvious or occult) or massive tissue injury (systemic inflammatory response syndrome, SIRS). Subsequent complications of organ dysfunction, including death, may also stem from immunosuppression characteristic of what has been called the counter-regulatory anti-inflammatory response syndrome (CARS). At the cellular level, injurious stimuli trigger adaptive stress responses that include changes in gene expression. Multiple organ dysfunction syndrome (MODS) is the summation of these stress responses to severe systemic injury, integrated at the cellular, organ, and host levels. We hypothesize that a complete understanding at the molecular level of the stress responses induced by injury will aid in the development of therapeutic strategies for treating MODS in the critically ill surgical patient. This paper reviews recent data from our Cellular Injury and Adaptation Laboratory relevant to our understanding of MODS pathophysiology, particularly as it relates to stress-induced cell death by apoptosis. Our data suggest that inhibition of stress-induced apoptosis may improve survival after severe injury.

  18. Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome

    Directory of Open Access Journals (Sweden)

    Ruimin Qiao

    2015-06-01

    Full Text Available Microtia is a congenital malformation of the outer ears. Although both genetic and environmental components have been implicated in microtia, the genetic causes of this innate disorder are poorly understood. Pigs have naturally occurring diseases comparable to those in humans, providing exceptional opportunity to dissect the molecular mechanism of human inherited diseases. Here we first demonstrated that a truncating mutation in HOXA1 causes a monogenic disorder of microtia in pigs. We further performed RNA sequencing (RNA-Seq analysis on affected and healthy pig embryos (day 14.25. We identified a list of 337 differentially expressed genes (DEGs between the normal and mutant samples, shedding light on the transcriptional network involving HOXA1. The DEGs are enriched in biological processes related to cardiovascular system and embryonic development, and neurological, renal and urological diseases. Aberrant expressions of many DEGs have been implicated in human innate deformities corresponding to microtia-associated syndromes. After applying three prioritizing algorithms, we highlighted appealing candidate genes for human microtia from the 337 DEGs. We searched for coding variants of functional significance within six candidate genes in 147 microtia-affected individuals. Of note, we identified one EVC2 non-synonymous mutation (p.Asp1174Asn as a potential disease-implicating variant for a human microtia-associated syndrome. The findings advance our understanding of the molecular mechanisms underlying human microtia, and provide an interesting example of the characterization of human disease-predisposing variants using pig models.

  19. The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders

    Science.gov (United States)

    2014-01-01

    Background Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome. Results Here we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addressed to advance toward human clinical trials are specificity, toxicity, and delivery. Conclusions Artificial transcription factors have the potential to address these concerns on a level that meets and in some cases exceeds current small molecule therapies. We examine the possibilities of such approaches in the context of Angelman syndrome, as a template for other single-gene, neurologic disorders. PMID:24946931

  20. Direct immunofluorescence testing in the diagnosis of immunobullous disease, collagen vascular disease, and vascular injury syndromes.

    Science.gov (United States)

    Magro, Cynthia M; Roberts-Barnes, Jennifer; Crowson, A Neil

    2012-10-01

    Direct and indirect immunofluorescence (IF) plays a role in the evaluation of immunobullous diseases and their mimics, and in the investigation of vascular injury syndromes and autoimmune connective tissue disease (CTD). IF mapping may be an important adjunct in the assessment of congenital epidermolysis bullosa syndromes and in Alport disease, in which antibodies are directed at certain components of the basement membrane zone to assay for their deficiency. In many cases of immunobullous and autoimmune CTDs, correlation with direct IF results is useful and often decisive in lesional evaluation and thus in patient management. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. A molecular and histological characterization of cartilage from patients with Morquio syndrome.

    Science.gov (United States)

    De Franceschi, L; Roseti, L; Desando, G; Facchini, A; Grigolo, B

    2007-11-01

    To investigate the gene expression profile and the histological aspects of articular cartilage of patients affected by Morquio syndrome, a lysosomal storage disease characterized by the accumulation of glycosaminoglycans within the cells which result in abnormal formation and growth of the skeletal system. Articular cartilage samples were obtained from the femoral condyle of two siblings with Morquio syndrome during surgery performed to treat valgus knee. As controls, four biopsy samples of healthy cartilage were obtained from four different male multiorgan donors. A Real-Time Polymerase Chain reaction (RT-PCR) analysis was performed to evaluate the expression of type I and II collagens and aggrecan mRNAs. Histological and immunohistochemical analyses for some matrix proteins were carried out on paraffin embedded sections. Type I collagen mRNA mean level was higher in the samples of patients with Morquio syndrome compared to controls. Type II collagen and aggrecan mRNAs' mean expression was instead lower. The morphological appearance of the cartilage showed a poorly organized tissue structure with not homogeneously distributed cells that were larger compared to normal chondrocytes due to the presence inside the vacuoles of proteoglycans which were not metabolized. Chondrocytes were negative for collagen II immunostaining while the extracellular matrix was weakly positive. Collagen type I immunostaining was positive at cellular level. Keratan sulfate showed diffuse positivity and chondroitin-6-sulfate was present throughout the cartilaginous thickness. In cartilage of patients with Morquio syndrome, a low expression of collagen type II and a high expression of collagen type I both at protein and molecular levels are evidentiated. This finding could give evidence of the reduction in ankle and knee joint movement observable in these patients.

  2. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    Science.gov (United States)

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions. © The Author 2015. Published by Oxford University Press.

  3. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients.

    Science.gov (United States)

    Vincent, Marie; Geneviève, David; Ostertag, Agnès; Marlin, Sandrine; Lacombe, Didier; Martin-Coignard, Dominique; Coubes, Christine; David, Albert; Lyonnet, Stanislas; Vilain, Catheline; Dieux-Coeslier, Anne; Manouvrier, Sylvie; Isidor, Bertrand; Jacquemont, Marie-Line; Julia, Sophie; Layet, Valérie; Naudion, Sophie; Odent, Sylvie; Pasquier, Laurent; Pelras, Sybille; Philip, Nicole; Pierquin, Geneviève; Prieur, Fabienne; Aboussair, Nisrine; Attie-Bitach, Tania; Baujat, Geneviève; Blanchet, Patricia; Blanchet, Catherine; Dollfus, Hélène; Doray, Bérénice; Schaefer, Elise; Edery, Patrick; Giuliano, Fabienne; Goldenberg, Alice; Goizet, Cyril; Guichet, Agnès; Herlin, Christian; Lambert, Laetitia; Leheup, Bruno; Martinovic, Jelena; Mercier, Sandra; Mignot, Cyril; Moutard, Marie-Laure; Perez, Marie-José; Pinson, Lucile; Puechberty, Jacques; Willems, Marjolaine; Randrianaivo, Hanitra; Szakszon, Kateline; Szaskon, Kateline; Toutain, Annick; Verloes, Alain; Vigneron, Jacqueline; Sanchez, Elodie; Sarda, Pierre; Laplanche, Jean-Louis; Collet, Corinne

    2016-01-01

    Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

  4. Ellis-van Creveld syndrome: prenatal diagnosis, molecular analysis and genetic counseling.

    Science.gov (United States)

    Chen, Chih-Ping; Su, Yi-Ning; Hsu, Chin-Yuan; Chern, Schu-Rern; Tsai, Fuu-Jen; Wu, Pei-Chen; Chen, Po-Tsang; Wang, Wayseen

    2010-12-01

    To present the perinatal findings and molecular genetic analysis of two siblings with Ellis-van Creveld (EvC) syndrome. A 33-year-old woman, gravida 3, para 1, was referred for genetic counseling at 18 gestational weeks because of recurrent fetal skeletal dysplasia. Two years previously, she had delivered a 1,316-g dead male baby at 28 gestational weeks with a karyotype of 46,XY, postaxial polydactyly of the hands, thoracic narrowness, endocardial cushion defects, transposition of the great arteries, shortening of the long bones, malposition of the toes, and hypoplastic nails. During this pregnancy, prenatal ultrasound at 18 gestational weeks revealed shortening of the long bones (equivalent to 15 weeks), postaxial polydactyly of both hands, thoracic narrowness, and endocardial cushion defects. The pregnancy was subsequently terminated, and a 236-g female fetus was delivered with a karyotype of 46,XX, postaxial polydactyly of the hands, thoracic dysplasia, endocardial cushion defects, shortening of the long bones, and malposition of the toes and hypoplastic nails. The phenotype of each of the two siblings was consistent with EVC syndrome. Molecular analysis of the EVC and EVC2 genes revealed heterozygous mutations in the EVC2 gene. A heterozygous deletion mutation of a 26-bp deletion of c.871-2_894del26 encompassing the junction between intron 7 and exon 8 of the EVC2 gene was found in the mother and two siblings, and a heterozygous nonsense mutation of c.1195C >T, p.R399X in exon 10 of the EVC2 gene was found in the father and two siblings. Prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert clinicians to the possibility of EvC syndrome and prompt a careful search of hexadactyly of the hands. Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects

  5. Clinical and Molecular Epidemiology of Staphylococcal Toxic Shock Syndrome in the United Kingdom

    Science.gov (United States)

    Sharma, Hema; Smith, Debra; Turner, Claire E.; Game, Laurence; Pichon, Bruno; Hope, Russell; Hill, Robert; Kearns, Angela

    2018-01-01

    Staphylococcal toxic shock syndrome (TSS) was originally described in menstruating women and linked to TSS toxin 1 (TSST-1)–producing Staphylococcus aureus. Using UK national surveillance data, we ascertained clinical, molecular and superantigenic characteristics of TSS cases. Average annual TSS incidence was 0.07/100,000 population. Patients with nonmenstrual TSS were younger than those with menstrual TSS but had the same mortality rate. Children types are strongly associated with the tst+ clonal complex (CC) 30 methicillin-sensitive S. aureus lineage, which accounted for 49.4% of all TSS and produced more TSST-1 and superantigen bioactivity than did tst+ CC30 methicillin-resistant S. aureus strains. Better understanding of this MSSA lineage and infections in children could focus interventions to prevent TSS in the future. PMID:29350159

  6. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes

    DEFF Research Database (Denmark)

    Eggermann, Thomas; Brioude, Frédéric; Russo, Silvia

    2016-01-01

    Beckwith-Wiedemann and Silver-Russell syndromes (BWS/SRS) are two imprinting disorders (IDs) associated with disturbances of the 11p15.5 chromosomal region. In BWS, epimutations and genomic alterations within 11p15.5 are observed in >70% of patients, whereas in SRS they are observed in about 60% ......, the consequences for prenatal genetic testing and counseling and our cumulative experience in dealing with these disorders.European Journal of Human Genetics advance online publication, 28 October 2015; doi:10.1038/ejhg.2015.224....... molecular findings underlying these disorders are a challenge not only for laboratories offering these tests but also for geneticists counseling affected families. The scope of counseling must consider the range of detectable disturbances and their origin, the lack of precise quantitative knowledge...

  7. Ellis-van Creveld Syndrome in Grey Alpine Cattle: Morphologic, Immunophenotypic, and Molecular Characterization.

    Science.gov (United States)

    Muscatello, L V; Benazzi, C; Dittmer, K E; Thompson, K G; Murgiano, L; Drögemüller, C; Avallone, G; Gentile, A; Edwards, J F; Piffer, C; Bolcato, M; Brunetti, B

    2015-09-01

    Ellis-van Creveld (EvC) syndrome is a human autosomal recessive disorder caused by a mutation in either the EVC or EVC2 gene, and presents with short limbs, polydactyly, and ectodermal and heart defects. The aim of this study was to understand the pathologic basis by which deletions in the EVC2 gene lead to chondrodysplastic dwarfism and to describe the morphologic, immunohistochemical, and molecular hallmarks of EvC syndrome in cattle. Five Grey Alpine calves, with a known mutation in the EVC2 gene, were autopsied. Immunohistochemistry was performed on bone using antibodies to collagen II, collagen X, sonic hedgehog, fibroblast growth factor 2, and Ki67. Reverse transcription polymerase chain reaction was performed to analyze EVC1 and EVC2 gene expression. Autopsy revealed long bones that were severely reduced in length, as well as genital and heart defects. Collagen II was detected in control calves in the resting, proliferative, and hypertrophic zones and in the primary and secondary spongiosa, with a loss of labeling in the resting zone of 2 dwarfs. Collagen X was expressed in hypertrophic zone in the controls but was absent in the EvC cases. In affected calves and controls, sonic hedgehog labeled hypertrophic chondrocytes and primary and secondary spongiosa similarly. FGF2 was expressed in chondrocytes of all growth plate zones in the control calves but was lost in most EvC cases. The Ki67 index was lower in cases compared with controls. EVC and EVC2 transcripts were detected. Our data suggest that EvC syndrome of Grey Alpine cattle is a disorder of chondrocyte differentiation, with accelerated differentiation and premature hypertrophy of chondrocytes, and could be a spontaneous model for the equivalent human disease. © The Author(s) 2015.

  8. Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation

    Energy Technology Data Exchange (ETDEWEB)

    Thurman, Ryan D.; Kathir, Karuppanan Muthusamy; Rajalingam, Dakshinamurthy [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States); Kumar, Thallapuranam K. Suresh, E-mail: sthalla@uark.edu [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer The structural basis of the Kallmann syndrome is elucidated. Black-Right-Pointing-Pointer Kallmann syndrome mutation (A168S) induces a subtle conformational change(s). Black-Right-Pointing-Pointer Structural interactions mediated by beta-sheet G are most perturbed. Black-Right-Pointing-Pointer Ligand (FGF)-receptor interaction(s) is completely abolished by Kallmann mutation. Black-Right-Pointing-Pointer Kallmann mutation directly affects the FGF signaling process. -- Abstract: Kallmann syndrome (KS) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia. KS is commonly associated with mutations in the extracellular D2 domain of the fibroblast growth factor receptor (FGFR). In this study, for the first time, the molecular basis for the FGFR associated KS mutation (A168S) is elucidated using a variety of biophysical experiments, including multidimensional NMR spectroscopy. Secondary and tertiary structural analysis using far UV circular dichroism, fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D2 domain of FGFR. Results of isothermal titration calorimetry experiments show the KS mutation causes a 10-fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1) binding. {sup 1}H-{sup 15}N chemical perturbation data suggest that complete loss in the ligand (FGF) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D2 domain of FGFR. The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR.

  9. Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

    Directory of Open Access Journals (Sweden)

    Ritch Robert

    2004-06-01

    Full Text Available Abstract Background Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. Methods We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. Results Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1 probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. Conclusions Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

  10. Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome.

    Science.gov (United States)

    Helgeson, Maria; Keller-Ramey, Jennifer; Knight Johnson, Amy; Lee, Jennifer A; Magner, Daniel B; Deml, Brett; Deml, Jacea; Hu, Ying-Ying; Li, Zejuan; Donato, Kirsten; Das, Soma; Laframboise, Rachel; Tremblay, Sandra; Krantz, Ian; Noon, Sarah; Hoganson, George; Burton, Jennifer; Schaaf, Christian P; Del Gaudio, Daniela

    2018-03-01

    Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.

  11. Unambiguous molecular detections with multiple genetic approach for the complicated chromosome 22q11 deletion syndrome

    Directory of Open Access Journals (Sweden)

    Lin Lung-Huang

    2009-02-01

    Full Text Available Abstract Background Chromosome 22q11 deletion syndrome (22q11DS causes a developmental disorder during the embryonic stage, usually because of hemizygous deletions. The clinical pictures of patients with 22q11DS vary because of polymorphisms: on average, approximately 93% of affected individuals have a de novo deletion of 22q11, and the rest have inherited the same deletion from a parent. Methods using multiple genetic markers are thus important for the accurate detection of these microdeletions. Methods We studied 12 babies suspected to carry 22q11DS and 18 age-matched healthy controls from unrelated Taiwanese families. We determined genomic variance using microarray-based comparative genomic hybridization (array-CGH, quantitative real-time polymerase chain reaction (qPCR and multiplex ligation-dependent probe amplification (MLPA. Results Changes in genomic copy number were significantly associated with clinical manifestations for the classical criteria of 22q11DS using MPLA and qPCR (p Conclusion Both MLPA and qPCR could produce a clearly defined range of deleted genomic DNA, whereas there must be a deleted genome that is not distinguishable using MLPA. These data demonstrate that such multiple genetic approaches are necessary for the unambiguous molecular detection of these types of complicated genomic syndromes.

  12. Molecular cytogenetic detection of chromosome 15 deletions in patients with Prader-Willi and Angelman syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Chadwick, D.E.; Weksberg, R.; Shuman, C. [Hospital for Sick Children, Toronto (Canada)] [and others

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct genetic disorders involving alterations of chromosome 15q11-q13. Approximately 75% of individuals with PWS and AS have deletions within 15q11-q13 by molecular analysis. We have evaluated fluorescence in situ hybridization (FISH) for the clinical laboratory detection of del(15)(q11q13) using the cosmid probes D15S11 and GABRB3 (ONCOR, Gaithersburg, NY). 4/4 PWS and 1/1 AS patients previously identified as having cytogenetic deletions were deleted for both probes. In a prospectively ascertained series of 54 patient samples referred to rule out either PWS or AS, 8 were deleted for D15S11 and GABRB3. In addition, an atypical deletion patient with PWS was also identified who was found to be deleted for GABRB3 but not D15S11. The SNRPN locus was also deleted in this patient. Only 4 of the 9 patient samples having molecular cytogenetic deletions were clearly deleted by high resolution banding (HRB) analysis. The microscopic and submicroscopic deletions have been confirmed by dinucleotide (CA) repeat analysis. Microsatellite polymorphism analysis was also used to demonstrate that five non-deletion patients in this series had biparental inheritance of chromosome 15, including region q11-q13. Deletions were not detected by either HRB, FISH or microsatellite polymorphism analysis in samples obtained from parents of the deletion patients. Methylation studies of chromosome 15q11-q13 are in progress for this series of PWS and AS families. FISH analysis of chromosome 15q11-q13 in patients with PWS and AS is a rapid, sensitive and reliable method for deletion detection.

  13. Molecular and clinical analysis of Ellis-van Creveld syndrome in the United Arab Emirates

    Directory of Open Access Journals (Sweden)

    Rahmani Aiman

    2010-02-01

    Full Text Available Abstract Background Ellis-van Creveld (EvC syndrome is an autosomal recessive chondrodysplastic condition with clinical manifestations that include short-limbs and ribs, postaxial polydactyly and dysplastic nails and teeth. In about two thirds of patients, mutations in either EVC or EVC2 genes have been found to be the underlying cause. Methods In this paper, we describe the molecular (DNA sequencing and clinical analysis of six children diagnosed with EvC from four different families from the United Arab Emirates (UAE. Results All the children had the common clinical and radiological features of this syndrome. However, DNA sequence analysis of the genes shown to be involved (EVC and EVC2 revealed a novel splice site mutation (c.2047-1G>T in intron 13 of EVC2 gene in one family. In addition, we confirm previous mutational analyses that showed a truncating mutation in exon 13 of EVC gene (c.1813C>T; p.Q605X in the second family and a single nucleotide deletion (c.981delG; p.K327fs in exon 8 of EVC2 gene in the third family. No mutations in the exons, splice sites or the promoter regions of either gene have been found in the index case of the fourth family who exhibited "EvC-like" features. Conclusions Given the small population size of UAE, our data illustrates further the molecular heterogeneity observed in EvC patients and excludes the possibility of a common founder effect for this condition in the UAE reflecting the current ethnic diversity of the country.

  14. Molecular and clinical analysis of Ellis-van Creveld syndrome in the United Arab Emirates.

    Science.gov (United States)

    Ali, Bassam R; Akawi, Nadia A; Chedid, Faris; Bakir, Mahmood; Ur Rehman, Moghis; Rahmani, Aiman; Al-Gazali, Lihadh

    2010-02-25

    Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic condition with clinical manifestations that include short-limbs and ribs, postaxial polydactyly and dysplastic nails and teeth. In about two thirds of patients, mutations in either EVC or EVC2 genes have been found to be the underlying cause. In this paper, we describe the molecular (DNA sequencing) and clinical analysis of six children diagnosed with EvC from four different families from the United Arab Emirates (UAE). All the children had the common clinical and radiological features of this syndrome. However, DNA sequence analysis of the genes shown to be involved (EVC and EVC2) revealed a novel splice site mutation (c.2047-1G>T) in intron 13 of EVC2 gene in one family. In addition, we confirm previous mutational analyses that showed a truncating mutation in exon 13 of EVC gene (c.1813C>T; p.Q605X) in the second family and a single nucleotide deletion (c.981delG; p.K327fs) in exon 8 of EVC2 gene in the third family. No mutations in the exons, splice sites or the promoter regions of either gene have been found in the index case of the fourth family who exhibited "EvC-like" features. Given the small population size of UAE, our data illustrates further the molecular heterogeneity observed in EvC patients and excludes the possibility of a common founder effect for this condition in the UAE reflecting the current ethnic diversity of the country.

  15. Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

    Science.gov (United States)

    Mullegama, Sureni V.; Alaimo, Joseph T.; Chen, Li; Elsea, Sarah H.

    2015-01-01

    Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. PMID:25853262

  16. Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Sureni V. Mullegama

    2015-04-01

    Full Text Available Roughly 20% of autism spectrum disorders (ASD are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5 is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention.

  17. Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome.

    Science.gov (United States)

    Huang, Wei-Hsiang; Guenthner, Casey J; Xu, Jin; Nguyen, Tiffany; Schwarz, Lindsay A; Wilkinson, Alex W; Gozani, Or; Chang, Howard Y; Shamloo, Mehrdad; Luo, Liqun

    2016-10-19

    Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1 + or SF1 + cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Molecular Etiology of Hereditary Single-Side Deafness: Its Association With Pigmentary Disorders and Waardenburg Syndrome.

    Science.gov (United States)

    Kim, Shin Hye; Kim, Ah Reum; Choi, Hyun Seok; Kim, Min Young; Chun, Eun Hi; Oh, Seung-Ha; Choi, Byung Yoon

    2015-10-01

    Unilateral sensorineural hearing loss (USNHL)/single-side deafness (SSD) is a frequently encountered disability in children. The etiology of a substantial portion of USNHL/SSD still remains unknown, and genetic causes have not been clearly elucidated. In this study, the authors evaluated the heritability of USNHL/SSD.The authors sequentially recruited 50 unrelated children with SSD. For an etiologic diagnosis, we performed a rigorous review on the phenotypes of family members of all children and conducted, if necessary, molecular genetic tests including targeted exome sequencing of 129 deafness genes.Among the 50 SSD children cohort, the authors identify 4 (8%) unrelated SSD probands from 4 families (SH136, SB173, SB177, and SB199) with another hearing impaired family members. Notably, all 4 probands in our cohort with a familial history of SSD also have pigmentary abnormalities such as brown freckles or premature gray hair within first degree relatives, which may indicate that genes whose products are involved with pigmentary disorder could be candidates for heritable SSD. Indeed, SH136 and SB199 turned out to segregate a mutation in MITF and PAX3, respectively, leading to a molecular diagnosis of Waardenburg syndrome (WS).We report, for the first time in the literature, a significant heritability of pediatric SSD. There is a strong association between the heritability of USNHL/SSD and the pigmentary abnormality, shedding a new light on the understanding of the molecular basis of heritable USNHL/SSD. In case of children with congenital SSD, it would be mandatory to rigorously screen pigmentary abnormalities. WS should also be included in the differential diagnosis of children with USNHL/SSD, especially in a familial form.

  19. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation

    Energy Technology Data Exchange (ETDEWEB)

    Saitoh, S.; Cassidy, S.B.; Conroy, J.M. [Univ. of Hospitals of Cleveland, OH (United States)] [and others

    1997-01-20

    Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences. 49 refs., 4 figs., 3 tabs.

  20. MLPA and cDNA analysis improves COL4A5 mutation detection in X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, JM; Juncker, I; Marcussen, N

    2008-01-01

    for 10-15% of mutations. We have established a method for mutation analysis of COL4A5 based on reverse transcriptase-polymerase chain reaction analysis of mRNA from cultured skin fibroblasts and multiplex ligation-dependent probe amplification (MLPA) on genomic DNA. One advantage of using skin biopsies...

  1. Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies

    Directory of Open Access Journals (Sweden)

    Hager Karl

    2012-04-01

    Full Text Available Abstract Background Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations. Objective To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter, 47,XYY, 48,XXYY and 48,XXXY syndromes. Methods The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117 and 46,XY (n = 206 karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method. Results Receiver operator characteristic (ROC curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96% with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4% had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo. Conclusions Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.

  2. Alterações moleculares em síndrome mielodisplásica Molecular abnormalities in myelodysplastic syndrome

    Directory of Open Access Journals (Sweden)

    Maria de Lourdes L. F. Chauffaille

    2006-09-01

    Full Text Available A síndrome mielodisplásica (SMD representa um grupo heterogêneo de doenças hematopoéticas clonais. As alterações cromossômicas observadas em SMD foram o ponto de partida para uma série de estudos para a caracterização da patogênese molecular nessa doença. A perda de material genético leva à hipótese de inativação de genes supressores tumorais (GST, mas essa teoria não explica o evento inicial desencadeador da vantagem de crescimento das células progenitoras hematopoéticas, estando outros mecanismos envolvidos, dos quais sobressaem a ativação de oncogenes, alteração de vias de sinalização e fatores de transcrição. Mutações de oncogenes, como RAS, P53, PDGF, FLT3 e MLL, dentre outros, podem contribuir para o desenvolvimento da SMD. A mutação em tandem do FLT3 é evento genético tardio no curso da doença e os pacientes portadores da mesma tendem a apresentar prognóstico desfavorável e transformação iminente para leucemia aguda. Tanto aberrações qualitativas como quantitativas de fatores de transcrição induzem o desequilíbrio ou bloqueio de diferenciação da célula hematopoética, que, por sua vez, se traduz em hematopoese ineficaz. Alterações epigenéticas são caracterizadas por metilação de DNA que tem papel no controle da expressão gênica. Hipermetilação e inativação de genes reguladores exercem função no desenvolvimento da doença. SMD de alto risco está associada à elevada prevalência de inativação do gene supressor tumoral p15INK4B por hipermetilação do promotor. Encurtamento do telômero correlaciona-se a cariótipos complexos, indicando instabilidade genômica e pior prognóstico.Myelodysplastic syndrome (MDS is a heterogenous group of clonal hematopoietic disorders. Chromosomal abnormalities detected in this disease were the start to many studies in order to characterize molecular pathogenesis. The loss of genetic material observed in most patients with MDS leads to the

  3. Myhre and LAPS syndromes : clinical and molecular review of 32 patients

    NARCIS (Netherlands)

    Michot, Caroline; Le Goff, Carine; Mahaut, Clementine; Afenjar, Alexandra; Brooks, Alice S.; Campeau, Philippe M.; Destree, Anne; Di Rocco, Maja; Donnai, Dian; Hennekam, Raoul; Heron, Delphine; Jacquemont, Sebastien; Kannu, Peter; Lin, Angela E.; Manouvrier-Hanu, Sylvie; Mansour, Sahar; Marlin, Sandrine; McGowan, Ruth; Murphy, Helen; Raas-Rothschild, Annick; Rio, Marlene; Simon, Marleen; Stolte-Dijkstra, Irene; Stone, James R.; Sznajer, Yves; Tolmie, John; Touraine, Renaud; van den Ende, Jenneke; Van der Aa, Nathalie; van Essen, Ton; Verloes, Alain; Munnich, Arnold; Cormier-Daire, Valerie

    2014-01-01

    Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy,

  4. Myhre and LAPS syndromes: clinical and molecular review of 32 patients

    NARCIS (Netherlands)

    Michot, Caroline; Le Goff, Carine; Mahaut, Clémentine; Afenjar, Alexandra; Brooks, Alice S.; Campeau, Philippe M.; Destree, Anne; Di Rocco, Maja; Donnai, Dian; Hennekam, Raoul; Heron, Delphine; Jacquemont, Sébastien; Kannu, Peter; Lin, Angela E.; Manouvrier-Hanu, Sylvie; Mansour, Sahar; Marlin, Sandrine; McGowan, Ruth; Murphy, Helen; Raas-Rothschild, Annick; Rio, Marlène; Simon, Marleen; Stolte-Dijkstra, Irene; Stone, James R.; Sznajer, Yves; Tolmie, John; Touraine, Renaud; van den Ende, Jenneke; van der Aa, Nathalie; van Essen, Ton; Verloes, Alain; Munnich, Arnold; Cormier-Daire, Valérie

    2014-01-01

    Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy,

  5. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  6. Cytogenetic and molecular characterization of 57 individuals with the Parder-Willi syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Butler, M.G.; Forrest, K.B.; Miller, L.K. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

    1994-09-01

    Prader-Willi syndrome (PWS) is characterized by hypotonia, early childhood obesity, mental deficiency, hypogonadism and an interstitial deletion of 15q11q13 of paternal origin in 50-70% of patients. The remaining patients have either submicroscopic deletions, maternal disomy or other anomalies of chromosome 15. We have undertaken cytogenetic and molecular genetic studies of 57 individuals presenting with features consistent with PWS (28 males and 29 females; age range of 3 months to 38 years), 25 with recognizable 15q11q13 deletions (44%), 28 with normal appearing chromosomes (49%), and four patients with other chromosome 15 anomalies (7%). High resolution chromosome analysis and PCR amplification were performed utilizing 17 STRs from 15q11q13 region, quantitative Southern hybridization using seven 15q11q13 probes, and fluorescence in situ hybridization (FISH) using four 15q11q13 probes (4-3R, SNRPN, 3-21, and GABRB3). The cytogenetic deletion was paternal in all PWS families studied but the deletion varied in size in 10 patients. Parental DNA studies from 20 of 28 non-deletion patients showed maternal disomy in 7 patients and biparental inheritance in 13 non-deletion patients. In order to evaluate for submicroscopic deletions, PCR amplification with several loci in the area of the PWS minimal critical region, FISH using SNRPN and quantitative hybridization using a PCR product generated from primers of exons E and H of the SNRPN gene were undertaken on the non-deletion patients. Quantitative hybridization and FISH using SNRPN from 3 of 11 non-deletion patients (excluding maternal disomy cases) showed a submicroscopic deletion. One of these patients also showed a paternal deletion of D15S128 and MN1. We furthur support the use of both cytogenetic and molecular genetic methods for determining the genetic status of PWS patients.

  7. CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study.

    Science.gov (United States)

    Del Giudice, Ennio; Macca, Marina; Imperati, Floriana; D'Amico, Alessandra; Parent, Philippe; Pasquier, Laurent; Layet, Valerie; Lyonnet, Stanislas; Stamboul-Darmency, Veronique; Thauvin-Robinet, Christel; Franco, Brunella

    2014-05-10

    Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.

  8. Evolutionary and molecular analysis of the emergent severe fever with thrombocytopenia syndrome virus.

    Science.gov (United States)

    Lam, Tommy Tsan-Yuk; Liu, Wei; Bowden, Thomas A; Cui, Ning; Zhuang, Lu; Liu, Kun; Zhang, Yao-Yun; Cao, Wu-Chun; Pybus, Oliver G

    2013-03-01

    In 2009, a novel Bunyavirus, called severe fever with thrombocytopenia syndrome virus (SFTSV) was identified in the vicinity of Huaiyangshan, China. Clinical symptoms of this zoonotic virus included severe fever, thrombocytopenia, and leukocytopenia, with a mortality rate of ~10%. By the end of 2011 the disease associated with this pathogen had been reported from eleven Chinese provinces and human-to-human transmission suspected. However, current understanding of the evolution and molecular epidemiology of SFTSV before and after its identification is limited. To address this we undertake phylogenetic, evolutionary and structural analyses of all available SFTSV genetic sequences, including a new SFTSV complete genome isolated from a patient from Henan in 2011. Our discovery of a mosaic L segment sequence, which is descended from two major circulating lineages of SFTSV in China, represents the first evidence that homologous recombination plays a role in SFTSV evolution. Selection analyses indicate that negative selection is predominant in SFTSV genes, yet differences in selective forces among genes are consistent between Phlebovirus species. Further analysis reveals structural conservation between SFTSV and Rift Valley fever virus in the residues of their nucleocapsids that are responsible for oligomerisation and RNA-binding, suggesting the viruses share similar modes of higher-order assembly. We reconstruct the epidemic history of SFTSV using molecular clock and coalescent-based methods, revealing that the extant SFTSV lineages originated 50-150 years ago, and that the viral population experienced a recent growth phase that concurs with and extends the earliest serological reports of SFTSV infection. Taken together, our combined structural and phylogenetic analyses shed light into the evolutionary behaviour of SFTSV in the context of other, better-known, pathogenic Phleboviruses. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome.

    Science.gov (United States)

    Avagliano, Laura; Grazioli, Paolo; Mariani, Milena; Bulfamante, Gaetano P; Selicorni, Angelo; Massa, Valentina

    2017-11-21

    Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome.

  10. Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome

    Directory of Open Access Journals (Sweden)

    Laura Avagliano

    2017-11-01

    Full Text Available Abstract Cornelia de Lange Syndrome (CdLS is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development in patients with Cornelia de Lange Syndrome.

  11. Molecular analysis of DiGeorge Syndrome-related translocation breakpoints in 22q11.2

    Energy Technology Data Exchange (ETDEWEB)

    Chieffo, C.; Barnoski, B.L.; Emanuel, B.S. [Children`s Hospital of Philadelphia, PA (United States)] [and others

    1994-09-01

    22q11 demonstrates a high frequency of disease-specific rearrangements. Several of the rearrangements are associated with developmental abnormalities such as DiGeorge Syndrome (DGS), Velocardiofacial Syndrome (VCFS), Cat Eye Syndrome (CES) and Supernumerary der(22)t(11;22) Syndrome. DGS and VCFS involve deletions of 22q11.2 resulting from unbalanced translocations or microdeletions. In contrast, CES and Supernumerary der(22)t(11;22) Syndrome result from duplications of this region via inter- or intra- chromosomal exchange. Although the molecular mechanism giving rise to these rearrangements has yet to be elucidated, the presence of known 22q11 repetitive elements are likely to be involved. GM5878 is a 46,XY,t(10;22) cell line from a balanced translocation carrier father of an unbalanced DGS patient. GM0980 is a cell line from a patient with features of DGS/VCFS with an unbalanced karyotype. Using FISH cosmids, we have localized these translocation breakpoints near pH160b (D22S66) which maps to the center of the DiGeorge chromosomal region (DGCR). To further localize the breakpoint of GM5878, overlapping cosmids spanning this region were used as probes for FISH. Use of additional overlapping cosmids allowed the sublocalization of the breakpoint to a 10kb region. A 4.8 kb BglII fragment predicted to cross the breakpoint was isolated. When this fragment was used as a probe to normal and GM5878 DNA, novel bands were detected in GM5878 DNA digested with EcoRI and BglII. Similar analysis of the GM0980 breakpoint is being pursued. Full molecular characterization of these translocations is in progress using inverse PCR to clone the junctional fragments for sequencing. Detailed analysis of the region may reveal molecular features which make this a rearrangement prone area of the genome and help elucidate its relationship to human cytogenetic disease.

  12. Molecular Characterization of Peripheral Extracellular Vesicles in Clinically Isolated Syndrome: Preliminary Suggestions from a Pilot Study

    Directory of Open Access Journals (Sweden)

    Nicoletta Nuzziello

    2017-09-01

    Full Text Available Extracellular vesicles (EVs, nanoparticles originated from different cell types, seem to be implicated in several cellular activities. In the Central Nervous System (CNS, glia and neurons secrete EVs and recent studies have demonstrated that the intercellular communication mediated by EVs has versatile functional impact in the cerebral homeostasis. This essential role may be due to their proteins and RNAs cargo that possibly modify the phenotypes of the targeted cells. Despite the increasing importance of EVs, little is known about their fluctuations in physiological as well as in pathological conditions. Furthermore, only few studies have investigated the contents of contemporary EVs subgroups (microvesicles, MVs and exosomes, EXOs with the purpose of discriminating between their features and functional roles. In order to possibly shed light on these issues, we performed a pilot study in which MVs and EXOs extracted from serum samples of a little cohort of subjects (patients with the first clinical evidence of CNS demyelination, also known as Clinically Isolated Syndrome and Healthy Controls were submitted to deep small-RNA sequencing. Data were analysed by an in-home bioinformatics platform. In line with previous reports, distinct classes of non-coding RNAs have been detected in both the EVs subsets, offering interesting suggestions on their origins and functions. We also verified the feasibility of this extensive molecular approach, thus supporting its valuable use for the analysis of circulating biomarkers (e.g., microRNAs in order to investigate and monitor specific diseases.

  13. Molecular targets for the therapy of cancer associated with metabolic syndrome (transcription and growth factors).

    Science.gov (United States)

    Yunusova, Natalia V; Kondakova, Irina V; Kolomiets, Larisa A; Afanas'ev, Sergey G; Chernyshova, Alena L; Kudryavtsev, Igor V; Tsydenova, Anastasia A

    2017-11-08

    Metabolic syndrome (MS) is one of the leading risk factors for the development of cardiovascular diseases, type II diabetes mellitus and reproductive system diseases. Currently, not only cardiovascular disease and reproductive history risks related with MS are frequently discussed, but it has been also shown that MS is associated with increased risk of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer, biliary tract cancers and liver cancer for men). Further studies are required to understand the mechanisms of the involvement of MS components in the pathogenesis of malignant neoplasms. Changes in the expression of transcription and growth factors in the peripheral tissues as well as in cancer tissues of patients with MS were revealed. Transcription factors (AMP-activated protein kinase-1, STAT3, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-γ), leptin and adiponectin receptors seem to be the most promising molecular targets for the therapy of cancers associated with MS. © 2017 John Wiley & Sons Australia, Ltd.

  14. Trapped neutrophil syndrome in a Border Collie dog: clinical, clinico-pathologic, and molecular findings.

    Science.gov (United States)

    Mizukami, Keijiro; Shoubudani, Tomoaki; Nishimoto, Seira; Kawamura, Ryuta; Yabuki, Akira; Yamato, Osamu

    2012-06-01

    Trapped neutrophil syndrome (TNS) is an autosomal recessive inherited neutropenia known in Border Collies since the 1990's. Recently, the causative mutation has been identified in the canine VPS13B gene and a DNA-based diagnosis has now become available. The present paper describes clinical and clinico-pathologic findings in a Border Collie with TNS that was molecularly diagnosed for the first time in Japan. In a 10-week-old male Border Collie with microgenesis and symptoms related to recurrent infections, a hematological examination revealed severe leukopenia due to neutropenia, suggesting the dog to be affected by inherited neutropenic immunodeficiency. Direct DNA sequencing demonstrated that the dog was homozygous for the causative mutation of TNS and both its parents were heterozygous carriers. In addition, a simple and rapid polymerase chain reaction-based length polymorphism analysis coupled with microchip electrophoresis was developed for the genotyping of TNS. This assay could discriminate clearly all genotypes, suggesting that it was suitable for both individual diagnosis and large-scale surveys for prevention.

  15. PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome.

    Science.gov (United States)

    Jurkowski, W; Roomp, K; Crespo, I; Schneider, J G; Del Sol, A

    2011-08-11

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ-RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network.

  16. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Directory of Open Access Journals (Sweden)

    Pavan Kumar P

    2014-03-01

    Full Text Available TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  17. TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome.

    Science.gov (United States)

    Kumar P, Pavan; Franklin, Sarah; Emechebe, Uchenna; Hu, Hao; Moore, Barry; Lehman, Chris; Yandell, Mark; Moon, Anne M

    2014-03-01

    TBX3 is a member of the T-box family of transcription factors with critical roles in development, oncogenesis, cell fate, and tissue homeostasis. TBX3 mutations in humans cause complex congenital malformations and Ulnar-mammary syndrome. Previous investigations into TBX3 function focused on its activity as a transcriptional repressor. We used an unbiased proteomic approach to identify TBX3 interacting proteins in vivo and discovered that TBX3 interacts with multiple mRNA splicing factors and RNA metabolic proteins. We discovered that TBX3 regulates alternative splicing in vivo and can promote or inhibit splicing depending on context and transcript. TBX3 associates with alternatively spliced mRNAs and binds RNA directly. TBX3 binds RNAs containing TBX binding motifs, and these motifs are required for regulation of splicing. Our study reveals that TBX3 mutations seen in humans with UMS disrupt its splicing regulatory function. The pleiotropic effects of TBX3 mutations in humans and mice likely result from disrupting at least two molecular functions of this protein: transcriptional regulation and pre-mRNA splicing.

  18. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

    Science.gov (United States)

    Nunn, Laurence M; Lopes, Luis R; Syrris, Petros; Murphy, Cian; Plagnol, Vincent; Firman, Eileen; Dalageorgou, Chrysoula; Zorio, Esther; Domingo, Diana; Murday, Victoria; Findlay, Iain; Duncan, Alexis; Carr-White, Gerry; Robert, Leema; Bueser, Teofila; Langman, Caroline; Fynn, Simon P; Goddard, Martin; White, Anne; Bundgaard, Henning; Ferrero-Miliani, Laura; Wheeldon, Nigel; Suvarna, Simon K; O'Beirne, Aliceson; Lowe, Martin D; McKenna, William J; Elliott, Perry M; Lambiase, Pier D

    2016-06-01

    The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  19. Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

    Directory of Open Access Journals (Sweden)

    Ashwin Unnikrishnan

    2017-07-01

    Full Text Available Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5 signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.

  20. Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate.

    Directory of Open Access Journals (Sweden)

    Gerson Shigeru Kobayashi

    Full Text Available Non-syndromic cleft lip/palate (NSCL/P is a complex, frequent congenital malformation, determined by the interplay between genetic and environmental factors during embryonic development. Previous findings have appointed an aetiological overlap between NSCL/P and cancer, and alterations in similar biological pathways may underpin both conditions. Here, using a combination of transcriptomic profiling and functional approaches, we report that NSCL/P dental pulp stem cells exhibit dysregulation of a co-expressed gene network mainly associated with DNA double-strand break repair and cell cycle control (p = 2.88×10(-2-5.02×10(-9. This network included important genes for these cellular processes, such as BRCA1, RAD51, and MSH2, which are predicted to be regulated by transcription factor E2F1. Functional assays support these findings, revealing that NSCL/P cells accumulate DNA double-strand breaks upon exposure to H2O2. Furthermore, we show that E2f1, Brca1 and Rad51 are co-expressed in the developing embryonic orofacial primordia, and may act as a molecular hub playing a role in lip and palate morphogenesis. In conclusion, we show for the first time that cellular defences against DNA damage may take part in determining the susceptibility to NSCL/P. These results are in accordance with the hypothesis of aetiological overlap between this malformation and cancer, and suggest a new pathogenic mechanism for the disease.

  1. Proteomics of follicular fluid from women with polycystic ovary syndrome suggests molecular defects in follicular development.

    Science.gov (United States)

    Ambekar, Aditi S; Kelkar, Dhanashree S; Pinto, Sneha M; Sharma, Rakesh; Hinduja, Indira; Zaveri, Kusum; Pandey, Akhilesh; Prasad, T S Keshava; Gowda, Harsha; Mukherjee, Srabani

    2015-02-01

    Polycystic ovary syndrome (PCOS), a major cause of anovulatory infertility, is characterized by arrested follicular growth. Altered protein levels in the follicular fluid surrounding the ovum may reflect the molecular defects of folliculogenesis in these women. To identify differentially regulated proteins in PCOS by comparing the follicular fluid protein repertoire of PCOS with healthy women. The follicular fluid samples were collected from PCOS and normo-ovulatory women undergoing in vitro fertilization. Follicular fluid proteins were subjected to digestion using trypsin, and resultant peptides were labeled with isobaric tags for relative and absolute quantification reagents and analyzed by liquid chromatography tandem mass spectrometry. Differential abundance of selected proteins was confirmed by ELISA. A total of 770 proteins were identified, of which 186 showed differential abundance between controls and women with PCOS. Proteins involved in various processes of follicular development including amphiregulin; heparan sulfate proteoglycan 2; tumor necrosis factor, α-induced protein 6; plasminogen; and lymphatic vessel endothelial hyaluronan receptor 1 were found to be deregulated in PCOS. We also identified a number of new proteins from follicular fluid, whose function in the ovary is not yet clearly established. These include suprabasin; S100 calcium binding protein A7; and helicase with zinc finger 2, transcriptional coactivator. Proteins indispensable for follicular growth were found to be differentially expressed in follicular fluid of women with PCOS, which may in part explain the aberrant folliculogenesis observed in these women.

  2. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome

    Science.gov (United States)

    Hanakawa, Yasushi; Schechter, Norman M.; Lin, Chenyan; Garza, Luis; Li, Hong; Yamaguchi, Takayuki; Fudaba, Yasuyuki; Nishifuji, Koji; Sugai, Motoyuki; Amagai, Masayuki; Stanley, John R.

    2002-01-01

    Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis. PMID:12093888

  3. Molecular pathogenesis of Spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins

    Science.gov (United States)

    Bin, Bum-Ho; Hojyo, Shintaro; Hosaka, Toshiaki; Bhin, Jinhyuk; Kano, Hiroki; Miyai, Tomohiro; Ikeda, Mariko; Kimura-Someya, Tomomi; Shirouzu, Mikako; Cho, Eun-Gyung; Fukue, Kazuhisa; Kambe, Taiho; Ohashi, Wakana; Kim, Kyu-Han; Seo, Juyeon; Choi, Dong-Hwa; Nam, Yeon-Ju; Hwang, Daehee; Fukunaka, Ayako; Fujitani, Yoshio; Yokoyama, Shigeyuki; Superti-Furga, Andrea; Ikegawa, Shiro; Lee, Tae Ryong; Fukada, Toshiyuki

    2014-01-01

    The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS. PMID:25007800

  4. Cytological and molecular studies of chromosomal radiosensitivity in Down Syndrome cells

    International Nuclear Information System (INIS)

    MacLaren, R.A.

    1988-01-01

    Molecular, cellular and cytogenetic studies were conducted to determine if altered levels of poly(ADP-ribose) polymerase, a DNA repair-related enzyme, is responsible for the reported formation of excess X-ray induced chromosome aberrations in cells derived from Down Syndrome (DS) patients. Nonstimulated lymphocytes from normal and DS subjects were pretreated with 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase, for 30 minutes before exposure to X-rays and the levels of induced chromosome aberrations were determined in mitotic cells. DS lymphocytes exhibited significantly higher frequencies of chromosome aberrations in the presence of 3-aminobenzamide that normal lymphocytes. No difference was observed in the absence of 3-aminobenzamide. Additional studies were done using normal and DS lymphoblastoid cell lines which exhibited a similar response at the DNA level as the lymphocytes. Analysis of poly(ADP-ribose) polymerase activity based on incorporation of the substrate, NAD + , into acid insoluble materials, revealed that there was no significant difference in the ability to form poly (ADP-ribose) in the DS or normal cells. 3-aminobenzamide effectively inhibited poly(ADP-ribose) polymerase in both the normal and DS cells

  5. Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Mastroianni, N.; De Fusco, M.; Casari, G. [Univsersita` di Milano (Italy)] [and others

    1996-11-01

    A hereditary defect of the distal tubule accounts for the clinical features of Gitelman syndrome (GS), an autosomal recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Recently, we cloned the cDNA coding for the human Na-Cl thiazide-sensitive cotransporter (TSC; also known as {open_quotes}NCCT{close_quotes} or {open_quotes}SLC12A3{close_quotes}) as a possible candidate for GS, and Simon et al., independently, described rotation in patients with GS. Now, we show 12 additional mutations consistent with a loss of function of the Na-Cl cotransporter in GS. Two missense replacements, R09W and P349L, are common to both studies and could represent ancient mutations. The other mutations include three deletions, two insertions, and six missense mutations. When all mutations from both studies are considered, missense mutations seem to be more frequently localized within the intracellular domains of the molecule, rather than in transmembrane or extracellular domains. One family, previously reported as a GS form with dominant inheritance, has proved to be recessive, with the affected child being a compound heterozygote. A highly informative intragenic tetranucleotide marker, useful for molecular diagnostic studies, has been identified at the acceptor splice site of exon 9. 12 refs., 3 figs., 2 tabs.

  6. Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome

    Science.gov (United States)

    Krueger, Dilja D.; Bear, Mark F.

    2011-01-01

    Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism. PMID:21090964

  7. Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.

    Science.gov (United States)

    Unnikrishnan, Ashwin; Papaemmanuil, Elli; Beck, Dominik; Deshpande, Nandan P; Verma, Arjun; Kumari, Ashu; Woll, Petter S; Richards, Laura A; Knezevic, Kathy; Chandrakanthan, Vashe; Thoms, Julie A I; Tursky, Melinda L; Huang, Yizhou; Ali, Zara; Olivier, Jake; Galbraith, Sally; Kulasekararaj, Austin G; Tobiasson, Magnus; Karimi, Mohsen; Pellagatti, Andrea; Wilson, Susan R; Lindeman, Robert; Young, Boris; Ramakrishna, Raj; Arthur, Christopher; Stark, Richard; Crispin, Philip; Curnow, Jennifer; Warburton, Pauline; Roncolato, Fernando; Boultwood, Jacqueline; Lynch, Kevin; Jacobsen, Sten Eirik W; Mufti, Ghulam J; Hellstrom-Lindberg, Eva; Wilkins, Marc R; MacKenzie, Karen L; Wong, Jason W H; Campbell, Peter J; Pimanda, John E

    2017-07-18

    Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. Molecular and cellular mechanisms of tight junction dysfunction in the irritable bowel syndrome.

    Science.gov (United States)

    Cheng, Peng; Yao, Jianning; Wang, Chunfeng; Zhang, Lianfeng; Kong, Wuming

    2015-09-01

    The pathophysiological mechanisms of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, are complex and have not been fully elucidated. The present study aimed to investigate the molecular and cellular mechanisms of tight junction (TJ) dysfunction in IBS. Intestinal tissues of IBS and non‑IBS patients were examined to observe cellular changes by cell chemical tracer electron microscopy and transmission electron microscopy, and intestinal claudin‑1 protein was detected by immunohistochemistry, western blot analysis and fluorescence quantitative polymerase chain reaction. Compared with the control group, TJ broadening and the tracer extravasation phenomenon were observed in the diarrhea‑predominant IBS group, and a greater number of neuroendocrine cells and mast cells filled with high‑density particles in the endocrine package pulp as well as a certain extent of vacuolization were present. The expression of claudin‑1 in diarrhea‑predominant IBS patients was decreased, while it was increased in constipation‑predominant IBS patients. In conclusion, the results of the present study indicated that changes in cellular structure and claudin‑1 levels were associated with Tjs in IBS.

  9. Integrated Modules Analysis to Explore the Molecular Mechanisms of Phlegm-Stasis Cementation Syndrome with Ischemic Heart Disease

    Science.gov (United States)

    Xu, Wei-Ming; Yang, Kuo; Jiang, Li-Jie; Hu, Jing-Qing; Zhou, Xue-Zhong

    2018-01-01

    Background: Ischemic heart disease (IHD) has been the leading cause of death for several decades globally, IHD patients usually hold the symptoms of phlegm-stasis cementation syndrome (PSCS) as significant complications. However, the underlying molecular mechanisms of PSCS complicated with IHD have not yet been fully elucidated. Materials and Methods: Network medicine methods were utilized to elucidate the underlying molecular mechanisms of IHD phenotypes. Firstly, high-quality IHD-associated genes from both human curated disease-gene association database and biomedical literatures were integrated. Secondly, the IHD disease modules were obtained by dissecting the protein-protein interaction (PPI) topological modules in the String V9.1 database and the mapping of IHD-associated genes to the PPI topological modules. After that, molecular functional analyses (e.g., Gene Ontology and pathway enrichment analyses) for these IHD disease modules were conducted. Finally, the PSCS syndrome modules were identified by mapping the PSCS related symptom-genes to the IHD disease modules, which were further validated by both pharmacological and physiological evidences derived from published literatures. Results: The total of 1,056 high-quality IHD-associated genes were integrated and evaluated. In addition, eight IHD disease modules (the PPI sub-networks significantly relevant to IHD) were identified, in which two disease modules were relevant to PSCS syndrome (i.e., two PSCS syndrome modules). These two modules had enriched pathways on Toll-like receptor signaling pathway (hsa04620) and Renin-angiotensin system (hsa04614), with the molecular functions of angiotensin maturation (GO:0002003) and response to bacterium (GO:0009617), which had been validated by classical Chinese herbal formulas-related targets, IHD-related drug targets, and the phenotype features derived from human phenotype ontology (HPO) and published biomedical literatures. Conclusion: A network medicine

  10. Clinical and molecular analyses of Beckwith-Wiedemann syndrome: Comparison between spontaneous conception and assisted reproduction techniques.

    Science.gov (United States)

    Tenorio, Jair; Romanelli, Valeria; Martin-Trujillo, Alex; Fernández, García-Moya; Segovia, Mabel; Perandones, Claudia; Pérez Jurado, Luis A; Esteller, Manel; Fraga, Mario; Arias, Pedro; Gordo, Gema; Dapía, Irene; Mena, Rocío; Palomares, María; Pérez de Nanclares, Guiomar; Nevado, Julián; García-Miñaur, Sixto; Santos-Simarro, Fernando; Martinez-Glez, Víctor; Vallespín, Elena; Monk, David; Lapunzina, Pablo

    2016-10-01

    Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by an excessive prenatal and postnatal growth, macrosomia, macroglossia, and hemihyperplasia. The molecular basis of this syndrome is complex and heterogeneous, involving genes located at 11p15.5. BWS is correlated with assisted reproductive techniques. BWS in individuals born following assisted reproductive techniques has been found to occur four to nine times higher compared to children with to BWS born after spontaneous conception. Here, we report a series of 187 patients with to BWS born either after assisted reproductive techniques or conceived naturally. Eighty-eight percent of BWS patients born via assisted reproductive techniques had hypomethylation of KCNQ1OT1:TSS-DMR in comparison with 49% for patients with BWS conceived naturally. None of the patients with BWS born via assisted reproductive techniques had hypermethylation of H19/IGF2:IG-DMR, neither CDKN1 C mutations nor patUPD11. We did not find differences in the frequency of multi-locus imprinting disturbances between groups. Patients with BWS born via assisted reproductive techniques had an increased frequency of advanced bone age, congenital heart disease, and decreased frequency of earlobe anomalies but these differences may be explained by the different molecular background compared to those with BWS and spontaneous fertilization. We conclude there is a correlation of the molecular etiology of BWS with the type of conception. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Clinical and molecular characterization of enhanced S-cone syndrome in children.

    Science.gov (United States)

    Hull, Sarah; Arno, Gavin; Sergouniotis, Panagiotis I; Tiffin, Peter; Borman, Arundhati Dev; Chandra, Aman; Robson, Anthony G; Holder, Graham E; Webster, Andrew R; Moore, Anthony T

    2014-11-01

    Enhanced S-cone syndrome (ESCS) forms part of the differential diagnosis of night blindness in childhood. To report in detail the clinical phenotype and molecular genetic findings in a series of children with ESCS. Nine children with ESCS from 5 families underwent full ophthalmic examination, electrophysiological testing, and retinal imaging at a genetic eye disease clinic of a tertiary referral eye hospital. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of NR2E3 was performed. Results of ophthalmic examination and sequence analysis of NR2E3. In total, 5 girls and 4 boys with a diagnosis of ESCS were included in the study. All patients had developed nyctalopia from early childhood. Visual acuity ranged from 0.00 to 1.20 logMAR (20/20 to 20/320 Snellen). All patients had hyperopia. Three patients had nummular pigmentary lesions along the arcades as typically seen in adults, 4 patients had mild pigmentary disturbance or white dots along the arcades, and 2 patients had a normal retinal appearance, although their fundus autofluorescence imaging demonstrated foci of increased autofluorescence along the arcades. Three patients had macular schisis-like changes on optical coherence tomography. Eight patients had electrophysiological testing at a mean age of 8.6 years (age range, 3-14 years), and in each patient the findings were consistent with the diagnosis of ESCS. Direct sequencing of NR2E3 identified 3 previously described mutations and 4 novel mutations. Seven patients were compound heterozygous for mutations in NR2E3, and 2 additional sibling patients were presumed to be homozygous for a missense change based on parental sequencing. In this sample, children with ESCS had an early onset of night blindness and hyperopia but no nystagmus. Based on this study, children with ESCS may initially manifest a normal fundus appearance but later develop mottled retinal pigment epithelium change along the arcades, followed by the appearance of white dots

  12. A model for the molecular underpinnings of tooth defects in Axenfeld–Rieger syndrome

    Science.gov (United States)

    Li, Xiao; Venugopalan, Shankar R.; Cao, Huojun; Pinho, Flavia O.; Paine, Michael L.; Snead, Malcolm L.; Semina, Elena V.; Amendt, Brad A.

    2014-01-01

    Patients with Axenfeld–Rieger Syndrome (ARS) present various dental abnormalities, including hypodontia, and enamel hypoplasia. ARS is genetically associated with mutations in the PITX2 gene, which encodes one of the earliest transcription factors to initiate tooth development. Thus, Pitx2 has long been considered as an upstream regulator of the transcriptional hierarchy in early tooth development. However, because Pitx2 is also a major regulator of later stages of tooth development, especially during amelogenesis, it is unclear how mutant forms cause ARS dental anomalies. In this report, we outline the transcriptional mechanism that is defective in ARS. We demonstrate that during normal tooth development Pitx2 activates Amelogenin (Amel) expression, whose product is required for enamel formation, and that this regulation is perturbed by missense PITX2 mutations found in ARS patients. We further show that Pitx2-mediated Amel activation is controlled by chromatin-associated factor Hmgn2, and that Hmgn2 prevents Pitx2 from efficiently binding to and activating the Amel promoter. Consistent with a physiological significance to this interaction, we show that K14-Hmgn2 transgenic mice display a severe loss of Amel expression on the labial side of the lower incisors, as well as enamel hypoplasia—consistent with the human ARS phenotype. Collectively, these findings define transcriptional mechanisms involved in normal tooth development and shed light on the molecular underpinnings of the enamel defect observed in ARS patients who carry PITX2 mutations. Moreover, our findings validate the etiology of the enamel defect in a novel mouse model of ARS. PMID:23975681

  13. Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

    Science.gov (United States)

    Rice, Gillian ; Patrick, Teresa ; Parmar, Rekha ; Taylor, Claire F. ; Aeby, Alec ; Aicardi, Jean ; Artuch, Rafael ; Montalto, Simon Attard ; Bacino, Carlos A. ; Barroso, Bruno ; Baxter, Peter ; Benko, Willam S. ; Bergmann, Carsten ; Bertini, Enrico ; Biancheri, Roberta ; Blair, Edward M. ; Blau, Nenad ; Bonthron, David T. ; Briggs, Tracy ; Brueton, Louise A. ; Brunner, Han G. ; Burke, Christopher J. ; Carr, Ian M. ; Carvalho, Daniel R. ; Chandler, Kate E. ; Christen, Hans-Jürgen ; Corry, Peter C. ; Cowan, Frances M. ; Cox, Helen ; D’Arrigo, Stefano ; Dean, John ; De Laet, Corinne ; De Praeter, Claudine ; Déry, Catherine ; Ferrie, Colin D. ; Flintoff, Kim ; Frints, Suzanna G. M. ; Garcia-Cazorla, Angels ; Gener, Blanca ; Goizet, Cyril ; Goutières, Françoise ; Green, Andrew J. ; Guët, Agnès ; Hamel, Ben C. J. ; Hayward, Bruce E. ; Heiberg, Arvid ; Hennekam, Raoul C. ; Husson, Marie ; Jackson, Andrew P. ; Jayatunga, Rasieka ; Jiang, Yong-Hui ; Kant, Sarina G. ; Kao, Amy ; King, Mary D. ; Kingston, Helen M. ; Klepper, Joerg ; van der Knaap, Marjo S. ; Kornberg, Andrew J. ; Kotzot, Dieter ; Kratzer, Wilfried ; Lacombe, Didier ; Lagae, Lieven ; Landrieu, Pierre Georges ; Lanzi, Giovanni ; Leitch, Andrea ; Lim, Ming J. ; Livingston, John H. ; Lourenco, Charles M. ; Lyall, E. G. Hermione ; Lynch, Sally A. ; Lyons, Michael J. ; Marom, Daphna ; McClure, John P. ; McWilliam, Robert ; Melancon, Serge B. ; Mewasingh, Leena D. ; Moutard, Marie-Laure ; Nischal, Ken K. ; Østergaard, John R. ; Prendiville, Julie ; Rasmussen, Magnhild ; Rogers, R. Curtis ; Roland, Dominique ; Rosser, Elisabeth M. ; Rostasy, Kevin ; Roubertie, Agathe ; Sanchis, Amparo ; Schiffmann, Raphael ; Scholl-Bürgi, Sabine ; Seal, Sunita ; Shalev, Stavit A. ; Corcoles, C. Sierra ; Sinha, Gyan P. ; Soler, Doriette ; Spiegel, Ronen ; Stephenson, John B. P. ; Tacke, Uta ; Tan, Tiong Yang ; Till, Marianne ; Tolmie, John L. ; Tomlin, Pam ; Vagnarelli, Federica ; Valente, Enza Maria ; Van Coster, Rudy N. A. ; Van der Aa, Nathalie ; Vanderver, Adeline ; Vles, Johannes S. H. ; Voit, Thomas ; Wassmer, Evangeline ; Weschke, Bernhard ; Whiteford, Margo L. ; Willemsen, Michel A. A. ; Zankl, Andreas ; Zuberi, Sameer M. ; Orcesi, Simona ; Fazzi, Elisa ; Lebon, Pierre ; Crow, Yanick J. 

    2007-01-01

    Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation–positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. PMID:17846997

  14. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome.

    Science.gov (United States)

    AlOlaby, Reem Rafik; Sweha, Stefan R; Silva, Marisol; Durbin-Johnson, Blythe; Yrigollen, Carolyn M; Pretto, Dalyir; Hagerman, Randi J; Tassone, Flora

    2017-06-01

    Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS. Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24-72months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models. A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P=0.008) and the cognitive T score (P=0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study. This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  15. The antioxidative and antilipidemic effects of different molecular weight chitosans in metabolic syndrome model rats.

    Science.gov (United States)

    Anraku, Makoto; Michihara, Akihiro; Yasufuku, Taira; Akasaki, Kenji; Tsuchiya, Daiju; Nishio, Hiroaki; Maruyama, Toru; Otagiri, Masaki; Maezaki, Yuji; Kondo, Yuko; Tomida, Hisao

    2010-01-01

    The effect of high and low molecular weight chitosans (HMC; 1000 kDa, LMC; 30 kDa) on oxidative stress and hypercholesterolemia was investigated using male 6-week-old Wistar Kyoto rats as a normal model (Normal-rats) and spontaneously hypertensive rat/ND mcr-cp (SHP/ND) as a metabolic syndrome model (MS-rats), respectively. In Normal-rats, the ingestion of both chitosans over a 4 week period resulted in a significant decrease in total body weight (BW), glucose (Gl), triglyceride (TG), low density lipoprotein (LDL) and serum creatinine (Cre) levels. The ingestion of both chitosans also resulted in a lowered ratio of oxidized to reduced albumin and an increase in total plasma antioxidant activity. In addition to similar results in Normal-rats, the ingestion of only HMC over a 4 week period resulted in a significant decrease in total cholesterol levels in MS-rats. Further, the ingestion of LMC resulted in a significantly higher antioxidant activity than was observed for HMC in both rat models. In in vitro studies, LMC caused a significantly higher reduction in the levels of two stable radicals, compared to HMC, and the effect was both dose- and time-dependent. The findings also show that LDL showed strong binding in the case of HMC. These results suggest that LMC has a high antioxidant activity as well as antilipidemic effects, while HMC results in a significant reduction in the levels of pro-oxidants such as LDL in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation in metabolic model rats.

  16. [Molecular pathogenesis of Waardenburg syndrome type II resulting from SOX10 gene mutation].

    Science.gov (United States)

    Zhang, Hua; Chen, Hongsheng; Feng, Yong; Qian, Minfei; Li, Jiping; Liu, Jun; Zhang, Chun

    2016-08-01

    To explore the molecular mechanism of Waardenburg syndrome type II (WS2) resulting from SOX10 gene mutation E248fs through in vitro experiment. 293T cells were transiently transfected with wild type (WT) SOX10 and mutant type (MT) E248fs plasmids. The regulatory effect of WT/MT SOX10 on the transcriptional activity of MITF gene and influence of E248fs on WT SOX10 function were determined with a luciferase activity assay. The DNA binding capacity of the WT/MT SOX10 with the promoter of the MITF gene was determined with a biotinylated double-stranded oligonucleotide probe containing the SOX10 binding sequence cattgtc to precipitate MITF and E248fs, respectively. The stability of SOX10 and E248fs were also analyzed. As a loss-of-function mutation, the E248fs mutant failed to transactivate the MITF promoter as compared with the WT SOX10 (P<0.01), which also showed a dominant-negative effect on WT SOX10. The WT SOX10 and E248fs mutant were also able to bind specifically to the cattgtc motif in the MITF promoter, whereas E248fs had degraded faster than WT SOX10. Despite the fact that the E248fs has a dominant-negative effect on SOX10, its reduced stability may down-regulate the transcription of MITF and decrease the synthesis of melanin, which may result in haploinsufficiency of SOX10 protein and cause the milder WS2 phenotype.

  17. Molecular Testing of MECP2 Gene in Rett Syndrome Phenotypes in Indian Girls.

    Science.gov (United States)

    Lallar, Meenakshi; Rai, Archana; Srivastava, Priyanka; Mandal, Kausik; Gupta, Neerja; Kabra, Madhulika; Phadke, Shubha R

    2018-02-09

    To assess yield of MECP2 gene sequence variations analysis and large deletions in suspected cases of Rett syndrome. Descriptive study. Tertiary-care medical genetics center. Girls with neuroregression, postnatal microcephaly and signs and symptoms suggestive of classical and atypical Rett syndrome were classified into two groups. Group I consisted of girls with Classical and atypical Rett syndrome on basis on the Revised Rett Syndrome diagnostic criteria, 2010. Group II included girls with neuroregression and postnatal microcephaly and other Rett like features but not fulfilling the above criteria. Sanger sequencing of coding regions and large deletional analysis of MECP2 gene. Identification of mutation in MECP2 gene. Mutation in MECP2 gene was identified in 74% (14/19) in group I and none (0/17) in group II. The mutation detection rate was 92% (13/14) in group I classical Rett syndrome girls (2 with large deletions identified with Multiplex ligation dependent probe amplification) and 20% (1/5) in group I atypical Rett syndrome girls. One novel MECP2 sequence variation was identified in group I classical Rett syndrome. The yield of the mutation detection in MECP2 is much higher in classical than in atypical Rett syndrome. In girls with some Rett like features, but not fulfilling revised Rett syndrome diagnostic criteria, mutation testing for MECP2 gene has a low yield.

  18. Diagnostic Strategies for Early Lynch Syndrome Detection: From Molecular Testing to Economic Evaluation

    NARCIS (Netherlands)

    C.H.M. Leenen (Celine)

    2015-01-01

    markdownabstract__Abstract__ Lynch syndrome (LS) is an autosomal dominant inherited syndrome that predisposes to multiple malignancies, in particular colorectal cancer (CRC) and endometrial cancer (EC). The lifetime risk of developing CRC for a LS mutation carrier is 25 to 70%, while women

  19. A Malay boy with the Cornelia de Lange syndrome: clinical and molecular findings

    NARCIS (Netherlands)

    Bhuiyan, Z. A.; Zilfalil, B. A.; Hennekam, R. C. M.

    2006-01-01

    The Cornelia de Lange syndrome is a multiple congenital anomaly syndrome characterised by dysmorphic facial features, hirsutism, severe growth and developmental delays, and malformed upper limbs. The prevalence is estimated to be one per 10,000. Recently, several independent groups proved that

  20. [Genetic and molecular basis for sodium channel-mediated Brugada syndrome].

    Science.gov (United States)

    Barajas-Martínez, Héctor; Hu, Dan; Antzelevitch, Charles

    2013-01-01

    Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. This syndrome is linked to mutations in the SCN5A gene in approximately 20% of Brugada syndrome probands. SCN5A encodes the α subunit of the cardiac sodium channel. Studies conducted over the past decade have identified 11 other Brugada syndrome susceptibility genes besides to SCN5A, pointing to genetic heterogeneity of the syndrome. Transmission of the disease shows an autosomal dominant inheritance pattern. This brief review focuses on a reported case of sodium channel-mediated Brugada syndrome, guiding the reader through the process of identification of the genetic variants responsible for the clinically-diagnosed syndrome, mutagenesis to clone SCN5A with and without the 2 variants identified and transfection of the 2 variants into TSA201 cells to determine the functional consequence of these genetic variants on sodium channel expression and function. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  1. Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability.

    Science.gov (United States)

    Gauthier-Vasserot, Alexandra; Thauvin-Robinet, Christel; Bruel, Ange-Line; Duffourd, Yannis; St-Onge, Judith; Jouan, Thibaud; Rivière, Jean-Baptiste; Heron, Delphine; Donadieu, Jean; Bellanné-Chantelot, Christine; Briandet, Claire; Huet, Frédéric; Kuentz, Paul; Lehalle, Daphné; Duplomb-Jego, Laurence; Gautier, Elodie; Maystadt, Isabelle; Pinson, Lucile; Amram, Daniel; El Chehadeh, Salima; Melki, Judith; Julia, Sophia; Faivre, Laurence; Thevenon, Julien

    2017-01-01

    Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Molecular diagnosis of fragile X syndrome using methylation sensitive techniques in a cohort of patients with intellectual disability.

    Science.gov (United States)

    Chaudhary, Adeel G; Hussein, Ibtessam R; Abuzenadah, Adel; Gari, Mamdouh; Bassiouni, Randa; Sogaty, Samira; Lary, Sahira; Al-Quaiti, Maha; Al Balwi, Mohammed; Al Qahtani, Mohammed

    2014-04-01

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by expansion of CGG trinucleotide repeat at the 5' untranslated region of the FMR1 gene at Xq27. In affected individuals, the CGG repeat expansion leads to hypermethylation and the gene is transcriptionally inactive. Our aim was to identify fragile X syndrome among children with intellectual disability in Saudi Arabia. The study included 63 patients (53 males, 10 females) presented with intellectual disability, 29 normal subjects, and 23 other family members. DNA samples from six patients previously diagnosed with fragile X syndrome by Southern blot technique were used as positive controls. The method was based on bisulfite treatment of DNA followed by two different techniques. The first technique applied polymerase chain reaction amplification using one set of primers specific for amplifying methylated CpG dinucleotide region; another set designed to amplify the unmethylated CGG repeats. The second technique used the methylation-specific melting curve analysis for detection of methylation status of the FMR1 promoter region. Molecular testing using methylation sensitive polymerase chain reaction had shown amplified products in all normal subjects using unmethylated but not methylated primers indicating normal alleles, whereas amplified products were obtained using methylated polymerase chain reaction primers in fragile X syndrome-positive samples and in 9 of 53 males, indicating affected individuals. Molecular testing using melting curve analysis has shown a single low melting peak in all normal males and in (44/53) patients indicating unmethylated FMR1 gene, whereas high melting peak indicating methylated gene was observed in the fragile X syndrome-positive samples and in 9 of 53 patients. We found 100% concordance between results of both techniques and the results of Southern blot analysis. Three samples have shown both methylated and unmethylated alleles, indicating possible

  3. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

    Science.gov (United States)

    Staines, Donald R

    2004-01-01

    Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All

  4. The effect of sugar and artificial sweetener on molecular markers of metabolic syndrome: a mice study

    Directory of Open Access Journals (Sweden)

    Subali, D.,

    2017-06-01

    Full Text Available The usage of aspartame, as one of the most widely used sweetener, has been approved in many types of food products. Moreover, many studies have proven that replacing sugar with aspartame would contribute favorable effects on several health parameters; such as, body weight, blood glucose level, and inflammatory status. In this experiment, we examined the effects of aspartame consumption on some biomarkers; which potentially acted as early signals for a personal metabolic status. This study was aimed to investigate the effect of aspartame on the expression of a number of molecular markers related with appetite regulation (fto, fat accumulation markers (fabp4 and alt2 and inflammation marker (tnf-α in Sprague Dawley rats. The population of Clostridium coccoides was also observed to give an insight about the effect of sweetener consumption on gut microbiota profiles. 15 healthy, male, eight-weeks old Sprague-Dawley rats were fed a standard diet and divided into 3 groups (n=5 for each: water only, sucrose (30% b/v, and aspartame (0.15% b/v. Body weight was measured weekly and blood glucose measurement was carried out on day 1 and 40. At the end of the experiment, all rats were euthanized and blood was collected from the vein. The liver, brain, and visceral adipose tissue were excised, weighed, and grinded with liquid nitrogen. Feces samples were collected on day 0 and 40. At the end of our experimental period; the body weight, liver weight, and blood glucose level of sucrose-treated rats were significantly higher (p <0.05 than aspartame and control group. Sucrose showed the lowest level of fto gene expression; yet, the fto gene expression in aspartame group was still lower than the control group. Expression of several genes considered as metabolic syndrome-related biomarkers were measured (fabp4, alt2, and tnf-α; and our data demonstrated that sucrose treatment gave the highest increase in expression level of those genes; while aspartame treatment

  5. Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies.

    Science.gov (United States)

    Palos, Fernando; García-Rendueles, María E R; Araujo-Vilar, David; Obregon, Maria Jesús; Calvo, Rosa Maria; Cameselle-Teijeiro, Jose; Bravo, Susana B; Perez-Guerra, Oscar; Loidi, Lourdes; Czarnocka, Barbara; Alvarez, Paula; Refetoff, Samuel; Dominguez-Gerpe, Lourdes; Alvarez, Clara V; Lado-Abeal, Joaquin

    2008-01-01

    We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter. Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes. Interventions included extraction of DNA and of thyroid tissue. Propositi and 10 members of the two families participated in the study. Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416-1G-->A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics. Proposita A was heterozygous for c.578C-->T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416-1G-->A; some deaf relatives were homozygous for c.416-1G-->A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention. c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416-1G-->A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.

  6. High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects

    OpenAIRE

    de Abreu, Virg?nia Genelhu; Martins, Cyro Jos? de Moraes; de Oliveira, Patricia Aguiar Cardoso; Francischetti, Emilio Antonio

    2017-01-01

    Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsib...

  7. Angelman syndrome: Validation of molecular cytogenetic analysis of chromosome 15q11-q13 for deletion detection

    Energy Technology Data Exchange (ETDEWEB)

    White, L.; Knoll, J.H.M. [Harvard Medical School, Boston, MA (United States)

    1995-03-13

    In a series of 18 individuals comprising parents of Angelman syndrome (AS) patients and AS patients with large deletions, microdeletions, and no deletions, we utilized fluorescence in situ hybridization (FISH) with genomic phage clones for loci D15S63 and GABRB3 for deletion detection of chromosome 15q11-q13. Utilization of probes at these loci allows detection of common large deletions and permits discrimination of less common small deletions. In all individuals the molecular cytogenetic data were concordant with the DNA deletion analyses. FISH provides an accurate method of deletion detection for chromosome 15q11-q13. 23 refs., 2 figs., 1 tab.

  8. Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect

    DEFF Research Database (Denmark)

    Schulze, A; Hansen, Claus; Baekgaard, P

    1997-01-01

    Prader-Willi syndrome (PWS) is a neuroendocrine disorder caused by a non-functioning paternally derived gene(s) within the chromosome region 15q11-q13. Most cases result from microscopically visible deletions of paternal origin, or maternal uniparental disomy of chromosome 15. In both instances...... no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When...

  9. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone

    International Nuclear Information System (INIS)

    Adachi, A.; Gendelman, H.E.; Koenig, S.; Folks, T.; Willey, R.; Rabson, A.; Martin, M.A.

    1986-01-01

    The authors considered an infectious molecular clone of acquired immunodeficiency syndrome-associated retrovirus. Upon transfection, this clone directed the production of infectious virus particles in a wide variety of cells in addition to human T4 cells. The progeny, infectious virions, were synthesized in mouse, mink, monkey, and several human non-T cell lines, indicating the absence of any intracellular obstacle to viral RNA or protein production or assembly. During the course of these studies, a human colon carcinoma cell line, exquisitely sensitive to DNA transfection, was identified

  10. Gastrointestinal Polyposis Syndromes : Clinical and molecular aspects of Familial Adenomatous Polyposis and Juvenile Polyposis

    NARCIS (Netherlands)

    Brosens, L.A.A.

    2008-01-01

    Colorectal cancer (CRC) is an important cause death. In the Netherlands, approximately 10.000 patients are diagnosed with CRC each year. Rare hereditary gastrointestinal polyposis syndromes predisposing to CRC, including familial adenomatous polyposis (FAP), juvenile polyposis (JPS) and

  11. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism.

    Science.gov (United States)

    Matsuzawa, Yuji; Funahashi, Tohru; Nakamura, Tadashi

    2011-01-01

    Although abdominal obesity or visceral obesity is considered to be one of the components of metabolic syndrome and to have an important role in a cluster of cardiovascular risks, there is no consensus about the definition and diagnostic criteria for this syndrome, probably because there is considerable disagreement about the location and definition of abdominal obesity or visceral obesity.In this review article, the important role of visceral fat accumulation in the development of a variety of lifestyle-related diseases is shown, including cardiovascular disease based on our clinical studies using CT scans, and the mechanism of these disorders is discussed, focusing on adipocytokines, especially adiponectin.The importance of diagnosing metabolic syndrome, in which visceral fat accumulation plays an essential role in the development of multiple risk factors, should be emphasized because lifestyle modification for the reduction of visceral fat may be very effective for the reduction of risks of this type, namely metabolic syndrome in the narrow sense.

  12. Cardiac aspects of DiGeorge syndrome: a report of two cases with molecular analysis

    Directory of Open Access Journals (Sweden)

    Senka Mesihović Dinarević

    2014-04-01

    Full Text Available DiGeorge syndrome (DGS which is also known as velocardiofacial syndrome is caused by a submicroscopic chromosome deletion of band 22q11. It is associated with a disturbed development of the pharyngeal arches. In this report we describe two unrelated male children with clinical features consistent with 22q11.2 microdeletion syndrome characterized by cardiac defect, recurrent respiratory infections and developmental deficiency. Definitive diagnosis is made by Fluorescence In Situ Hybridization analysis (FISH. Children underwent surgical correction of congenital heart defects. During surgery thymic aplasia was confirmed in both children, postoperative course proceeded without major complications. Our report suggests that the criteria in searching for microdeletion 22q11.2 should be expanded and applied in patients with conotruncal and non-conotruncal congenital heart defects and at least one typical feature of this syndrome.

  13. Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome.

    Science.gov (United States)

    Wong, Meihua; Chu, Ying-Hsia; Tan, Hwei Ling; Bessho, Hideharu; Ngeow, Joanne; Tang, Tiffany; Tan, Min-Han

    2016-08-15

    Von Hippel-Lindau (VHL) syndrome is a dominantly inherited multisystem cancer syndrome caused by a heterozygous mutation in the VHL tumor suppressor gene. Previous studies suggested that similar populations of Caucasian and Japanese patients have similar genotype or phenotype characteristics. In this comprehensive study of East Asian patients, we investigated the genetic and clinical characteristics of patients with VHL syndrome. To create a registry of clinical characteristics and mutations reported in East Asian patients with VHL syndrome, we conducted a comprehensive review of English language and non-English language articles identified through a literature search. Publications in Japanese or Chinese language were read by native speakers of the language, who then performed the data extraction. Of 237 East Asian patients with VHL syndrome, 154 unique kindreds were identified for analysis. Analyzed by kindred, missense mutations were the most common (40.9%, 63/154), followed by large/complete deletions (32.5%, 50/154) and nonsense mutations (11.7%, 18/154). Compared with a previously reported study of both East Asian and non-East Asian patients, we found several key differences. First, missense and frameshift mutations in the VHL gene occurred less commonly in our population of East Asian patients (40.9% vs. 52.0%; P = 0.012 and 8.4% vs. 13.0%; P syndrome, the incidence of retinal capillary hemangioblastoma was lower, whereas the incidence of renal cell carcinoma was higher. Evidence suggests that the genotypic and phenotypic characteristics of East Asian patients with VHL syndrome differ from other populations. This should be considered when making screening recommendations for VHL syndrome in Asia.

  14. Editorial: X-chromosome-linked Kallmann's syndrome: Pathology at the molecular level

    Energy Technology Data Exchange (ETDEWEB)

    Prager, D.; Braunstein, G.D. (Cedars-Sinai Medical Center, Los Angeles, CA (United States))

    1993-04-01

    Kallmann's syndrome or olfactogenital dysplasia refers to a disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia which can occur sporadically or in a familial setting. Originally described in 1856, the first familial cases were reported by Kallmann et al., in 1944. Based on segregation analysis of multiple families, three modes of transmission have been documented: X-linked, autosomal dominant with variable penetrance, and autosomal recessive. Kallmann's syndrome occurs in less than 1 in 10,000 male births, with a 5-fold excess of affected males to females, suggesting that the X-linked form is the most frequent. By genetic linkage analysis the X-linked form of Kallmann's syndrome was localized to Xp22.3. This was confirmed by the description of patients with contiguous gene syndromes due to deletions of various portions of the distal short arm of the X-chromosome. Such patients present with complex phenotypes characterized by a combination of Kallmann's syndrome with X-linked icthyosis due to steroid sulfatase deficiency, chondrodysplasia punctata, short stature, and mental retardation. DNA analysis has identified and mapped the genes responsible for these disorders. 10 refs., 1 fig., 1 tab.

  15. Molecular Basis of DFNB73: Mutations of BSND Can Cause Nonsyndromic Deafness or Bartter Syndrome

    Science.gov (United States)

    Riazuddin, Saima; Anwar, Saima; Fischer, Martin; Ahmed, Zubair M.; Khan, Shahid Y.; Janssen, Audrey G.H.; Zafar, Ahmad U.; Scholl, Ute; Husnain, Tayyab; Belyantseva, Inna A.; Friedman, Penelope L.; Riazuddin, Sheikh; Friedman, Thomas B.; Fahlke, Christoph

    2009-01-01

    BSND encodes barttin, an accessory subunit of renal and inner ear chloride channels. To date, all mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating nonsyndromic deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND mutations that cause renal failure and deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent nonsyndromic deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or nonsyndromic deafness. PMID:19646679

  16. Velocardiofacial Syndrome

    Science.gov (United States)

    Gothelf, Doron; Frisch, Amos; Michaelovsky, Elena; Weizman, Abraham; Shprintzen, Robert J.

    2009-01-01

    Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the…

  17. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation

    Science.gov (United States)

    2011-01-01

    Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA) (OMIM 225400) is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4) due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial), independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity. PMID:21699693

  18. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA: clinical, molecular and biochemical delineation

    Directory of Open Access Journals (Sweden)

    Kariminejad Ariana

    2011-06-01

    Full Text Available Abstract Background The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA (OMIM 225400 is a rare inheritable connective tissue disorder characterized by a deficiency of collagen lysyl hydroxylase 1 (LH1; EC 1.14.11.4 due to mutations in PLOD1. Biochemically this results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP and hydroxylysyl pyridinoline (HP crosslinks excreted in the urine. Clinically the disorder is characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Severe hypotonia usually leads to delay in gross motor development, whereas cognitive development is reported to be normal. Methods We describe the clinical, biochemical and molecular characterisation, as well as electron microscopy findings of skin, in 15 patients newly diagnosed with this rare type of Ehlers-Danlos syndrome. Results Age at diagnosis ranged from 5 months to 27 years, with only 1/3 of the patients been diagnosed correctly in the first year of life. A similar disease frequency was found in females and males, however a broad disease severity spectrum (intra- and interfamilial, independent of molecular background or biochemical phenotype, was observed. Kyphoscoliosis, one of the main clinical features was not present at birth in 4 patients. Importantly we also noted the occurrence of vascular rupture antenatally and postnatally, as well as developmental delay in 5 patients. Conclusion In view of these findings we propose that EDS VIA is a highly variable clinical entity, presenting with a broad clinical spectrum, which may also be associated with cognitive delay and an increased risk for vascular events. Genotype/phenotype association studies and additional molecular investigations in more extended EDS VIA populations will be necessary to further elucidate the cause of the variability of the disease severity.

  19. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity

    NARCIS (Netherlands)

    Gordillo, Miriam; Vega, Hugo; Trainer, Alison H.; Hou, Fajian; Sakai, Norio; Luque, Ricardo; Kayserili, Hülya; Basaran, Seher; Skovby, Flemming; Hennekam, Raoul C. M.; Uzielli, Maria L. Giovannucci; Schnur, Rhonda E.; Manouvrier, Sylvie; Chang, Susan; Blair, Edward; Hurst, Jane A.; Forzano, Francesca; Meins, Moritz; Simola, Kalle O. J.; Raas-Rothschild, Annick; Schultz, Roger A.; McDaniel, Lisa D.; Ozono, Keiichi; Inui, Koji; Zou, Hui; Jabs, Ethylin Wang

    2008-01-01

    Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth

  20. Elastins from patients with Williams-Beuren syndrome and healthy individuals differ on the molecular level

    DEFF Research Database (Denmark)

    Heinz, Andrea; Huertas, Angela C Mora; Schräder, Christoph U

    2016-01-01

    Williams-Beuren syndrome (WBS) is a congenital disorder, which involves the heterozygous deletion of the elastin gene and other genes on chromosome 7. Clinical symptoms that are associated with hemizygosity of the essential extracellular matrix protein elastin include premature aging of the skin...

  1. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity

    DEFF Research Database (Denmark)

    Gordillo, M.; Vega, H.; Trainer, A.H.

    2008-01-01

    Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced grow...

  2. A molecular analysis of fecal and mucosal bacterial communities in irritable bowel syndrome.

    LENUS (Irish Health Repository)

    Codling, Caroline

    2010-02-01

    The objectives of this study were, firstly, to determine the diversity of the host\\'s gut microbiota in irritable bowel syndrome (IBS) using a culture-independent method (DGGE of the 16S rRNA gene) and, secondly, to examine mucosal biopsies of IBS patients and compare them to their own fecal microbiota.

  3. Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes

    Directory of Open Access Journals (Sweden)

    Bijal Vyas

    2016-01-01

    Conclusions: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

  4. Molecular characterization of Salmonella strains in individuals with acute diarrhea syndrome in the State of Sucre, Venezuela.

    Science.gov (United States)

    Rodulfo, Hectorina; De Donato, Marcos; Luiggi, Jesús; Michelli, Elvia; Millán, Adriana; Michelli, Miriam

    2012-06-01

    In Venezuela, acute diarrheic syndrome (ADS) is a primary cause of morbi-mortality, often involving the Salmonella genus. Salmonella infections are associated with acute gastroenteritis, one of the most common alimentary intoxications, and caused by the consumption of contaminated water and food, especially meat. Conventional and molecular methods were used to detect Salmonella strains from 330 fecal samples from individuals of different ages and both sexes with ADS. Polymerase chain reaction (PCR) was used for the molecular characterization of Salmonella, using invA, sefA, and fliC genes for the identification of this genus and the serotypes Enteritidis and Typhimurium, respectively. The highest frequency of individuals with ADS was found in children 0-2 years old (39.4%), and the overall frequency of positive coprocultures was 76.9%. A total of 14 (4.2%) strains were biochemically and immunologically identified as Salmonella enterica subsp. enterica, of which 7 were classified as belonging to the Enteritidis serotype, 4 to the Typhimurium serotype, and 3 to other serotypes. The S. enterica strains were distributed more frequently in the age groups 3-4 and 9-10 years old. The molecular characterization method used proved to be highly specific for the typing of S. enterica strains using DNA extracted from both the isolated colonies and selective enrichment broths directly inoculated with fecal samples, thus representing a complementary tool for the detection and identification of ADS-causing bacteria.

  5. Prenatal diagnosis of Wolf-Hirschhorn syndrome: Ultrasonography and molecular karyotyping results.

    Science.gov (United States)

    Zhen, Li; Fan, Shu-Shu; Huang, Lv-Yin; Pan, Min; Han, Jin; Yang, Xin; Li, Dong-Zhi

    2018-03-31

    To present the experience on prenatal diagnosis of Wolf-Hirschhorn syndrome (WHS) to further delineate the fetal presentation of this syndrome. This was a retrospective analysis of ten pregnancies with fetal WHS identified by chromosomal microarray (CMA). Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes. Three cases were diagnosed at the first trimester because of an increased NT or cystic hygroma. The remaining seven cases were identified at late gestation for abnormal ultrasound findings. CMA revealed 4p deletions to be terminal in all of the ten cases. Deletion sizes ranged from 2.05 to 19.02 Mb. Prenatal findings such as increased NT, severe and early onset intrauterine growth retardation, and renal dysplasia or oligohydramnios should warrant the diagnosis of WHS and invasive testing using CMA. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome

    Science.gov (United States)

    Dumesic, Daniel A.; Oberfield, Sharon E.; Stener-Victorin, Elisabet; Marshall, John C.; Laven, Joop S.

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a heterogeneous and complex disorder that has both adverse reproductive and metabolic implications for affected women. However, there is generally poor understanding of its etiology. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries. Criteria that require hyperandrogenism tend to identify a more severe reproductive and metabolic phenotype. The phenotype can vary by race and ethnicity, is difficult to define in the perimenarchal and perimenopausal period, and is exacerbated by obesity. The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. PCOS clusters in families and both female and male relatives can show stigmata of the syndrome, including metabolic abnormalities. Genome-wide association studies have identified a number of candidate regions, although their role in contributing to PCOS is still largely unknown. PMID:26426951

  7. Isolated micropenis reveals partial androgen insensitivity syndrome confirmed by molecular analysis

    OpenAIRE

    Bhangoo, Amrit; Paris, Francoise; Philibert, Pascal; Audran, Francoise; Ten, Svetlana; Sultan, Charles

    2010-01-01

    Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with micropenis, peno-scrotal hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-α reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated micropenis: one in a 14-...

  8. Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response

    OpenAIRE

    Schulze-Bahr, E; Fenge, H; Etzrodt, D; Haverkamp, W; Mönnig, G; Wedekind, H; Breithardt, G; Kehl, H-G

    2004-01-01

    Intrauterine and neonatal manifestations of congenital long QT syndrome are associated with a high cardiac risk, particularly when atrioventricular block and excessive QT prolongation (> 600 ms1/2) are present. In a female newborn with these features, treatment with propranolol and mexiletine led to complete reduction of arrhythmia that was maintained 1.5 years later. High throughput genetic analysis found a sodium channel gene (LQT3) mutation. Disappearance of the 2:1 atrioventricular block ...

  9. Molecular study of chromosome 15 in 22 patients with Angelman syndrome

    NARCIS (Netherlands)

    Beuten, J.; Mangelschots, K.; Buntinx, I.; Coucke, P.; Brouwer, O. F.; Hennekam, R. C.; van Broeckhoven, C.; Willems, P. J.

    1993-01-01

    DNA studies in 22 families with Angelman syndrome (AS) were performed using the chromosome 15 marker loci D15S9, D15S10, D15S11, D15S12, D15S13, D15S18, D15S24, D15S86, the alpha-actin gene and the GABA beta 3 receptor gene (GABRB3). Uniparental disomy of chromosome 15 was excluded in all patients.

  10. Molecular pathogenesis of a malformation syndrome associated with a pericentric chromosome 2 inversion

    OpenAIRE

    Cardoso, Manuela

    2017-01-01

    Tese de mestrado em Biologia Humana e do Ambiente, apresentada à Faculdade de Ciências da Universidade de Lisboa, 2017. Orientador Dezso David - Departamento de Genética Humana do Instituto Nacional de Saúde Congenital malformation syndromes can be caused by genomic and/or chromosome rearrangements. It is difficult to establish the underlying causes of malformations because of their high level of complexity. Although balanced chromosome inversions are in most cases subclinical, those di...

  11. Identification of mutations in TCOF1: use of molecular analysis in the pre- and postnatal diagnosis of Treacher Collins syndrome.

    Science.gov (United States)

    Dixon, Jill; Ellis, Ian; Bottani, Armand; Temple, Karen; Dixon, Michael James

    2004-06-15

    Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development, which results from mutations in TCOF1. TCS comprises conductive hearing loss, hypoplasia of the mandible and maxilla, downward sloping palpebral fissures and cleft palate. Although, there is usually a reasonable degree of bilateral symmetry, a high degree of both inter- and intrafamilial variability is characteristic of TCS. The wide variation in the clinical presentation of different patients, together with the fact that more than 60% of cases arise de novo, can complicate the diagnosis of mild cases and genetic counselling. In the current study, we describe how molecular techniques have been used to facilitate pre- and postnatal disease diagnoses in 13 TCS families. Copyright 2004 Wiley-Liss, Inc.

  12. Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia

    DEFF Research Database (Denmark)

    Storr, Helen L; Mitchell, J H; Swords, F M

    2004-01-01

    BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due...... to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean...... systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based...

  13. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

    Science.gov (United States)

    Rossi, Benedito Mauro; Palmero, Edenir Inêz; López-Kostner, Francisco; Sarroca, Carlos; Vaccaro, Carlos Alberto; Spirandelli, Florencia; Ashton-Prolla, Patricia; Rodriguez, Yenni; de Campos Reis Galvão, Henrique; Reis, Rui Manuel; Escremim de Paula, André; Capochin Romagnolo, Luis Gustavo; Alvarez, Karin; Della Valle, Adriana; Neffa, Florencia; Kalfayan, Pablo German; Spirandelli, Enrique; Chialina, Sergio; Gutiérrez Angulo, Melva; Castro-Mujica, Maria Del Carmen; Sanchez de Monte, Julio; Quispe, Richard; da Silva, Sabrina Daniela; Rossi, Norma Teresa; Barletta-Carrillo, Claudia; Revollo, Susana; Taborga, Ximena; Morillas, L Lena; Tubeuf, Hélène; Monteiro-Santos, Erika Maria; Piñero, Tamara Alejandra; Dominguez-Barrera, Constantino; Wernhoff, Patrik; Martins, Alexandra; Hovig, Eivind; Møller, Pål; Dominguez-Valentin, Mev

    2017-09-05

    Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

  14. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

    Science.gov (United States)

    Matsunaga, Kimie; Tanabe, Katsuya; Inoue, Hiroshi; Okuya, Shigeru; Ohta, Yasuharu; Akiyama, Masaru; Taguchi, Akihiko; Kora, Yukari; Okayama, Naoko; Yamada, Yuichiro; Wada, Yasuhiko; Amemiya, Shin; Sugihara, Shigetaka; Nakao, Yuzo; Oka, Yoshitomo; Tanizawa, Yukio

    2014-01-01

    Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

  15. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome.

    Science.gov (United States)

    Sanz-Ortega, Julian; Vocke, Cathy; Stratton, Pamela; Linehan, William Marston; Merino, Maria J

    2013-01-01

    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome in which affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Uterine leiomyomas are present in up to 77% of women with this syndrome. Previous studies have shown that inactivation of the FH gene is unusual for nonsyndromic leiomyomas. Therefore, it might be possible to distinguish 2 genetic groups of smooth muscle tumors: the most common group of sporadic uterine leiomyomas without FH gene inactivation and the more unusual group of HLRCC leiomyomas in patients who harbor a germline mutation of FH, although the exact prevalence of hereditary HLRCC is unknown. We reviewed the clinical, morphologic, and genotypic features of uterine leiomyomas in 19 HLRCC patients with FH germline mutations. Patients with HLRCC syndrome were younger in age compared with those with regular leiomyomata. DNA was extracted by microdissection, and analysis of loss of heterozygosity (LOH) at 1q43 was performed. Uterine leiomyomas in HLRCC have young age of onset and are multiple, with size ranging from 1 to 8 cm. Histopathologically, HLRCC leiomyomas frequently had increased cellularity, multinucleated cells, and atypia. All cases showed tumor nuclei with large orangeophilic nucleoli surrounded by a perinucleolar halo similar to the changes found in HLRCC. Occasional mitoses were found in 3 cases; however, the tumors did not fulfill the criteria for malignancy. Our study also showed that LOH at 1q43 was frequent in HLRCC leiomyomas (8/10 cases), similarly to what has been previously found in renal cell carcinomas from HLRCC patients. LOH is considered to be the second hit that inactivates the FH gene. We conclude that uterine leiomyomas associated with HLRCC syndrome have characteristic morphologic

  16. A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey.

    NARCIS (Netherlands)

    Demir, K.; Yntema, H.G.; Altincik, A.; Bober, E.

    2010-01-01

    Noonan syndrome is an autosomal dominant disorder characterized by short stature, typical craniofacial features, and congenital heart defects. The underlying genetic defects were not clear until 2001. This report is the first to describe a molecular analysis and associated clinical features of a

  17. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.

    Science.gov (United States)

    Arnaud, Pauline; Hanna, Nadine; Aubart, Mélodie; Leheup, Bruno; Dupuis-Girod, Sophie; Naudion, Sophie; Lacombe, Didier; Milleron, Olivier; Odent, Sylvie; Faivre, Laurence; Bal, Laurence; Edouard, Thomas; Collod-Beroud, Gwenaëlle; Langeois, Maud; Spentchian, Myrtille; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine

    2017-02-01

    Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience

    Directory of Open Access Journals (Sweden)

    Sun-Jeong Shin

    2015-03-01

    Full Text Available PurposeIsolated gonadotropin-releasing hormone (GnRH deficiency (IGD is classified as Kallmann syndrome (KS with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH. This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH.MethodsTwenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological findings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality features or deafness.ResultsOf the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67±1.35 in males, -1.12±1.86 in females; testis volume was 2.0±1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6 and congenital heart disease (n=4. Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identified in 5 patients from 4 families (16.0%, 4/25 pedigrees. After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function.ConclusionThis study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort.

  19. Clinical, endocrinological, and molecular characterization of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: a single center experience.

    Science.gov (United States)

    Shin, Sun-Jeong; Sul, Yeonah; Kim, Ja Hye; Cho, Ja Hyang; Kim, Gu-Hwan; Kim, Jae Hyun; Choi, Jin-Ho; Yoo, Han-Wook

    2015-03-01

    Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified as Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This study was undertaken to investigate the clinical, endocrinological, and molecular characteristics in Korean patients with KS and nIHH. Twenty-six patients from 25 unrelated families were included. Their clinical, endocrinological, and radiological findings were analyzed retrospectively. Mutation analysis of the GNRH1, GNRHR, KISS1, KISS1R, PROK2, PROKR2, TAC3, TACR3, FGF8, FGFR1, and KAL1 genes was performed in all patients. CHD7 and SOX10 were analyzed in patients with CHARGE (Coloboma, Heart defects, choanae Atresia, Growth retardation, Genitourinary abnormality, Ear abnormality) features or deafness. Of the 26 patients, 16 had KS and 10 had nIHH. At diagnosis, mean chronologic age was 18.1 years in males and 18.0 years in females; height SDS were -0.67±1.35 in males, -1.12±1.86 in females; testis volume was 2.0±1.3 mL; and Tanner stage was 1.5. There were associated anomalies in some of the KS patients: hearing loss (n=6) and congenital heart disease (n=4). Absence or hypoplasia of the olfactory bulb/sulci was found in 84.62% of patients with KS. Molecular defects in KAL1, SOX10, and CHD7 were identified in 5 patients from 4 families (16.0%, 4/25 pedigrees). After sex hormone replacement therapy, there were improvement in sexual characteristics and the sexual function. This study described the clinical, endocrinological, and molecular genetic features in IGD patients in Korea. Although the mutation screening was performed in 10 genes that cause IGD, molecular defects were identified in relatively small proportions of the cohort.

  20. Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics

    Science.gov (United States)

    Wildhardt, Gabriele; Zirn, Birgit; Graul-Neumann, Luitgard M; Wechtenbruch, Juliane; Suckfüll, Markus; Buske, Annegret; Bohring, Axel; Kubisch, Christian; Vogt, Stefanie; Strobl-Wildemann, Gertrud; Greally, Marie; Bartsch, Oliver; Steinberger, Daniela

    2013-01-01

    Objectives Till date, mutations in the genes PAX3 and MITF have been described in Waardenburg syndrome (WS), which is clinically characterised by congenital hearing loss and pigmentation anomalies. Our study intended to determine the frequency of mutations and deletions in these genes, to assess the clinical phenotype in detail and to identify rational priorities for molecular genetic diagnostics procedures. Design Prospective analysis. Patients 19 Caucasian patients with typical features of WS underwent stepwise investigation of PAX3 and MITF. When point mutations and small insertions/deletions were excluded by direct sequencing, copy number analysis by multiplex ligation-dependent probe amplification was performed to detect larger deletions and duplications. Clinical data and photographs were collected to facilitate genotype–phenotype analyses. Setting All analyses were performed in a large German laboratory specialised in genetic diagnostics. Results 15 novel and 4 previously published heterozygous mutations in PAX3 and MITF were identified. Of these, six were large deletions or duplications that were only detectable by copy number analysis. All patients with PAX3 mutations had typical phenotype of WS with dystopia canthorum (WS1), whereas patients with MITF gene mutations presented without dystopia canthorum (WS2). In addition, one patient with bilateral hearing loss and blue eyes with iris stroma dysplasia had a de novo missense mutation (p.Arg217Ile) in MITF. MITF 3-bp deletions at amino acid position 217 have previously been described in patients with Tietz syndrome (TS), a clinical entity with hearing loss and generalised hypopigmentation. Conclusions On the basis of these findings, we conclude that sequencing and copy number analysis of both PAX3 and MITF have to be recommended in the routine molecular diagnostic setting for patients, WS1 and WS2. Furthermore, our genotype–phenotype analyses indicate that WS2 and TS correspond to a clinical spectrum

  1. Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.

    Science.gov (United States)

    Casey, Ruth T; Warren, Anne Y; Martin, Jose Ezequiel; Challis, Benjamin G; Rattenberry, Eleanor; Whitworth, James; Andrews, Katrina A; Roberts, Thomas; Clark, Graeme R; West, Hannah; Smith, Philip S; Docquier, France M; Rodger, Fay; Murray, Vicki; Simpson, Helen L; Wallis, Yvonne; Giger, Olivier; Tran, Maxine; Tomkins, Susan; Stewart, Grant D; Park, Soo-Mi; Woodward, Emma R; Maher, Eamonn R

    2017-11-01

    The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare. To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series. A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS. Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds. Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition. Copyright © 2017 Endocrine Society

  2. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.

    Science.gov (United States)

    Wieczorek, Dagmar; Bögershausen, Nina; Beleggia, Filippo; Steiner-Haldenstätt, Sabine; Pohl, Esther; Li, Yun; Milz, Esther; Martin, Marcel; Thiele, Holger; Altmüller, Janine; Alanay, Yasemin; Kayserili, Hülya; Klein-Hitpass, Ludger; Böhringer, Stefan; Wollstein, Andreas; Albrecht, Beate; Boduroglu, Koray; Caliebe, Almuth; Chrzanowska, Krystyna; Cogulu, Ozgur; Cristofoli, Francesca; Czeschik, Johanna Christina; Devriendt, Koenraad; Dotti, Maria Teresa; Elcioglu, Nursel; Gener, Blanca; Goecke, Timm O; Krajewska-Walasek, Malgorzata; Guillén-Navarro, Encarnación; Hayek, Joussef; Houge, Gunnar; Kilic, Esra; Simsek-Kiper, Pelin Özlem; López-González, Vanesa; Kuechler, Alma; Lyonnet, Stanislas; Mari, Francesca; Marozza, Annabella; Mathieu Dramard, Michèle; Mikat, Barbara; Morin, Gilles; Morice-Picard, Fanny; Ozkinay, Ferda; Rauch, Anita; Renieri, Alessandra; Tinschert, Sigrid; Utine, G Eda; Vilain, Catheline; Vivarelli, Rossella; Zweier, Christiane; Nürnberg, Peter; Rahmann, Sven; Vermeesch, Joris; Lüdecke, Hermann-Josef; Zeschnigk, Michael; Wollnik, Bernd

    2013-12-20

    Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.

  3. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis.

    Science.gov (United States)

    Eikelboom, J W; Anand, S S; Malmberg, K; Weitz, J I; Ginsberg, J S; Yusuf, S

    2000-06-03

    In acute coronary syndrome without ST elevation, the role of unfractionated and low-molecular-weight heparin in aspirin-treated patients remains unclear, and there is conflicting evidence regarding the efficacy and safety of low-molecular-weight heparin (LMWH) relative to unfractionated heparin. We did a systematic overview of the randomised trials to assess the effect of unfractionated heparin and LMWH on death, myocardial infarction, and major bleeding. Randomised trials comparing unfractionated heparin or LMWH with placebo or untreated control, or comparing unfractionated heparin with LMWH, for the short-term and long-term management of patients with acute coronary syndrome without ST elevation, were identified by electronic and manual searches and through contact with experts and industry representatives. Odds ratios for death, myocardial infarction, and major bleeding were calculated for each trial, and results for the individual trials were combined by a modification of the Mantel-Haenszel method. 12 trials, involving a total of 17157 patients, were included. The summary odds ratio (OR) for myocardial infarction or death during short-term (up to 7 days) unfractionated heparin or LMWH compared with placebo or untreated control was 0.53 (95% CI 0.38-0.73; p=0.0001) or 29 events prevented per 1000 patients treated; during short-term LMWH compared with unfractionated heparin was 0.88 (0.69-1.12; p=0.34); and during long-term LMWH (up to 3 months) compared with placebo or untreated control was 0.98 (0.81-1.17; p=0.80). Long-term LMWH was associated with a significantly increased risk of major bleeding (OR 2.26, [95% CI 1.63-3.14], paspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death. There is no convincing difference in efficacy or safety between LMWH and unfractionated heparin. Long-term LMWH has not been proven to confer benefit additional to

  4. Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia

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    Al-Kayal Fadi

    2009-11-01

    Full Text Available Abstract Background Children with Severe Combined Immunodeficiency (SCID lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome is characterized by the sole emergence of oligoclonal auto-reactive T lymphocytes, resulting in erythroderma and enteropathy. Omenn syndrome (OS shares the genetic aetiology of T-B-NK+ SCID, with mutations in RAG1, RAG2, or DCLRE1C. Methods Patients diagnosed with T-B-NK+ SCID or phenotypes suggestive of Omenn syndrome were investigated by molecular genetic studies using gene tightly linked microsatellite markers followed by direct sequencing of the coding regions and splice sites of the respective candidate genes. Results We report the molecular genetic basis of T-B-NK+ SCID in 22 patients and of OS in seven patients all of Arab descent from Saudi Arabia. Among the SCID patients, six (from four families displayed four homozygous missense mutations in RAG1 including V433M, R624H, R394W, and R559S. Another four patients (from three familes showed 3 novel homozygous RAG2 mutations including K127X, S18X, and Q4X; all of which predict unique premature truncations of RAG2 protein. Among Omenn patients, four (from two families have S401P and R396H mutations in RAG1, and a fifth patient has a novel I444M mutation in RAG2. Seven other patients (six SCID and one OS showed a gross deletion in exons 1-3 in DCLRE1C. Altogether, mutations in RAG1/2 and DCLRE1C account for around 50% and 25%, respectively, in our study cohort, a proportion much higher than in previous reported series. Seven (24% patients lack a known genetic aetiology, strongly suggesting that they carry mutations in novel genes associated with SCID and Omenn disorders that are yet to be discovered in the Saudi population. Conclusion Mutation-free patients who lack a known genetic aetiology are likely to carry mutations in the regulatory elements in the SCID-causing genes or in novel genes that are yet to be discovered

  5. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity

    DEFF Research Database (Denmark)

    Gordillo, M.; Vega, H.; Trainer, A.H.

    2008-01-01

    Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth...... and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS...

  6. Narcolepsy and familial advanced sleep-phase syndrome: molecular genetics of sleep disorders.

    NARCIS (Netherlands)

    Tafti, M.; Dauvilliers, Y.; Overeem, S.

    2007-01-01

    Sleep disorders are very prevalent and represent an emerging worldwide epidemic. However, research into the molecular genetics of sleep disorders remains surprisingly one of the least active fields. Nevertheless, rapid progress is being made in several prototypical disorders, leading recently to the

  7. Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

    Science.gov (United States)

    Pucheta-Martinez, Encarna; D'Amelio, Nicola; Lelli, Moreno; Martinez-Torrecuadrada, Jorge L.; Sudol, Marius; Saladino, Giorgio; Gervasio, Francesco Luigi

    2016-07-01

    WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.

  8. Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland

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    Tommiska Johanna

    2011-06-01

    Full Text Available Abstract Background Kallmann syndrome (KS, comprised of congenital hypogonadotropic hypogonadism (HH and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients. Methods Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland. Results The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000 and females (1:125 000 (p = 0.02. The reproductive phenotype of 30 probands (25 men; 5 women ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11 in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men and FGFR1 (all 5 women vs. 4/25 men, but not in other genes. Conclusions Our results suggest that Finnish KS men harbor mutations in gene(s yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies, possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.

  9. C-reactive protein, high-molecular-weight adiponectin and development of metabolic syndrome in the Japanese general population: a longitudinal cohort study.

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    Yoshifumi Saisho

    Full Text Available AIMS: To clarify predictive values of C-reactive protein (CRP and high-molecular-weight (HMW adiponectin for development of metabolic syndrome. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46±8 years who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis. RESULTS: Among 750 subjects, 61 (8.1% developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III criteria and 53 (7.1% developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome. CONCLUSION: Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population.

  10. Molecular characterization of Cystoisospora belli and unizoite tissue cyst in patients with Acquired Immunodeficiency Syndrome.

    Science.gov (United States)

    Velásquez, Jorge Néstor; Osvaldo, Germán Astudillo; Di Risio, Cecilia; Etchart, Cristina; Chertcoff, Agustín Víctor; Perissé, Gladys Elisabet; Carnevale, Silvana

    2011-03-01

    Cystoisospora belli is a coccidian protozoan that can cause chronic diarrhoea, acalculous cholecystitis and cholangiopathy in AIDS patients. We applied molecular methods to identify Cystoisospora at species level in AIDS patients presenting with and without the presence of unizoites in lamina propria. Coprological and histological analyses were performed in stool and/or biopsy samples from 8 Cystoisospora-infected patients. DNA from the same samples was used to amplify 2 fragments of the SSU-rRNA gene and the ITS-1 region. Sequencing of the resulting amplicons identified C. belli infections in all cases, independent of the presence or absence of unizoite tissue cysts. Further work should be considered in order to find molecular targets related to strain variations in C. belli.

  11. Mowat-Wilson syndrome: neurological and molecular study in seven patients

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    José Albino da Paz

    2015-01-01

    Full Text Available Objective To present a seven-cases serie of Mowat-Wilson syndrome (MWS. Method All patients with positive mutation for the ZEB2 were evaluated by a geneticist and a neurologist, with clinical and laboratorial characterization. Results A peculiar facies and mental retardation were present in all patients. The Denver II scale showed intense delay in all aspects, especially fine motor and adaptive. Acquired microcephaly was observed in five patients. Only one patient did not present epilepsy. Epilepsy was focal and predominating in sleep, with status epilepticus in three patients. The initial seizure was associated with fever in most patients (4/6. The EEG showed epileptic focal activity (5/7. The imaging studies revealed total agenesis (4/7 and partial agenesis of the corpus callosum (1/7. Conclusion Physicians who care for patients with mental retardation and epilepsy should be aware of SMW.

  12. The blind leading the obese: the molecular pathophysiology of a human obesity syndrome.

    Science.gov (United States)

    Sheffield, Val C

    2010-01-01

    Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder affecting multiple organ systems and resulting in blindness, obesity, cognitive impairment, and congenital defects. Interest in the etiology of this disorder stems, in part, from the fact that patients with BBS develop common clinical problems, including obesity, diabetes and hypertension. Twelve genes independently causing BBS have been identified. The heterogeneity is explained by the existence of two BBS complexes, the BBSome consisting of seven known BBS proteins, and the BBS chaperone complex consisting of three known BBS proteins. The formation of the BBSome requires the function of the BBS chaperone complex. Both mouse and zebrafish data support a role for BBS genes in cilia function, and in intracellular and intraflagellar trafficking. From the work described here, a common primary function of BBS proteins has emerged, specifically the mediation and regulation of microtubule-based intracellular transport.

  13. Myelodysplastic syndromes: advantages of a combined cytogenetic and molecular diagnostic workup.

    Science.gov (United States)

    Ciabatti, Elena; Valetto, Angelo; Bertini, Veronica; Ferreri, Maria Immacolata; Guazzelli, Alice; Grassi, Susanna; Guerrini, Francesca; Petrini, Iacopo; Metelli, Maria Rita; Caligo, Maria Adelaide; Rossi, Simona; Galimberti, Sara

    2017-10-03

    In this study we present a new diagnostic workup for the myelodysplastic syndromes (MDS) including FISH, aCGH, and somatic mutation assays in addition to the conventional cytogenetics (CC). We analyzed 61 patients by CC, FISH for chromosome 5, 7, 8 and PDGFR rearrangements, aCGH, and PCR for ASXL1, EZH2, TP53, TET2, RUNX1, DNMT3A, SF3B1 somatic mutations. Moreover, we quantified WT1 and RPS14 gene expression levels, in order to find their possible adjunctive value and their possible clinical impact. CC analysis showed 32% of patients with at least one aberration. FISH analysis detected chromosomal aberrations in 24% of patients and recovered 5 cases (13.5%) at normal karyotype (two 5q- syndromes, one del(7) case, two cases with PDGFR rearrangement). The aGCH detected 10 "new" unbalanced cases in respect of the CC, including one with alteration of the ETV6 gene. After mutational analysis, 33 patients (54%) presented at least one mutation and represented the only marker of clonality in 36% of all patients. The statistical analysis confirmed the prognostic role of CC either on overall or on progression-free-survival. In addition, deletions detected by aCGH and WT1 over-expression negatively conditioned survival. In conclusion, our work showed that 1) the addition of FISH (at least for chr. 5 and 7) can improve the definition of the risk score; 2) mutational analysis, especially for the TP53 and SF3B1, could better define the type of MDS and represent a "clinical warning"; 3) the aCGH use could be probably applied to selected cases (with suboptimal response or failure).

  14. Pathogenicity and molecular characterization of emerging porcine reproductive and respiratory syndrome virus in Vietnam in 2007.

    Science.gov (United States)

    Metwally, S; Mohamed, F; Faaberg, K; Burrage, T; Prarat, M; Moran, K; Bracht, A; Mayr, G; Berninger, M; Koster, L; To, T L; Nguyen, V L; Reising, M; Landgraf, J; Cox, L; Lubroth, J; Carrillo, C

    2010-10-01

    In 2007, Vietnam experienced swine disease outbreaks causing clinical signs similar to the 'porcine high fever disease' that occurred in China during 2006. Analysis of diagnostic samples from the disease outbreaks in Vietnam identified porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV-2). Additionally, Escherichia coli and Streptococcus equi subspecies zooepidemicus were cultured from lung and spleen, and Streptococcus suis from one spleen sample. Genetic characterization of the Vietnamese PRRSV isolates revealed that this virus belongs to the North American genotype (type 2) with a high nucleotide identity to the recently reported Chinese strains. Amino acid sequence in the nsp2 region revealed 95.7-99.4% identity to Chinese strain HUN4, 68-69% identity to strain VR-2332 and 58-59% identity to strain MN184. A partial deletion in the nsp2 gene was detected; however, this deletion did not appear to enhance the virus pathogenicity in the inoculated pigs. Animal inoculation studies were conducted to determine the pathogenicity of PRRSV and to identify other possible agents present in the original specimens. Pigs inoculated with PRRSV alone and their contacts showed persistent fever, and two of five pigs developed cough, neurological signs and swollen joints. Necropsy examination showed mild to moderate bronchopneumonia, enlarged lymph nodes, fibrinous pericarditis and polyarthritis. PRRSV was re-isolated from blood and tissues of the inoculated and contact pigs. Pigs inoculated with lung and spleen tissue homogenates from sick pigs from Vietnam developed high fever, septicaemia, and died acutely within 72 h, while their contact pigs showed no clinical signs throughout the experiment. Streptococcus equi subspecies zooepidemicus was cultured, and PRRSV was re-isolated only from the inoculated pigs. Results suggest that the cause of the swine deaths in Vietnam is a multifactorial syndrome with PRRSV as a major factor. © 2010

  15. [Molecular cytogenetic analysis of a case with ring chromosome 3 syndrome].

    Science.gov (United States)

    Zhang, Kaihui; Song, Fengling; Zhang, Dongdong; Zhang, Haiyan; Wang, Ying; Dong, Rui; Zhang, Yufeng; Liu, Yi; Gai, Zhongtao

    2016-12-10

    To investigate the genetic cause for a child with developmental delay and congenital heart disease through molecular cytogenetic analysis. G-banded karyotyping and chromosomal microarray analysis (CMA) were performed for the patient and his parents. The proband's karyotype was detected as ring chromosome 3, and a 3q26.3-25.3 deletion encompassing 45 genes has been found with CMA. Testing of both parents was normal. Clinical phenotype of the patient with ring chromosome 3 mainly depends on the involved genes. It is necessary to combine CMA and karyotyping for the diagnosis of ring chromosome, as CMA can provide more accurate information for variations of the genome.

  16. Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

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    Kimie Matsunaga

    Full Text Available BACKGROUND: Wolfram syndrome (WFS is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1. However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. METHODOLOGY: The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. PRINCIPAL FINDINGS: Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49% having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5% had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5% had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. CONCLUSION/SIGNIFICANCE: This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may

  17. Revisiting the Molecular Mechanism of Neurological Manifestations in Antiphospholipid Syndrome: Beyond Vascular Damage

    Science.gov (United States)

    Carecchio, M.; Cantello, R.; Comi, C.

    2014-01-01

    Antiphospholipid syndrome (APS) is a multiorgan disease often affecting the central nervous system (CNS). Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. In these cases, alterations of the coagulation system at various levels caused by multiple effects of antiphospholipid antibodies (aPL) have been postulated to explain the vascular damage to the CNS in APS. However, several nonvascular neurological manifestations of APS have progressively emerged over the past years. Nonthrombotic, immune-mediated mechanisms altering physiological basal ganglia function have been recently suggested to play a central role in the pathogenesis of these manifestations that include, among others, movement disorders such as chorea and behavioral and cognitive alterations. Similar clinical manifestations have been described in other autoimmune CNS diseases such as anti-NMDAR and anti-VGCK encephalitis, suggesting that the spectrum of immune-mediated basal ganglia disorders is expanding, possibly sharing some pathophysiological mechanisms. In this review, we will focus on thrombotic and nonthrombotic neurological manifestations of APS with particular attention to immune-mediated actions of aPL on the vascular system and the basal ganglia. PMID:24741580

  18. Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome

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    Inka Sastalla

    2017-06-01

    Full Text Available Autosomal dominant hyper IgE syndrome (AD-HIES is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3. This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST, protein A (spa typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13 found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL, and staphylococcal enterotoxins K and Q (SEK, SEQ. Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.

  19. Revisiting the Molecular Mechanism of Neurological Manifestations in Antiphospholipid Syndrome: Beyond Vascular Damage

    Directory of Open Access Journals (Sweden)

    M. Carecchio

    2014-01-01

    Full Text Available Antiphospholipid syndrome (APS is a multiorgan disease often affecting the central nervous system (CNS. Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. In these cases, alterations of the coagulation system at various levels caused by multiple effects of antiphospholipid antibodies (aPL have been postulated to explain the vascular damage to the CNS in APS. However, several nonvascular neurological manifestations of APS have progressively emerged over the past years. Nonthrombotic, immune-mediated mechanisms altering physiological basal ganglia function have been recently suggested to play a central role in the pathogenesis of these manifestations that include, among others, movement disorders such as chorea and behavioral and cognitive alterations. Similar clinical manifestations have been described in other autoimmune CNS diseases such as anti-NMDAR and anti-VGCK encephalitis, suggesting that the spectrum of immune-mediated basal ganglia disorders is expanding, possibly sharing some pathophysiological mechanisms. In this review, we will focus on thrombotic and nonthrombotic neurological manifestations of APS with particular attention to immune-mediated actions of aPL on the vascular system and the basal ganglia.

  20. Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5.

    Directory of Open Access Journals (Sweden)

    Joshi Stephen

    Full Text Available Hermansky-Pudlak syndrome (HPS is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs, which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts.

  1. Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome.

    Science.gov (United States)

    Clarke, S D

    2001-04-01

    This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the (n-3) family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation, and that they enhance glucose flux to glycogen. In doing this, PUFA may protect against the adverse symptoms of the metabolic syndrome and reduce the risk of heart disease. PUFA exert their beneficial effects by up-regulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA-binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA-binding activities of nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among criteria used in defining the dietary needs of (n-6) and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) needed for optimum health benefit.

  2. Molecular genetic analysis of individuals with Williams syndrome and supravalvar aortic stenosis

    Energy Technology Data Exchange (ETDEWEB)

    Smoot, L.B.; Lacro, R.V.; Kunkel, L.M. [Children`s Hospital, Boston, MA (United States); Pober, B. [Yale Univ., New Haven, CT (United States)

    1994-09-01

    Mutations at the elastin locus (chromosome 7q11.23) have been demonstrated in individuals with Williams syndrome (WS) and familial supravalvar aortic stenosis (SVAS). Relationships between elastin mutations and vascular and/or neurodevelopmental pathology have yet to be defined. In determining phenotype-genotype correlations in WS/SVAS, we examined 35 individuals with sporadic WS, families with SVAS affecting multiple members, and sporadic cases of isolated obstructive vascular disease. Full length elastin cDNA was used to probe a human genomic library from which multiple elastin genomic clones have been isolated and ordered relative to the elastin gene, covering a minimum of 35 kb. (Additional genomic clones are being obtained by {open_quote}walking{close_quote} 5{prime} and 3{prime} to elastin.) Elastin genomic clones were used as probes in fluorescent in situ hybridization of metaphase chromosomes from WS/SVAS patients. Preliminary analysis confirms elastin deletions in WS patients, but have not yet been demonstrated in patients with isolated vascular disease using this technique. Results of deletional analysis in individuals representing a wide spectrum of phenotypes will be presented.

  3. Analysis of molecular forms of urine Retinol-Binding Protein in Fanconi Syndrome and design of an accurate immunoassay.

    Science.gov (United States)

    Burling, Keith A; Cutillas, Pedro R; Church, David; Lapsley, Marta; Norden, Anthony G W

    2012-02-18

    Retinol-Binding Protein in urine (uRBP), a biomarker for the proximal renal tubular disease of congenital and acquired Fanconi Syndrome (FS) occurs in multiple forms. However these have not had quantitative mass spectrometric (MS) analysis, nor is there a validated assay for defined molecular species of uRBP with linearity on sample dilution. A 'Top-down' MS approach identified distinct forms of uRBP differing by only one amino acid. Based on this, we designed a dual-monoclonal antibody-based fluorescence immunoassay calibrated with intact plasma RBP4. LC-MS showed that uRBP in FS (one Dent disease urine) comprised intact plasma RBP4 and C-terminal-truncated RBP4, desL-RBP4 and desLL-RBP4 in molar ratio 2:2:1. DELFIA® assay calibrated with plasma RBP4, formulated with two monoclonal antibodies (HyTest, Finland), mAb48 for capture and biotinylated-mAb42 for detection, provided good sensitivity (1 μg/L), working range>500 μg/L and good linearity on sample dilution. The three predominant forms of uRBP were equipotent over the assay working range. uRBP reference range was <3 μg/mmol creatinine and FS patients had concentrations of 1000-5000 μg/mmol creatinine. Using 'Top-down' MS analysis of uRBP we devised an accurate, linear, fluorescence immunoassay with defined RBP molecular targets optimal for uRBP measurement. Discrimination of elevated uRBP from the upper limit of normal was some 10-fold greater than previous assays. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome

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    Chardot Christophe

    2011-01-01

    Full Text Available Abstract Background DNA polymerase γ (POLG is the only known mitochondrial DNA (mtDNA polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS. Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. Methods mtDNA content in various tissues (fibroblasts, muscle and liver was quantified using quantitative PCR (qPCR. OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. Results We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome. These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. Conclusions mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.

  5. Molecular Origin of Gerstmann-Str ussler-Scheinker Syndrome: Insight from Computer Simulation of an Amyloidogenic Prion Peptide

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    Diadone, Isabella [University of L' Aquila, L' Aquila, Italy; DiNola, Alfredo [University of Rome; Smith, Jeremy C [ORNL

    2011-01-01

    Prion proteins become pathogenic through misfolding. Here, we characterize the folding of a peptide consisting of residues 109 122 of the Syrian hamster prion protein (the H1 peptide) and of a more amyloidogenic A117V point mutant that leads in humans to an inheritable form of the Gerstmann-Straeussler-Scheinker syndrome. Atomistic molecular dynamics simulations are performed for 2.5 s. Both peptides lose their -helical starting conformations and assume a -hairpin that is structurally similar in both systems. In each simulation several unfolding/refolding events occur, leading to convergence of the thermodynamics of the conformational states to within 1 kJ/mol. The similar stability of the -hairpin relative to the unfolded state is observed in the two peptides. However, substantial differences are found between the two unfolded states. A local minimum is found within the free energy unfolded basin of the A117V mutant populated by misfolded collapsed conformations of comparable stability to the -hairpin state, consistent with increased amyloidogenicity. This population, in which V117 stabilizes a hydrophobic core, is absent in the wild-type peptide. These results are supported by simulations of oligomers showing a slightly higher stability of the associated structures and a lower barrier to association for the mutated peptide. Hence, a single point mutation carrying only two additional methyl groups is here shown to be responsible for rather dramatic differences of structuring within the unfolded (misfolded) state.

  6. ISOLATION OF EGG DROP SYNDROME VIRUS AND ITS MOLECULAR CHARACTERIZATION USING SODIUM DODECYL SULPHATE POLYACRYLAMIDE GEL ELECTROPHORESIS

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    M. H. Rasool, S. U. Rahman and M. K. Mansoor

    2005-10-01

    Full Text Available Six isolates of egg drop syndrome (EDS virus were recovered from five different outbreaks of EDS in commercial laying hens in and around Faisalabad. The aberrant eggs were fed to the susceptible laying hens for experimental induction of infection. The samples from infected birds (egg washing, cloacal swabs, oviducts and spleens were collected, processed and inoculated into 11-day old duck embryos. The presence of virus in harvested allanto-amniotic fluid was monitored by spot and microhaemagglutination tests and confirmed by haemagglutination inhibition and agar gel precipitation tests. The EDS virus grew well in duck embryos and agglutinated only avian but not mammalian red blood cells. These isolates were purified through velocity density gradient centrifugation. Protein concentration was determined through Lowry method and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE was conducted by loading 300 µg protein concentration on 12.5% gel using discontinuous buffer system. All the six isolates showed 13 polypeptides, which were identical to those described in the referral EDS-76 virus (strain-127. The molecular weights of the polypeptides ranged from 6.5 KDa to 126 KDa.

  7. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.

    Science.gov (United States)

    Weerakkody, Ruwan A; Vandrovcova, Jana; Kanonidou, Christina; Mueller, Michael; Gampawar, Piyush; Ibrahim, Yousef; Norsworthy, Penny; Biggs, Jennifer; Abdullah, Abdulshakur; Ross, David; Black, Holly A; Ferguson, David; Cheshire, Nicholas J; Kazkaz, Hanadi; Grahame, Rodney; Ghali, Neeti; Vandersteen, Anthony; Pope, F Michael; Aitman, Timothy J

    2016-11-01

    Ehlers-Danlos syndrome (EDS) comprises a group of overlapping hereditary disorders of connective tissue with significant morbidity and mortality, including major vascular complications. We sought to identify the diagnostic utility of a next-generation sequencing (NGS) panel in a mixed EDS cohort. We developed and applied PCR-based NGS assays for targeted, unbiased sequencing of 12 collagen and aortopathy genes to a cohort of 177 unrelated EDS patients. Variants were scored blind to previous genetic testing and then compared with results of previous Sanger sequencing. Twenty-eight pathogenic variants in COL5A1/2, COL3A1, FBN1, and COL1A1 and four likely pathogenic variants in COL1A1, TGFBR1/2, and SMAD3 were identified by the NGS assays. These included all previously detected single-nucleotide and other short pathogenic variants in these genes, and seven newly detected pathogenic or likely pathogenic variants leading to clinically significant diagnostic revisions. Twenty-two variants of uncertain significance were identified, seven of which were in aortopathy genes and required clinical follow-up. Unbiased NGS-based sequencing made new molecular diagnoses outside the expected EDS genotype-phenotype relationship and identified previously undetected clinically actionable variants in aortopathy susceptibility genes. These data may be of value in guiding future clinical pathways for genetic diagnosis in EDS.Genet Med 18 11, 1119-1127.

  8. Molecular etiology and genotype-phenotype correlation of Chinese Han deaf patients with type I and type II Waardenburg Syndrome

    Science.gov (United States)

    Sun, Lianhua; Li, Xiaohua; Shi, Jun; Pang, Xiuhong; Hu, Yechen; Wang, Xiaowen; Wu, Hao; Yang, Tao

    2016-01-01

    Waardenburg syndrome (WS) characterized by sensorineural hearing loss and pigmentary abnormalities is genetically heterogeneous and phenotypically variable. This study investigated the molecular etiology and genotype-phenotype correlation of WS in 36 Chinese Han deaf probands and 16 additional family members that were clinically diagnosed with WS type I (WS1, n = 8) and type II (WS2, n = 42). Mutation screening of six WS-associated genes detected PAX3 mutations in 6 (86%) of the 7 WS1 probands. Among the 29 WS2 probands, 13 (45%) and 10 (34%) were identified with SOX10 and MITF mutations, respectively. Nineteen of the 26 detected mutations were novel. In WS2 probands whose parental DNA samples were available, de novo mutations were frequently seen for SOX10 mutations (7/8) but not for MITF mutations (0/5, P = 0.005). Excessive freckle, a common feature of WS2 in Chinese Hans, was frequent in WS2 probands with MITF mutations (7/10) but not in those with SOX10 mutations (0/13, P = 4.9 × 10−4). Our results showed that mutations in SOX10 and MITF are two major causes for deafness associated with WS2. These two subtypes of WS2 can be distinguished by the high de novo rate of the SOX10 mutations and the excessive freckle phenotype exclusively associated with the MITF mutations. PMID:27759048

  9. Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC.

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    A Mesut Erzurumluoglu

    Full Text Available Papillon-Lefevre syndrome (PLS is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis. A previously reported missense mutation in the CTSC gene (NM_001814.4:c.899G>A:p.(G300D was identified in a homozygous state in two siblings diagnosed with PLS in a consanguineous family of Arabic ancestry. The variant was initially identified in a heterozygous state in a PLS unaffected sibling whose whole exome had been sequenced as part of a previous Primary ciliary dyskinesia study. Using this information, a proxy molecular diagnosis was made on the PLS affected siblings after consent was given to study this second disorder found to be segregating within the family. The prevalence of the mutation was then assayed in the local population using a representative sample of 256 unrelated individuals. The variant was absent in all subjects indicating that the variant is rare in Saudi Arabia. This family study illustrates how whole-exome sequencing can generate findings and inferences beyond its primary goal.

  10. Molecular cloning, expression and characterization of 100K gene of fowl adenovirus-4 for prevention and control of hydropericardium syndrome.

    Science.gov (United States)

    Shah, M S; Ashraf, A; Khan, M I; Rahman, M; Habib, M; Qureshi, J A

    2016-01-01

    Fowl adenovirus-4 is an infectious agent causing Hydropericardium syndrome in chickens. Adenovirus are non-enveloped virions having linear, double stranded DNA. Viral genome codes for few structural and non structural proteins. 100K is an important non-structural viral protein. Open reading frame for coding sequence of 100K protein was cloned with oligo histidine tag and expressed in Escherichia coli as a fusion protein. Nucleotide sequence of the gene revealed that 100K gene of FAdV-4 has high homology (98%) with the respective gene of FAdV-10. Recombinant 100K protein was expressed in E. coli and purified by nickel affinity chromatography. Immunization of chickens with recombinant 100K protein elicited significant serum antibody titers. However challenge protection test revealed that 100K protein conferred little protection (40%) to the immunized chicken against pathogenic viral challenge. So it was concluded that 100K gene has 2397 bp length and recombinant 100K protein has molecular weight of 95 kDa. It was also found that the recombinant protein has little capacity to affect the immune response because in-spite of having an important role in intracellular transport & folding of viral capsid proteins during viral replication, it is not exposed on the surface of the virus at any stage. Copyright © 2015 The International Alliance for Biological Standardization. All rights reserved.

  11. Respiratory Failure due to Severe Obesity and Kyphoscoliosis in a 24-Year-Old Male with Molecularly Confirmed Prader-Willi Syndrome in Tertiary Hospital in Northern Tanzania

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    Elichilia R. Shao

    2017-01-01

    Full Text Available Obesity, mild intellectual disability, hypotonia, poor sucking, cryptorchidism in males, hypogonadism, and kyphoscoliosis are common features of Prader-Willi syndrome (PWS. We report a case who had severe respiratory complications due to extreme obesity and kyphoscoliosis, which are important causes of morbidity and mortality, and discuss management. Furthermore, this is the first molecularly confirmed PWS case in Sub-Saharan Africa outside South Africa.

  12. Molecular analysis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5 reveals a specific spectrum of molecular mutations with prognostic impact: a study on 123 patients and 27 genes

    Science.gov (United States)

    Meggendorfer, Manja; Haferlach, Claudia; Kern, Wolfgang; Haferlach, Torsten

    2017-01-01

    The only cytogenetic aberration defining a myelodysplastic syndrome subtype is the deletion of the long arm of chromosome 5, which, along with morphological features, leads to the diagnosis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. These patients show a good prognosis and respond to treatment such as lenalidomide, but some cases progress to acute myeloid leukemia; however, the molecular mutation pattern is rarely characterized. Therefore, we investigated a large cohort of 123 myelodysplastic syndrome patients with isolated deletion of the long arm of chromosome 5, diagnosed following the World Health Organization classifications 2008 and 2016, by sequencing 27 genes. A great proportion of patients showed no or only one mutation. Only seven genes showed mutation frequencies >5% (SF3B1, DNMT3A, TP53, TET2, CSNK1A1, ASXL1, JAK2). However, the pattern of recurrently mutated genes was comparable to other myelodysplastic syndrome subtypes by comparison to a reference cohort, except that of TP53 which was significantly more often mutated in myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. As expected, SF3B1 was frequently mutated and correlated with ring sider-oblasts, while JAK2 mutations correlated with elevated platelet counts. Surprisingly, SF3B1 mutations led to significantly worse prognosis within cases with isolated deletion of the long arm of chromosome 5, but showed a comparable outcome to other myelodysplastic syndrome subtypes with SF3B1 mutation. However, addressing genetic stability in follow-up cases might suggest different genetic mechanisms for progression to secondary acute myeloid leukemia compared to overall myelodysplastic syndrome patients. PMID:28642303

  13. Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene.

    Science.gov (United States)

    Glushkova, Maria; Dimova, Petia; Yordanova, Iglika; Todorov, Tihomir; Tourtourikov, Ivan; Mitev, Vanyo; Todorova, Albena

    2018-02-01

    Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. To study five patients with clinically suspected Von Hippel-Lindau syndrome, who were referred for molecular genetic testing. Sanger sequencing of the coding regions of the VHL gene. Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies.

  14. High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects.

    Science.gov (United States)

    de Abreu, Virgínia Genelhu; Martins, Cyro José de Moraes; de Oliveira, Patricia Aguiar Cardoso; Francischetti, Emilio Antonio

    2017-01-01

    Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be

  15. Molecular responses of the Ts65Dn and Ts1Cje mouse models of Down syndrome to MK-801.

    Science.gov (United States)

    Siddiqui, A; Lacroix, T; Stasko, M R; Scott-McKean, J J; Costa, A C S; Gardiner, K J

    2008-10-01

    Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21-encoded, confirmed protein-coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the high-affinity N-methyl-d-aspartate (NMDA) receptor (NMDAR) channel blocker, MK-801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR-mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 protein-coding genes, is also hypersensitive to MK-801. To investigate the molecular basis for the responses to MK-801, we have measured levels of a subset of chr21 and phosphorylated non-chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK-801. We show that in euploid mice, the chr21-encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK-801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naïve, unstimulated mice, and the MK-801-induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain-region-specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.

  16. Epidemiology and Molecular Characteristics of Mycoplasma pneumoniae During an Outbreak of M. pneumoniae-associated Stevens-Johnson Syndrome.

    Science.gov (United States)

    Watkins, Louise K Francois; Olson, Daniel; Diaz, Maureen H; Lin, Xia; Demirjian, Alicia; Benitez, Alvaro J; Winchell, Jonas M; Robinson, Christine C; Bol, Kirk A; Glodé, Mary P; Dominguez, Samuel R; Miller, Lisa A; Kutty, Preeta K

    2017-06-01

    An increase in Mycoplasma pneumoniae-associated Stevens-Johnson syndrome (SJS) cases at a Colorado pediatric hospital led to an outbreak investigation. We describe the epidemiologic and molecular characteristics of M. pneumoniae among SJS case-patients and surrounding community members during the outbreak. M. pneumoniae polymerase chain reaction-positive respiratory specimens from 5 Colorado hospitals and 4 referral laboratories underwent confirmatory polymerase chain reaction testing; positive specimens then underwent multilocus variable-number tandem-repeat analysis (MLVA) and macrolide resistance testing. Three SJS-M. pneumoniae case-patient households were surveyed using a standardized questionnaire, and nasopharyngeal/oropharyngeal swabs were obtained from all consenting/assenting household contacts. International Classification of Diseases, 9th revision codes were used to identify pneumonia cases among Colorado patients 5-21 years of age from January 2009 to March 2014. Three different M. pneumoniae MLVA types were identified among the 5 SJS case-patients with confirmed infection; MLVA type 3-X-6-2 was seen more commonly in SJS case-patients (60%) than in 69 non-SJS community specimens (29%). Macrolide resistance was identified in 7% of community specimens but not among SJS case-patients. Of 15 household contacts, 5 (33%) were M. pneumoniae positive; all MLVA types were identical to those of the corresponding SJS case-patient, although the specimen from 1 contact was macrolide resistant. Overall pneumonia cases as well as those caused by M. pneumoniae specifically peaked in October 2013, coinciding with the SJS outbreak. The outbreak of M. pneumoniae-associated SJS may have been associated with a community outbreak of M. pneumoniae; clinicians should be aware of the M. pneumoniae-SJS relationship. Household transmission of M. pneumoniae was common within the households investigated.

  17. Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome

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    Samar M. Said

    2017-01-01

    Discussion: Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

  18. Inherited ichthyosis: Syndromic forms.

    Science.gov (United States)

    Yoneda, Kozo

    2016-03-01

    Among diseases that cause ichthyosis as one of the symptoms, there are some diseases that induce abnormalities in organs other than the skin. Of these, diseases with characteristic signs are regarded as syndromes. Although these syndromes are very rare, Netherton syndrome, Sjögren-Larsson syndrome, Conradi-Hünermann-Happle syndrome, Dorfman-Chanarin syndrome, ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome, and Refsum syndrome have been described in texts as representative ones. It is important to know the molecular genetics and pathomechanisms in order to establish an effective therapy and beneficial genetic counseling including a prenatal diagnosis. © 2016 Japanese Dermatological Association.

  19. Molecular diagnosis of Prader-Willi syndrome: Parent-of-origin dependent methylation sites and non-isotopic detection of (CA){sub n} dinucleotide repeat polymorphisms

    Energy Technology Data Exchange (ETDEWEB)

    Lerer, I.; Meiner, V.; Pashut-Lavon, I.; Abeliovich, D.

    1994-08-01

    We describe our experience in the molecular diagnosis of 22 patients suspected of Prader-Willi syndrome (PWS) using a DNA probe PW71 (D15S63) which detects a parent-of-origin specific methylated site in the PWS critical region. The cause of the syndrome was determined as deletion or uniparental disomy according to the segregation of (CA){sub n} dinucleotide repeat polymorphisms of the PWS/AS region and more distal markers of chromosome 15. In 10 patients the clinical diagnosis was confirmed by the segregation of (CA){sub n}, probably due to paternal microdeletion in the PWs critical region which did not include the loci D15S97, D15S113, GABRB3, and GABRA5. This case demonstrates the advantage of the DNA probe PW71 in the diagnosis of PWS. 31 refs., 2 figs., 3 tabs.

  20. Molecular cytogenetic analysis of Inv Dup(15) chromosomes, using probes specific for the Pradar-Willi/Angelman syndrome region: Clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    Leana-Cox, J. (Univ. of Maryland School of Medicine, Baltimore, MD (United States)); Jenkins, L. (Kaiser Permanente Medical Group, San Jose, CA (United States)); Palmer, C.G.; Plattner, R. (Indiana School of Medicine, Indianapolis, IN (United States)); Sheppard, L. (Palo Verde Laboratory, Inc., Chandler, AZ (United States)); Flejter, W.L. (Univ. of Michigan, Ann Arbor, MI (United States)); Zackowski, J. (Univ. of Florida Health Science Center, Gainsville, FL (United States)); Tsien, F. (Tulane Univ. School of Medicine, New Orleans, LA (United States)); Schwartz, S. (Case Western Reserve Univ., Cleveland, OH (United States))

    1994-05-01

    Twenty-seven cases of inverted duplications of chromosome 15 (inv dup[15]) were investigated by FISH with two DNA probes specific for the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on proximal 15q. Sixteen of the marker chromosomes displayed two copies of each probe, while in the remaining 11 markers no hybridization was observed. A significant association was found between the presence of this region and an abnormal phenotype (P<.01). This is the largest study to date of inv dup(15) chromosomes, that uses molecular cytogenetic methods and is the first to report a significant association between the presence of a specific chromosomal region in such markers and an abnormal phenotype. 30 refs., 1 fig., 4 tabs.

  1. Molecular Study of Three Lebanese and Syrian Patients with Waardenburg Syndrome and Report of Novel Mutations in the EDNRB and MITF Genes

    Science.gov (United States)

    Haddad, N.M.; Ente, D.; Chouery, E.; Jalkh, N.; Mehawej, C.; Khoueir, Z.; Pingault, V.; Mégarbané, A.

    2011-01-01

    Waardenburg syndrome (WS) is a genetic disorder characterized primarily by depigmentation of the skin and hair, heterochromia of the irides, sensorineural deafness, and sometimes by dystopia canthorum, and Hirschsprung disease. WS presents a large clinical and genetic heterogeneity. Four different types have been individualized and linked to 5 different genes. We report 2 cases of WS type II and 1 case of WS type IV from Lebanon and Syria. The genetic studies revealed 2 novel mutations in the MITF gene of the WS type II cases and 1 novel homozygous mutation in the EDNRB gene of the WS type IV case. This is the first molecular study of patients from the Arab world. Additional cases will enable a more detailed description of the clinical spectrum of Waardenburg syndrome in this region. PMID:21373256

  2. Congenital abnormalities of cranial nerve development: overview, molecular mechanisms, and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements.

    Science.gov (United States)

    Traboulsi, Elias I

    2004-01-01

    The clinical and molecular genetic classification of syndromes with congenital limitation of eye movements and evidence of cranial nerve dysgenesis continues to evolve. This monograph details clinical and molecular genetic data on a number of families and isolated patients with congenital fibrosis of the extraocular muscles (CFEOM) and related disorders, and presents an overview of the mechanisms of abnormal patterns of motor and sensory cranial nerve development in these rare syndromes. Clinical examination of one patient with CFEOM1, one family with clinical features of CFEOM2, one family with recessive CFEOM3, one family with horizontal gaze palsy and progressive scoliosis (HGPPS), and four patients with various combinations of congenital cranial nerve abnormalities. Genotyping of families with CFEOM and HGPPS for polymorphic markers in the regions of the three known CFEOM loci and in the HGPPS region, and mutation analysis of the ARIX and KIF21A genes in patients with CFEOM were performed according to standard published protocols. The patient with CFEOM1 had the second most common mutation in KIF21A, a 2861 G>A mutation that resulted in an R954Q substitution. The family with CFEOM2 phenotype did not map to the CFEOM2 locus. The family with recessive CFEOM3 did not map to any of the known loci. The HGPPS family mapped to 11q23-q25. One patient had optic nerve hypoplasia and fifth nerve dysfunction. Two patients had the rare combination of Möbius syndrome and CFEOM. One patient had Möbius syndrome and fifth nerve dysfunction. There is genetic heterogeneity in CFEOM2 and CFEOM3. Abnormalities in sensory nerves can also accompany abnormalities of motor nerves, further substantiating the effect of individual mutations on developing motor as well as sensory cranial nerve nuclei.

  3. Mandibulofacial dysostosis (Treacher-Collins syndrome) in the fetus: novel association with Pectus carinatum in a molecularly confirmed case and review of the fetal phenotype.

    Science.gov (United States)

    Konstantinidou, Anastasia E; Tasoulas, Jason; Kallipolitis, Georgios; Gasparatos, Spyros; Velissariou, Voula; Paraskevakou, Helen

    2013-12-01

    Treacher Collins syndrome is the most common mandibulofacial dysostosis of autosomal dominant or, rarely, recessive inheritance. Affected fetuses may be identified by prenatal ultrasound or diagnosed at autopsy in case of perinatal death or pregnancy termination. We describe the ultrasonographic, autopsy, and molecular findings in a 25-week-gestation affected fetus, and review the clinical, prenatal, and postmortem findings in 15 previously reported fetal and perinatal cases. A nearly complete spectrum of the typical facial characteristics can be present by the early second trimester of gestation, including subtle defects such as lower eyelid colobomas. Mandibular hypoplasia and bilateral auricle defects were constant findings in the affected fetal population. Downslanting palpebral fissures were the second more common feature, followed by midface hypoplasia, polyhydramnios, and ocular defects. Association with Pierre Robin sequence was common (38%) in the reviewed series. Previously unreported pectus carinatum was noted in our case bearing a heterozygous TCOF1 mutation. Other unique reported findings include salivary gland hyperplasia, single umbilical artery, and tracheo-esophageal fistula, all in molecularly unconfirmed cases. Treacher Collins syndrome can be prenatally detected by ultrasound and should be included in the wide range of genetic syndromes that can be diagnosed at perinatal autopsy. Affected fetuses tend to have a more severe phenotype than living patients. The reported association of Treacher Collins syndrome type 1 with pectus carinatum expands the phenotype, provides information on genotype-phenotype correlation, and suggests possible pathogenetic interactions between neural crest cell disorders and the formation of the sternum that merit investigation. Copyright © 2013 Wiley Periodicals, Inc.

  4. X-linked hyper-immunoglobulin M syndrome: molecular genetic study and long-time follow-up of three generations of a Chinese family.

    Science.gov (United States)

    Lin, Sheng-Chieh; Shyur, Shyh-Dar; Lee, Wen-I; Ma, Yi-Chun; Huang, Li-Hsin

    2006-01-01

    X-linked hyper-immunoglobulin M (IgM) syndrome (XHIGM) is a rare immunodeficiency disease caused by mutations of the CD40 ligand gene. Patients are subject to recurrent infections and have normal or elevated levels of IgM but markedly decreased serum IgG. We describe molecular genetic studies and clinical manifestations in three generations of one family, as well as results of long-term treatment of 2 young men with the disorder. Of 37 living family members, mutational analysis of the CD40 ligand gene was performed in 36 members. Laboratory data for patients and carriers were reviewed. Four male family members had died of unexplained causes. The 3 patients with XHIGM syndrome and the 5 carriers all had a novel mutation located at Tyr 169 Asn (T526A) in exon 5, the tumor necrosis factor domain of the CD40 ligand gene. In the 3 patients, CD40 ligand expression in activated CD4+ T cells was below 1%. In the carriers, about half of activated CD4+ cells expressed CD40 ligand. One carrier had malignant lymphoma. Long-term (>20 years) intravenous immunoglobulin therapy in 2 patients improved IgG levels but did not fully suppress the high levels of IgM, nor did it prevent late complications (bronchiectasis and sclerosing cholangitis). Diagnosis of a genetic immunodeficiency, especially an X-linked disease such as XHIGM syndrome, should prompt a survey of the entire family. Copyright 2006 S. Karger AG, Basel.

  5. Two Likely Pathogenic Variants of COL2A1 in Unrelated Korean Patients With Ocular-Only Variants of Stickler Syndrome: The First Molecular Diagnosis in Korea.

    Science.gov (United States)

    Yoon, Je Moon; Jang, Mi-Ae; Ki, Chang-Seok; Kim, Sang Jin

    2016-03-01

    Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, auditory, and musculoskeletal systems. Ocular-only variant of Stickler syndrome type 1 (OSTL1) is characterized by high risk of retinal detachment without systemic involvement and is caused by alternatively spliced exon 2 mutation of COL2A1. We report the cases of two Korean families with OSTL1 carrying likely pathogenic variants of COL2A1. All patients presented with membranous vitreous anomaly, peripheral retinal degeneration, and/or rhegmatogenous retinal detachment, but no systemic manifestations. By genetic analysis, two likely pathogenic non-exon 2 variants, c.2678dupC (p.Ala895Serfs*49) and c.3327+ 1G>C, were identified in COL2A1. Our results demonstrate that COL2A1 defects in OSTL1 are not confined to mutations in exon 2. Together with molecular data, ophthalmologists should consider genetic diagnosis of Stickler syndrome in patients with vitreous anomaly to prevent blindness from retinal detachment. To our knowledge, this is the first report of genetically confirmed OSTL1 in Korea.

  6. Discovery of molecular mechanism of a clinical herbal formula upregulating serum HDL-c levels in treatment of metabolic syndrome by in vivo and computational studies.

    Science.gov (United States)

    Chen, Meimei; Yang, Fafu; Kang, Jie; Gan, Huijuan; Lai, Xinmei; Gao, Yuxing

    2018-01-15

    Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Molecular typing of toxic shock syndrome toxin-1- and Enterotoxin A-producing methicillin-sensitive Staphylococcus aureus isolates from an outbreak in a neonatal intensive care unit.

    Science.gov (United States)

    Layer, Franziska; Sanchini, Andrea; Strommenger, Birgit; Cuny, Christiane; Breier, Ann-Christin; Proquitté, Hans; Bührer, Christoph; Schenkel, Karl; Bätzing-Feigenbaum, Jörg; Greutelaers, Benedikt; Nübel, Ulrich; Gastmeier, Petra; Eckmanns, Tim; Werner, Guido

    2015-10-01

    Outbreaks of Staphylococcus aureus are common in neonatal intensive care units (NICUs). Usually they are documented for methicillin-resistant strains, while reports involving methicillin-susceptible S. aureus (MSSA) strains are rare. In this study we report the epidemiological and molecular investigation of an MSSA outbreak in a NICU among preterm neonates. Infection control measures and interventions were commissioned by the Local Public Health Authority and supported by the Robert Koch Institute. To support epidemiological investigations molecular typing was done by spa-typing and Multilocus sequence typing; the relatedness of collected isolates was further elucidated by DNA SmaI-macrorestriction, microarray analysis and bacterial whole genome sequencing. A total of 213 neonates, 123 healthcare workers and 205 neonate parents were analyzed in the period November 2011 to November 2012. The outbreak strain was characterized as a MSSA spa-type t021, able to produce toxic shock syndrome toxin-1 and Enterotoxin A. We identified seventeen neonates (of which two died from toxic shock syndrome), four healthcare workers and three parents putatively involved in the outbreak. Whole-genome sequencing permitted to exclude unrelated cases from the outbreak and to discuss the role of healthcare workers as a reservoir of S. aureus on the NICU. Genome comparisons also indicated the presence of the respective clone on the ward months before the first colonized/infected neonates were detected. Copyright © 2015 Elsevier GmbH. All rights reserved.

  8. Molecular epidemiology and functional assessment of novel allelic variants of SLC26A4 in non-syndromic hearing loss patients with enlarged vestibular aqueduct in China.

    Directory of Open Access Journals (Sweden)

    Yongyi Yuan

    Full Text Available Mutations in SLC26A4, which encodes pendrin, are a common cause of deafness. SLC26A4 mutations are responsible for Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA. The mutation spectrum of SLC26A4 varies widely among ethnic groups. To investigate the incidence of EVA in Chinese population and to provide appropriate genetic testing and counseling to patients with SLC26A4 variants, we conducted a large-scale molecular epidemiological survey of SLC26A4.A total of 2352 unrelated non-syndromic hearing loss patients from 27 different regions of China were included. Hot spot regions of SLC26A4, exons 8, 10 and 19 were sequenced. For patients with one allelic variant in the hot spot regions, the other exons were sequenced one by one until two mutant alleles had been identified. Patients with SLC26A4 variants were then examined by temporal bone computed tomography scan for radiological diagnosis of EVA. Ten SLC26A4 variants were cloned for functional study. Confocal microscopy and radioisotope techniques were used to examine the membrane expression of pendrin and transporter function.Of the 86 types of variants found, 47 have never been reported. The ratio of EVA in the Chinese deaf population was at least 11%, and that in patients of Han ethnicity reached at least 13%. The mutational spectrum and mutation detection rate of SLC26A4 are distinct among both ethnicities and regions of Mainland China. Most of the variants caused retention of pendrin in the intracellular region. All the mutant pendrins showed significantly reduced transport capability.An overall description of the molecular epidemiological findings of SLC26A4 in China is provided. The functional assessment procedure can be applied to identification of pathogenicity of variants. These findings are valuable for genetic diagnosis, genetic counseling, prenatal testing and pre-implantation diagnosis in EVA families.

  9. A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies

    NARCIS (Netherlands)

    Bondurand, N.; Kuhlbrodt, K.; Pingault, V.; Enderich, J.; Sajus, M.; Tommerup, N.; Warburg, M.; Hennekam, R. C.; Read, A. P.; Wegner, M.; Goossens, M.

    1999-01-01

    The Yemenite deaf-blind hypopigmentation syndrome was first observed in a Yemenite sister and brother showing cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. A second case, observed in a girl with similar skin symptoms and hearing loss but

  10. Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report

    NARCIS (Netherlands)

    Adadi, N.; Lahrouchi, N.; Bouhouch, R.; Fellat, I.; Amri, R.; Alders, M.; Sefiani, A.; Bezzina, C.; Ratbi, I.

    2017-01-01

    Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval,

  11. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?

    NARCIS (Netherlands)

    Hofman, Nynke; Wilde, Arthur A. M.; Kääb, Stefan; van Langen, Irene M.; Tanck, Michael W. T.; Mannens, Marcel M. A. M.; Hinterseer, Martin; Beckmann, Britt-Maria; Tan, Hanno L.

    2007-01-01

    AIMS: Previously published diagnostic systems, based on ECG analysis and clinical parameters (Schwartz criteria and Keating criteria), have been used to estimate the probability of inherited long QT syndrome (LQTS). Nowadays, a certain diagnosis can often be made by DNA testing. We aimed to

  12. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: Do we need a scoring system?

    NARCIS (Netherlands)

    Hofman, Nynke; Wilde, Arthur A.M.; Kääb, Stefan; Van Langen, Irene M.; Tanck, Michael W.T.; Mannens, Marcel M.A.M.; Hinterseer, Martin; Beckmann, Britt-Maria; Tan, Hanno L.

    2007-01-01

    Aims: Previously published diagnostic systems, based on ECG analysis and clinical parameters (Schwartz criteria and Keating criteria), have been used to estimate the probability of inherited long QT syndrome (LQTS). Nowadays, a certain diagnosis can often be made by DNA testing. We aimed to

  13. Cellular and molecular deviations in bovine in vitro-produced embryos are related to the large offspring syndrome

    NARCIS (Netherlands)

    Lazzari, G.; Wrenzycki, C.; Herrmann, D.; Duchi, R.; Kruip, T.; Niemann, H.; Galli, C.

    2002-01-01

    The large offspring syndrome (LOS) is observed in bovine and ovine offspring following transfer of in vitro-produced (IVP) or cloned embryos and is characterized by a multitude of pathologic changes, of which extended gestation length and increased birthweight are predominant features. In the

  14. Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome

    Czech Academy of Sciences Publication Activity Database

    Raška, Ivan

    2010-01-01

    Roč. 3, č. 3 (2010), s. 89-93 ISSN 1337-6853 Grant - others:GA MŠk(CZ) LC535 Program:LC Institutional research plan: CEZ:AV0Z50110509 Keywords : laminopathies * Hutchinson-Gilford progeria syndrome * progerin Subject RIV: EA - Cell Biology

  15. Molecular characterization of a heterothallic mating system in Pseudogymnoascus destructans, the fungus causing white-nose syndrome of bats

    Science.gov (United States)

    Jonathan M. Palmer; Alena Kubatova; Alena. Novakova; Andrew M. Minnis; Miroslav Kolarik; Daniel L. Lindner

    2014-01-01

    White-nose syndrome (WNS) of bats has devastated bat populations in eastern North America since its discovery in 2006. WNS, caused by the fungus Pseudogymnoascus destructans, has spread quickly in North America and has become one of the most severe wildlife epidemics of our time. While P. destructans is spreading rapidly in North...

  16. Histology and synchrotron radiation-based microtomography of the inner ear in a molecularly confirmed case of CHARGE syndrome.

    NARCIS (Netherlands)

    Glueckert, R.; Rask-Andersen, H.; Sergi, C.; Schmutzhard, J.; Mueller, B.; Beckmann, F.; Rittinger, O.; Hoefsloot, L.H.; Schrott-Fischer, A.; Janecke, A.R.

    2010-01-01

    CHARGE (Coloboma of the iris or retina, heart defects, atresia of the choanae, retardation of growth and/or development, genital anomalies, ear anomalies) syndrome (OMIM #214800) affects about 1 in 10,000 children and is most often caused by chromodomain helicase DNA-binding protein-7 (CHD7)

  17. A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes.

    Science.gov (United States)

    Russo, Silvia; Calzari, Luciano; Mussa, Alessandro; Mainini, Ester; Cassina, Matteo; Di Candia, Stefania; Clementi, Maurizio; Guzzetti, Sara; Tabano, Silvia; Miozzo, Monica; Sirchia, Silvia; Finelli, Palma; Prontera, Paolo; Maitz, Silvia; Sorge, Giovanni; Calcagno, Annalisa; Maghnie, Mohamad; Divizia, Maria Teresa; Melis, Daniela; Manfredini, Emanuela; Ferrero, Giovanni Battista; Pecile, Vanna; Larizza, Lidia

    2016-01-01

    Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate. Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values ≤mean -3 standard deviations (SDs) compared to controls. Values ≥mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those ≤mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative

  18. Sustained High Levels of Both Total and High Molecular Weight Adiponectin in Plasma during the Convalescent Phase of Haemorrhagic Fever with Renal Syndrome Are Associated with Disease Severity

    Directory of Open Access Journals (Sweden)

    Kang Tang

    2017-01-01

    Full Text Available Haemorrhagic fever with renal syndrome (HFRS is characterised by an uncontrolled immune response that causes vascular leakage. Adiponectin (APN is an adipocytokine involved in prorevascularisation and immunomodulation. To investigate the possible effects of APN in the pathogenesis of HFRS, total and high molecular weight (HMW APN levels in the plasma of patients with HFRS were quantified using enzyme-linked immunosorbent assay (ELISA. Compared with those in healthy controls, the plasma total and HMW APN levels in patients were elevated to different degrees from the fever onset and remained high at the convalescent phase. Consistent with these results, western blot analysis additionally showed that low molecular weight (LMW, middle molecular weight (MMW, and HMW APN levels were all elevated and contributed to the elevation of the total APN level. Importantly, sustained high levels of total and HMW APN at the convalescent phase were significantly higher in patients with critical disease than those in patients with mild or moderate disease. Moreover, total and HMW APN levels negatively correlated with white blood cell count and positively correlated with platelet count and serum albumin level. These results may provide insights into understanding the roles of total and HMW APN in the pathogenesis of HFRS.

  19. C5b-9-targeted molecular MR imaging in rats with Heymann nephritis: a new approach in the evaluation of nephrotic syndrome.

    Directory of Open Access Journals (Sweden)

    Qiang Huang

    Full Text Available Membranous nephropathy (MN is the major cause of adult nephrotic syndrome, which severely affects patients' quality of life. Currently, percutaneous renal biopsy is required to definitively diagnose MN. However, this technique is invasive and may cause severe complications. Therefore, an urgent clinical need exists for dynamic noninvasive monitoring of the renal state. In-depth molecular imaging studies could assist in finding a solution. Membrane attack complex C5b-9 is the key factor in the development of MN, and this protein primarily deposits in the glomerulus. The present study bound polyclonal antibodies to C5b-9 with ultrasmall superparamagnetic iron oxide (USPIO nanoparticles to obtain C5b-9-targeted magnetic resonance molecular imaging probes. The probes were injected intravenously into rats with Heymann nephritis, a classic disease model of MN. The signal intensity in the T2*-weighted imaging of kidneys in vivo using 7.0 Tesla magnetic resonance imaging decreased significantly 24 hours after injection compared to the untargeted and control groups. This signal change was consistent with the finding of nanoparticle deposits in pathological glomeruli. This study demonstrated a novel molecular imaging technique for the assessment of MN.

  20. New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

    Science.gov (United States)

    Busquets-Garcia, Arnau; Maldonado, Rafael; Ozaita, Andrés

    2014-08-01

    Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report.

    Science.gov (United States)

    Adadi, N; Lahrouchi, N; Bouhouch, R; Fellat, I; Amri, R; Alders, M; Sefiani, A; Bezzina, C; Ratbi, I

    2017-04-02

    Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death. Jervell and Lange-Nielsen syndrome is caused by homozygous or compound heterozygous mutations in KCNQ1 on 11p15.5 or KCNE1 on 1q22.1-q22.2. We report the case of a 10-year-old Moroccan boy with congenital hearing loss and severely prolonged QT interval who presented with multiple episodes of syncope. His parents are first-degree cousins. We performed Sanger sequencing and identified a homozygous variant in KCNQ1 (c.1343dupC, p.Glu449Argfs*14). The identification of the genetic substrate in this patient confirmed the clinical diagnosis of Jervell and Lange-Nielsen syndrome and allowed us to provide him with appropriate management and genetic counseling to his family. In addition, this finding contributes to our understanding of genetic disease in the Moroccan population.

  2. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders.

    Science.gov (United States)

    Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

    2015-04-01

    Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed 'full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term 'abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the 'normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed 'premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing.

  3. Sanger sequencing as a first-line approach for molecular diagnosis of Andersen-Tawil syndrome [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Armando Totomoch-Serra

    2017-06-01

    Full Text Available In 1977, Frederick Sanger developed a new method for DNA sequencing based on the chain termination method, now known as the Sanger sequencing method (SSM.  Recently, massive parallel sequencing, better known as next-generation sequencing (NGS,  is replacing the SSM for detecting mutations in cardiovascular diseases with a genetic background. The present opinion article wants to remark that “targeted” SSM is still effective as a first-line approach for the molecular diagnosis of some specific conditions, as is the case for Andersen-Tawil syndrome (ATS. ATS is described as a rare multisystemic autosomal dominant channelopathy syndrome caused mainly by a heterozygous mutation in the KCNJ2 gene. KCJN2 has particular characteristics that make it attractive for “directed” SSM. KCNJ2 has a sequence of 17,510 base pairs (bp, and a short coding region with two exons (exon 1=166 bp and exon 2=5220 bp, half of the mutations are located in the C-terminal cytosolic domain, a mutational hotspot has been described in residue Arg218, and this gene explains the phenotype in 60% of ATS cases that fulfill all the clinical criteria of the disease. In order to increase the diagnosis of ATS we urge cardiologists to search for facial and muscular abnormalities in subjects with frequent ventricular arrhythmias (especially bigeminy and prominent U waves on the electrocardiogram.

  4. Molecular investigation by whole exome sequencing revealed a high proportion of pathogenic variants among Thai victims of sudden unexpected death syndrome.

    Directory of Open Access Journals (Sweden)

    Bhoom Suktitipat

    Full Text Available Sudden unexpected death syndrome (SUDS is an important cause of death in young healthy adults with a high incident rate in Southeast Asia; however, there are no molecular autopsy reports about these victims. We performed a combination of both a detailed autopsy and a molecular autopsy by whole exome sequencing (WES to investigate the cause of SUDS in Thai sudden death victims.A detailed forensic autopsy was performed to identify the cause of death, followed by a molecular autopsy, in 42 sudden death victims who died between January 2015 and August 2015. The coding sequences of 98 SUDS-related genes were sequenced using WES. Potentially causative variants were filtered based on the variant functions annotated in the dbNSFP database. Variants with inconclusive clinical significance evidence in ClinVar were resolved with a variant prediction algorithm, metaSVM, and the frequency data of the variants found in public databases, such as the 1000 Genome Project, ESP6500 project, and the Exome Aggregation Consortium (ExAc project.Combining both autopsy and molecular autopsy enabled the potential identification of cause of death in 81% of the cases. Among the 25 victims with WES data, 72% (18/25 were found to have potentially causative SUDS mutations. The majority of the victims had at a mutation in the TTN gene (8/18 = 44%, and only one victim had an SCN5A mutation.WES can help to identify the genetic causes in victims of SUDS and may help to further guide investigations into their relatives to prevent additional SUDS victims.

  5. Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact.

    Science.gov (United States)

    Bacher, Ulrike; Haferlach, Torsten; Schnittger, Susanne; Zenger, Melanie; Meggendorfer, Manja; Jeromin, Sabine; Roller, Andreas; Grossmann, Vera; Krauth, Maria-Theresa; Alpermann, Tamara; Kern, Wolfgang; Haferlach, Claudia

    2014-03-01

    In patients with myelodysplastic syndromes (MDS), sole 20q deletion [del(20q)] is a recurrent favourable abnormality. We studied additional molecular and cytogenetic lesions and their prognostic impact in 305 MDS patients with del(20q) (229 males/76 females; 29-90 years). All patients were investigated by cytomorphology and chromosome banding analysis (CBA), subsets by fluorescence in situ hybridization, molecular mutation screening, and array comparative genomic hybridization (aCGH). By aCGH (n = 30), the minimal common deleted region (CDR) was flanked by PTPRT (20q13·11) and EYA2 (20q13·12). 210 (68·9%) patients had 'early MDS' without blast increase, 95 (31·1%) 'advanced' MDS with blast increase (5-19%). Additional chromosomal abnormalities (ACAs) were detected in 88/305 (28·9%) patients. Patients with advanced MDS more frequently had ACAs (P = 0·003) and had a higher mean number of ACAs (P = 0·020) and of molecular mutations (P = 0·060). Spliceosome mutations were frequent (U2AF1: n = 31/155; 20·0%; SRSF2: n = 31/159; 19·5%; SF3B1mut: n = 8/159; 5·0%). ASXL1mut (25/153; 16·3%) were associated with advanced MDS (P = 0·001). Presence of ≥3 ACAs (P = 0·003) and ASXL1mut (P = 0·002) were associated with worse 2-year survival. In conclusion, the cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1mut is overrepresented in MDS with del(20q), and ASXL1mut is prognostically adverse. © 2013 John Wiley & Sons Ltd.

  6. Histology and synchrotron radiation-based microtomography of the inner ear in a molecularly confirmed case of CHARGE syndrome.

    Science.gov (United States)

    Glueckert, Rudolf; Rask-Andersen, Helge; Sergi, Consolato; Schmutzhard, Joachim; Mueller, Bert; Beckmann, Felix; Rittinger, Olaf; Hoefsloot, Lies H; Schrott-Fischer, Anneliese; Janecke, Andreas R

    2010-03-01

    CHARGE (Coloboma of the iris or retina, heart defects, atresia of the choanae, retardation of growth and/or development, genital anomalies, ear anomalies) syndrome (OMIM #214800) affects about 1 in 10,000 children and is most often caused by chromodomain helicase DNA-binding protein-7 (CHD7) mutations. Inner ear defects and vestibular abnormalities are particularly common. Specifically, semicircular canal (SCC) hypoplasia/aplasia and the presence of a Mondini malformation can be considered pathognomonic in the context of congenital malformations of the CHARGE syndrome. We obtained a temporal bone (TB) of a patient with CHARGE syndrome who died from bacteremia at 3 months of age. The clinical diagnosis was confirmed in the patient by direct DNA sequencing and the detection of a de novo, truncating CHD7 mutation, c.6169dup (p.R2057fs). We assessed changes of the TB and the degree of neural preservation, which may influence the potential benefit of cochlear implantation. The TB was analyzed using synchrotron radiation-based micro computed tomography, and by light microscopy. The vestibular partition consisted of a rudimentary vestibule with agenesis of the SCCs. The cochlea was hypoplastic with poor or deficient interscaling and shortened (Mondini dysplasia). The organ of Corti had near normal structure and innervation. Modiolus and Rosenthal's canal were hypoplastic with perikarya displaced along the axon bundles into the internal acoustic meatus, which may be explained by the arrest or limited migration and translocation of the cell nuclei into the cochlear tube during development. (c) 2010 Wiley-Liss, Inc.

  7. Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients

    Energy Technology Data Exchange (ETDEWEB)

    Christian, S.L.; Huang, B.; Ledbetter, D.H. [National Institutes of Health, Bethesda, MD (United States)] [and others

    1995-07-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11{minus}q13. Approximately 70% of these patients have a large deletion of {approximately}4 Mb extending from D15S9 (ML34) through D15S12 (IR10A). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated for YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of these markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542. 46 refs., 2 figs., 3 tabs.

  8. Molecular Characterization of a Heterothallic Mating System in Pseudogymnoascus destructans, the Fungus Causing White-Nose Syndrome of Bats

    Czech Academy of Sciences Publication Activity Database

    Palmer, J.M.; Kubátová, Alena; Nováková, Alena; Minnis, A.M.; Kolařík, Miroslav; Lindner, D.L.

    2014-01-01

    Roč. 4, č. 9 (2014), s. 1755-1763 ISSN 2160-1836 R&D Projects: GA ČR(CZ) GAP506/12/1064 Institutional support: RVO:61388971 Keywords : geomyces * sexual reproduction * mating type Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.198, year: 2014

  9. Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms.

    Science.gov (United States)

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2013-10-10

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS. © 2013 Elsevier B.V. All rights reserved.

  10. Prenatal diagnosis of chromosome 15 abnormalities in the Prader-Willi/Angelman syndrome region by traditional and molecular cytogenetics

    Energy Technology Data Exchange (ETDEWEB)

    Toth-Fejel, S.; Magenis, R.E.; Leff, S. [Oregon Health Sciences Univ., Portland, OR (United States)] [and others

    1995-02-13

    With improvements in culturing and banding techniques, amniotic fluid studies now achieve a level of resolution at which the Prader-Willi syndrome (PWS) and Angelman syndrome (AS) region may be questioned. Chromosome 15 heteromorphisms, detected with Q- and R-banding and used in conjunction with PWS/AS region-specific probes, can confirm a chromosome deletion and establish origin to predict the clinical outcome. We report four de novo cases of an abnormal-appearing chromosome 15 in amniotic fluid samples referred for advanced maternal age or a history of a previous chromosomally abnormal child. The chromosomes were characterized using G-, Q-, and R-banding, as well as isotopic and fluorescent in situ hybridization of DNA probes specific for the proximal chromosome 15 long arm. In two cases, one chromosome 15 homolog showed a consistent deletion of the ONCOR PWS/AS region A and B. In the other two cases, one of which involved an inversion with one breakpoint in the PWS/AS region, all of the proximal chromosome 15 long arm DNA probes used in the in situ hybridization were present on both homologs. Clinical follow-up was not available on these samples, as in all cases the parents chose to terminate the pregnancies. These cases demonstrate the ability to prenatally diagnose chromosome 15 abnormalities associated with PWS/AS. In addition, they highlight the need for a better understanding of this region for accurate prenatal diagnosis. 41 refs., 5 figs.

  11. Diagnosis of Familial Wolf-Hirschhorn Syndrome due to a Paternal Cryptic Chromosomal Rearrangement by Conventional and Molecular Cytogenetic Techniques

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    Carlos A. Venegas-Vega

    2013-01-01

    Full Text Available The use of conventional cytogenetic techniques in combination with fluorescent in situ hybridization (FISH and single-nucleotide polymorphism (SNP microarrays is necessary for the identification of cryptic rearrangements in the diagnosis of chromosomal syndromes. We report two siblings, a boy of 9 years and 9 months of age and his 7-years- and 5-month-old sister, with the classic Wolf-Hirschhorn syndrome (WHS phenotype. Using high-resolution GTG- and NOR-banding karyotypes, as well as FISH analysis, we characterized a pure 4p deletion in both sibs and a balanced rearrangement in their father, consisting in an insertion of 4p material within a nucleolar organizing region of chromosome 15. Copy number variant (CNV analysis using SNP arrays showed that both siblings have a similar size of 4p deletion (~6.5 Mb. Our results strongly support the need for conventional cytogenetic and FISH analysis, as well as high-density microarray mapping for the optimal characterization of the genetic imbalance in patients with WHS; parents must always be studied for recognizing cryptic balanced chromosomal rearrangements for an adequate genetic counseling.

  12. Vaccination and Infection as Causative Factors in Japanese Patients With Rasmussen Syndrome: Molecular Mimicry and HLA Class I

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    Yukitoshi Takahashi

    2006-01-01

    Full Text Available Rasmussen syndrome is an intractable epilepsy with a putative causal relation with cellular and humoral autoimmunity. Almost half of the patients have some preceding causative factors, with infections found in 38.2%, vaccinations in 5.9% and head trauma in 8.9% of Japanese patients. In a patient with seizure onset after influenza A infections, cross-reaction of the patient's lymphocytes with GluRε2 and influenza vaccine components was demonstrated by lymphocyte stimulation test. Database analyses revealed that influenza A virus hemagglutinin and GluRε2 molecules contain peptides with the patient's HLA class I binding motif (HLA ࢤ A*0201. The relative risks of HLA class I genotypes for Rasmussen syndrome are 6.1 (A*2402, 6.4 (A*0201, 6.3 (A*2601 and 11.4 (B*4601. The relative risks of HLA class I-A and B haplotypes are infinity (A*2601+B*5401, 21.1 (A*2402+B*1501, 13.3 (A*2402+B*4801 and 5.1 (A*2402+B*5201. Some alleles and haplotypes of HLA class I may be the risk factors in Japanese patients. Cross-reactivity of cytotoxic T lymphocytes may contribute to the processes leading from infection to the involvement of CNS.

  13. Molecular Characterization of Three Porcine Reproductive and Respiratory Syndrome Virus Isolates and Their Susceptibility to Antiviral Drugs

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    Hongxia Hu

    2014-01-01

    Full Text Available Porcine reproductive and respiratory syndrome virus (PRRSV is one of the most common swine pathogens that cause severe economic losses to the pig industry worldwide irrespective of the use of live or inactivated vaccines. This study aims to investigate the biological characteristics of three PRRSV isolates and their susceptibility to two antiviral drugs. Sequence analysis of the NSP2 gene classified two isolates as highly pathogenic (isolates FY and ZS and one as classically pathogenic (isolate JX. Isolate FY grew faster than the other two isolates in MARC-145 cells; however, its RNA replication was lower than isolate ZS. By contrast, isolate JX exhibited slower growth and lower RNA replication capability. PRRSV infection suppressed the production of interferon β induced by poly (I:C. The viruses also differed in their susceptibility to antiviral drugs. Ribavirin exerted potent antiviral activity against all three viral isolates at concentrations of 7.5 and 15 μg/mL in MARC-145 cells. Acyclovir was found effective only on the classically pathogenic isolate. We suggest that ribavirin could have potential as an antiviral therapy for porcine reproductive and respiratory syndrome when vaccination is not able to provide effective protection.

  14. Pfeiffer syndrome

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    Fryns Jean-Pierre

    2006-06-01

    Full Text Available Abstract Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet. Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows, abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic testing is important to confirm the diagnosis. Management includes multiple-staged surgery of craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial hypoplasia.

  15. Molecular Characterization of Down Syndrome Embryonic Stem Cells Reveals a Role for RUNX1 in Neural Differentiation

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    Tomer Halevy

    2016-10-01

    Full Text Available Down syndrome (DS is the leading genetic cause of mental retardation and is caused by a third copy of human chromosome 21. The different pathologies of DS involve many tissues with a distinct array of neural phenotypes. Here we characterize embryonic stem cell lines with DS (DS-ESCs, and focus on the neural aspects of the disease. Our results show that neural progenitor cells (NPCs differentiated from five independent DS-ESC lines display increased apoptosis and downregulation of forehead developmental genes. Analysis of differentially expressed genes suggested RUNX1 as a key transcription regulator in DS-NPCs. Using genome editing we were able to disrupt all three copies of RUNX1 in DS-ESCs, leading to downregulation of several RUNX1 target developmental genes accompanied by reduced apoptosis and neuron migration. Our work sheds light on the role of RUNX1 and the importance of dosage balance in the development of neural phenotypes in DS.

  16. Molecular and functional characterization of Kv 7 channels in penile arteries and corpus cavernosum of healthy and metabolic syndrome rats

    DEFF Research Database (Denmark)

    Jepps, T A; Olesen, S P; Greenwood, I A

    2016-01-01

    BACKGROUND AND PURPOSE: KCNQ-encoded voltage-dependent potassium channels (Kv 7) are involved in the regulation of vascular tone. In this study we evaluated the influence of Kv 7 channel activation on smooth muscle relaxation in rat penile arteries and corpus cavernosum from normal...... and spontaneously hypertensive, heart failure-prone (SHHF) rats - a rat model of human metabolic syndrome. EXPERIMENTAL APPROACH: Quantitative PCR and immunohistochemistry were used to determine the expression of KCNQ isoforms in penile tissue. Isometric tension was measured in intracavernous arterial rings...... and corpus cavernosum strips isolated from normal and SHHF rats. KEY RESULTS: Transcripts for KCNQ3, KCNQ4 and KCNQ5 were detected in penile arteries and corpus cavernosum. KCNQ1 was only found in corpus cavernosum. Immunofluorescence signals to Kv 7.4 and Kv 7.5 were found in penile arteries, penile veins...

  17. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders

    Science.gov (United States)

    Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

    2015-01-01

    Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. PMID:25227148

  18. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients

    DEFF Research Database (Denmark)

    Bonnet, Crystel; Riahi, Zied; Chantot-Bastaraud, Sandra

    2016-01-01

    of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy.......5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.European Journal of Human Genetics advance online publication, 27 July 2016; doi:10.1038/ejhg.2016.99....

  19. Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect

    DEFF Research Database (Denmark)

    Schulze, A; Hansen, Claus; Baekgaard, P

    1997-01-01

    no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When...... the imprinting mutation is inherited from a carrier father, the risk that future children will be affected is theoretically 50%. It is therefore important that these families are referred to a geneticist for counselling and further investigation. Prenatal diagnosis is currently only feasible when the mutation...

  20. Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

    Science.gov (United States)

    Bedeschi, Maria Francesca; Marangi, Giuseppe; Calvello, Maria Rosaria; Ricciardi, Stefania; Leone, Francesca Pia Chiara; Baccarin, Marco; Guerneri, Silvana; Orteschi, Daniela; Murdolo, Marina; Lattante, Serena; Frangella, Silvia; Keena, Beth; Harr, Margaret H; Zackai, Elaine; Zollino, Marcella

    2017-11-01

    Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4-6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1-4 and exons 4-6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7-8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9-19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations. Copyright

  1. Does sudden unexplained nocturnal death syndrome remain the autopsy negative disorder: a gross, microscopic, and molecular autopsy investigation in Southern China

    Science.gov (United States)

    Zhang, Liyong; Tester, David J.; Lang, Di; Chen, Yili; Zheng, Jinxiang; Gao, Rui; Corliss, Robert F.; Tang, Shuangbo; Kyle, John W.; Liu, Chao; Ackerman, Michael J.; Makielski, Jonathan C.; Cheng, Jianding

    2016-01-01

    Objective To look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS). Methods and Results 148 SUNDS victims and 444 controls (matched 1:3 on gender, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998 to December 31, 2014 to search morphological changes. Additional 17 Brugada syndrome (BrS) patients collected from January 1, 2006 to December 31, 2014 served as a comparative disease cohort. The Target Captured Next Generation sequencing for 80 genes associated with arrhythmia/cardiomyopathy were performed in 44 SUNDS victims and 17 BrS patients to characterize the molecular spectrum. SUNDS had slight but statistically significantly increased heart weight and valve circumference compared to controls. 12/44 SUNDS victims (SCN5A, SCN1B, CACNB2, CACNA1C, AKAP9, KCNQ1, KCNH2, KCNJ5, GATA4, NUP155, ABCC9) and 6/17 BrS patients (SCN5A, CACNA1C, P>.05) carried rare variants in primary arrhythmia-susceptibility genes. Only 2/44 SUNDS cases compared to 5/17 BrS patients hosted a rare variant in the most common BrS causing gene, SCN5A (P=.01). Using the strict American College of Medical Genetics guideline-based definition, only 2/44 (KCNQ1) SUNDS and 3/17 (SCN5A) BrS patients hosted a “(likely) pathogenic” variant. The 14/44 SUNDS cases with cardiomyopathy-related variants had a subtle but significantly decreased circumference of cardiac valves, and tended to die on average 5–6 years younger compared to the remaining 30 cases (P=.02). Conclusions We present the first comprehensive autopsy evidence that SUNDS victims may have concealed cardiac morphological changes. SUNDS and BrS may result from different molecular pathological underpinnings. The distinct association between cardiomyopathy-related rare variants and SUNDS warrants further investigation. PMID:27707468

  2. Molecular-genetic risk assessement of determining angiotensin-converting enzyme hyperactivity in hemorrhagic fever with renal syndrome

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    Ildar R. Minniakhmetov

    2012-09-01

    Full Text Available The present study was designed to investigate changes in angiotensin-converting enzyme (ACE blood activity and angiotensin II type 1 receptor gene polymorphism as a possible disease predictor in hemorrhagic fever with renal syndrome (HFRS. Four hundred and nine patients (346 males and 63 females with HFRS serologic confirmation were enrolled in the study. Their age ranged from 15 to 65 years. ACE blood activity was assessed kinetically using the Bühlmann (Switzerland kit. Peripheral blood genomic DNA was isolated by a phenol-chloroform extraction. The genotyping of DNA loci was done using a polymerase chain reaction of DNA synthesis. Statistically, ACE blood activity was significantly higher throughout the entire HFRS course with diverse severity apart from the feverish phase of moderate-to-severe uncomplicated disease forms. *A1166 and *C1166 alleles, *A1166/*A1166 and *C1166/*C1166 genotypes of angiotensin II type 1 receptor gene were not associated with HFRS severity. The results of this study indicate that high ACE activity has not adaptive characteristics due to abnormalities in angiotensin II reception. It is an adequate metabolic response of the body to endotheliotropic virus activity.

  3. Molecular effect of fenofibrate on PBMC gene transcription related to lipid metabolism in patients with metabolic syndrome.

    Science.gov (United States)

    Moreno-Indias, I; Tinahones, F J; Clemente-Postigo, M; Castellano-Castillo, D; Fernández-García, J C; Macias-Gonzalez, M; Queipo-Ortuño, M I; Cardona, F

    2017-06-01

    Both fasting and postprandial hypertriglyceridaemia are considered independent risk factors for atherosclerosis. Treatment of hypertriglyceridaemia is based on fibrates, which activate the peroxisome proliferator-activated receptor alpha (PPARα). However, the metabolic pathways that activate or inhibit fibrates, and how the postprandial triglyceride levels are modified, have not yet been fully described. Accordingly, the aim of this study was to determine the feasibility of peripheral blood mononuclear cells (PBMC) to study the effects of fenofibrate in patients with the metabolic syndrome. A fat overload was given to 50 patients before and after treatment with fenofibrate for 3 months. Anthropometric and biochemical variables as well as gene expression in PBMC were analysed. After treatment with fenofibrate, we observed a decrease in both baseline and postprandial (3 h after the fat overload) levels of serum triglycerides, cholesterol and uric acid and an increase in HDL cholesterol and apolipoprotein AI levels. After treatment, there was also a rise in PPARα and RXRα expression and changes in genes regulated by PPARα, both baseline and postprandial. Furthermore, in vitro experiments showed that a PPARα agonist changed the expression of genes related with lipid metabolism. Treatment with fenofibrate reduced fasting and postprandial serum triglyceride levels, possibly through a mechanism related with an increase in the expression of RXRα and PPARα, by activating the pathways involved in the uptake and degradation of triglycerides and increasing the synthesis of apolipoprotein. These results suggest that PBMC may be useful for the easy study of fenofibrate actions. © 2017 John Wiley & Sons Ltd.

  4. A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers.

    Science.gov (United States)

    Herbert, Brittney-Shea; Chanoux, Rebecca A; Liu, Yunlong; Baenziger, Peter H; Goswami, Chirayu P; McClintick, Jeanette N; Edenberg, Howard J; Pennington, Robert E; Lipkin, Steven M; Kopelovich, Levy

    2010-10-01

    Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.

  5. Clinical and molecular genetic analysis of a new mutation in children with Wolfram syndrome: a case report.

    Science.gov (United States)

    Xu, Qianqian; Qu, Huaiyu; Wei, Shihui

    2013-03-01

    A 12‑year‑old Chinese girl presented with gradual vision loss and insulin‑dependent diabetes mellitus and was suspected to suffer from Wolfram syndrome (WFS). A series of clinical examinations were performed, as well as direct DNA sequencing to screen the entire coding region of the WFS1 gene in the patient's family, including her parents and a brother. Ophthalmological examination revealed counting fingers/10 cm in the right eye and hand motions/10 cm in the left eye. Ophthalmoscopical examination identified bilateral optic atrophy without any signs of diabetic retinopathy. A hearing test was performed and revealed that the hearing ability for high frequency sounds was decreased. Urinary output in 24 h was >5,000 ml. In addition, a base substitution at c.2411T>C (Leu804Pro) in exon 8 was identified which was homozygous with the patient and heterozygous with the healthy parents and the brother. In the present case, a neuroophthalmology consult performed in the early stages of the disease was crucial for early diagnosis. In addition, this case study highlights the importance of performing a hearing test as well as collecting and analyzing 24‑h urine output in patients presenting with juvenile diabetes mellitus patients and optic atrophy without any signs of diabetic retinopathy.

  6. Mucosal pathobiology and molecular signature of epithelial barrier dysfunction in the small intestine in irritable bowel syndrome.

    Science.gov (United States)

    González-Castro, Ana M; Martínez, Cristina; Salvo-Romero, Eloísa; Fortea, Marina; Pardo-Camacho, Cristina; Pérez-Berezo, Teresa; Alonso-Cotoner, Carmen; Santos, Javier; Vicario, María

    2017-01-01

    Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders in developed countries. Its etiology remains unknown; however, a common finding, regardless of IBS subtype, is the presence of altered intestinal barrier. In fact, signaling and location of cell-to-cell adhesion proteins, in connection with increased immune activity, seem abnormal in the intestinal epithelium of IBS patients. Despite that most research is performed on distal segments of the intestine, altered permeability has been reported in both, the small and the large bowel of all IBS subtypes. The small intestine carries out digestion and nutrient absorption and is also the site where the majority of immune responses to luminal antigens takes place. In fact, the upper intestine is more exposed to environmental antigens than the colon and is also a site of symptom generation. Recent studies have revealed small intestinal structural alterations of the epithelial barrier and mucosal immune activation in association with intestinal dysfunction, suggesting the commitment of the intestine as a whole in the pathogenesis of IBS. This review summarizes the most recent findings on mucosal barrier alterations and its relationship to symptoms arising from the small intestine in IBS, including epithelial structural abnormalities, mucosal immune activation, and microbial dysbiosis, further supporting the hypothesis of an organic origin of IBS. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  7. Molecular diagnosis of Fragile X syndrome in subjects with intellectual disability of unknown origin: implications of its prevalence in regional Pakistan.

    Directory of Open Access Journals (Sweden)

    Madiha Kanwal

    Full Text Available Fragile-X syndrome (FXS is the most common form of inherited intellectual disability (ID and affects 0.7-3.0% of intellectually compromised population of unknown etiology worldwide. It is mostly caused by repeat expansion mutations in the FMR1 at chromosome Xq27.3. The present study aimed to develop molecular diagnostic tools for a better detection of FXS, to assess implementation of diagnostic protocols in a developing country and to estimate the prevalence of FXS in a cohort of intellectually disabled subjects from Pakistan. From a large pool of individuals with below normal IQ range, 395 subjects with intellectual disability of unknown etiology belonging to different regions of the country were recruited. Conventional-PCR, modified-PCR and Southern blot analysis methods were employed for the detection of CGG repeat polymorphisms in the FMR1 gene. Initial screening with conventional-PCR identified 13 suspected patients. Subsequent investigations through modified PCR and Southern blot analyses confirmed the presence of the FMR1 mutation, suggesting a prevalence of 3.5% and 2.8% (mean 3.3% among the male and female ID patients, respectively. These diagnostic methods were further customized with the in-house conditions to offer robust screening of referral patients/families for diagnostics and genetic counseling. Prescreening and early diagnosis are crucial for designing a prudent strategy for the management of subjects with ID. Outcome of the study recommends health practitioners for implementation of molecular based FXS diagnosis in routine clinical practice to give a better care for patients similar to the ones included in the study.

  8. A rapid NGS strategy for comprehensive molecular diagnosis of Birt-Hogg-Dubé syndrome in patients with primary spontaneous pneumothorax.

    Science.gov (United States)

    Zhang, Xinxin; Ma, Dehua; Zou, Wei; Ding, Yibing; Zhu, Chengchu; Min, Haiyan; Zhang, Bin; Wang, Wei; Chen, Baofu; Ye, Minhua; Cai, Minghui; Pan, Yanqing; Cao, Lei; Wan, Yueming; Jin, Yu; Gao, Qian; Yi, Long

    2016-05-27

    Primary spontaneous pneumothorax (PSP) or pulmonary cysts is one of the manifestations of Birt-Hogg-Dube syndrome (BHDS) that is caused by heterozygous mutations in FLCN gene. Most of the mutations are SNVs and small indels, and there are also approximately 10 % large intragenic deletions and duplications of the mutations. These molecular findings are generally obtained by disparate methods including Sanger sequencing and Multiple Ligation-dependent Probe Amplification in the clinical laboratory. In addition, as a genetically heterogeneous disorder, PSP may be caused by mutations in multiple genes include FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 genes. For differential diagnosis, these genes should also be screened which makes the diagnostic procedure more time-consuming and labor-intensive. Forty PSP patients were divided into 2 groups. Nineteen patients with different pathogenic mutations of FLCN previously identified by conventional Sanger sequencing and MLPA were included in test group, 21 random PSP patients without any genetic screening were included in blinded sample group. 7 PSP genes including FLCN, FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 were designed and enriched by Haloplex system, sequenced on a Miseq platform and analyzed in the 40 patients to evaluate the performance of the targeted-NGS method. We demonstrated that the full spectrum of genes associated with pneumothorax including FLCN gene mutations can be identified simultaneously in multiplexed sequence data. Noteworthy, by our in-house copy number analysis of the sequence data, we could not only detect intragenic deletions, but also determine approximate deletion junctions simultaneously. NGS based Haloplex target enrichment technology is proved to be a rapid and cost-effective screening strategy for the comprehensive molecular diagnosis of BHDS in PSP patients, as it can replace Sanger sequencing and MLPA by simultaneously detecting exonic and intronic SNVs, small indels, large intragenic

  9. Molecular Detection and Identification of Α-L-Iduronidase Gene Mutations in 5 Iranian Families Suspected for Muller Syndrome (Mucopolysaccharidosis I

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    B Nasr- Esfahani

    2007-07-01

    Full Text Available Introduction: Mucopolysaccharidosis I (MPS-I is an autosomal recessive lysosomal storage diseases, caused by α-L-iduronidase (IDUA enzyme deficiency. The clinical manifestations of MPS-I patients are variable ranging from severe to mild, and therefore prediction of disease severity is difficult. From when IDUA gene has been cloned more than 109 distinct mutations have been identified in it and this number is increasing. This mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes. The aim of this study was identification and molecular characterization of IDUA gene mutations in our subset of MPS I patients. Methods: The present study performed on 5 Iranian families, each with a suspected child for MPS-I. Initially by using enzyme activity assay, the Hurler syndrome was verified and then presence of L123R mutation was evaluated by PCR-SSCP. Finally by PCR amplification of all 14 exons of the gene, SSCP and sequencing the mutations underlying the disease were identified and characterized. Results: The detected mutations turned to be L123R (in 2 patients, W402X, P533R and G51D mutations in other 3 patients. Discussion: L123R mutation, which was reported for the first time from our centre, was also present in 2 of the patients of this study but other 3 mutations were not novel. From our results, as well others, it can be concluded that the range of mutations in IDUA gene differ in different geographical areas. This should be considered when designing mutation detection strategies for MPS-I.

  10. Serotonin syndrome

    Science.gov (United States)

    Hyperserotonemia; Serotonergic syndrome; Serotonin toxicity; SSRI - serotonin syndrome; MAO - serotonin syndrome ... brain area. For example, you can develop this syndrome if you take migraine medicines called triptans together ...

  11. Molecular and clinical characterization of Waardenburg syndrome type I in an Iranian cohort with two novel PAX3 mutations.

    Science.gov (United States)

    Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Farhadi, Mohammad; Bahrami, Tayeb; Emamdjomeh, Hesam; Noori-Daloii, Mohammad Reza

    2015-12-15

    Waardenburg syndrome (WS) is a disease of abnormal neural-crest derived melanocyte development characterized by hearing loss and pigmentary disturbances in hair, eyes and skin. WS is subdivided into four major types, WS1-WS4, where WS1 is recognized by the presence of dystopia canthorum, with PAX3 being the only known gene involved. This study aimed at investigating PAX3 mutations and clinical characteristics of WS1 in a group of Iranian patients. A total of 12 WS1 patients from four unrelated Iranian families were enrolled. Waardenburg consortium guidelines were used for WS1 diagnosis. A detailed family history was traced and a thorough clinical examination was performed for all participants. Furthermore, WS1 patients underwent screening for PAX3 mutations using PCR-sequencing. Dystopia canthorum, broad high nasal root and synophrys were observed in all patients. Early graying, hair discoloration, hypoplastic blue eyes (characteristic brilliant blue iris) and hearing loss were the most common features observed, while heterochromia iridis was the least frequently observed sign among the studied Iranian WS1 patients. Genetic analysis of PAX3 revealed four mutations including c.667C>T, c.784C>T, c.951delT and c.451+3A>C. Two of the four mutations reported here (c.951delT and c.451+3A>C) are being reported for the first time in this study. Our data provide insight into genotypic and phenotypic spectrum of WS1 in an Iranian series of patients. Our results expand the spectrum of PAX3 mutations and may have implications for the genetic counseling of WS in Iran. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Porcine reproductive and respiratory syndrome virus: antigenic and molecular diversity of British isolates and implications for diagnosis.

    Science.gov (United States)

    Frossard, Jean-Pierre; Fearnley, Catherine; Naidu, Brindha; Errington, Jane; Westcott, David G; Drew, Trevor W

    2012-08-17

    Porcine reproductive and respiratory syndrome (PRRS) is an endemic disease of pigs, caused by PRRS virus, a member of the Arteriviridae family. First seen in Britain in 1991, the disease continues to be a significant economic and welfare problem for pig producers. To date, only PRRSV genotype 1 has been found in Britain. At the genetic level, a considerable increase has been reported in the diversity of PRRS viruses isolated in Britain between 2003 and 2007, versus the early 1990 s. In this study, the diversity has been shown to extend to the antigenic level too, with potential consequences for diagnostic methods. Antigenic diversity was assessed using a panel of twelve monoclonal antibodies, only one of which reacted with all isolates tested. Nine diverse viruses were compared as potential antigens in immunoperoxidase monolayer assays, where each one produced quite different results for a common panel of sera. As a single virus is used in each diagnostic assay, results must therefore be interpreted cautiously. For a real-time RT-PCR assay, published oligonucleotide primer and probe sequences were evaluated against available genetic sequences of British and European viruses, and were re-designed where considerable mismatches were found. The multiplex assay incorporating these modified primers to detect genotype 1 and 2 PRRS viruses was then validated for use with diagnostic sera and tissues. As the increasing degree of diversity exhibited by British strains is mirrored in other countries, PRRSV will continue to provide an ongoing challenge to diagnosis at a global, as well as national level. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  13. Molecular Analysis of Collagen XVIII Reveals Novel Mutations, Presence of a Third Isoform, and Possible Genetic Heterogeneity in Knobloch Syndrome

    Science.gov (United States)

    Suzuki, O. T.; Sertié, A. L.; Der Kaloustian, V. M.; Kok, F.; Carpenter, M.; Murray, J.; Czeizel, A. E.; Kliemann, S. E.; Rosemberg, S.; Monteiro, M.; Olsen, B. R.; Passos-Bueno, M. R.

    2002-01-01

    Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy. PMID:12415512

  14. Morphological and molecular characterizations of psychrophilic fungus Geomyces destructans from New York bats with White Nose Syndrome (WNS.

    Directory of Open Access Journals (Sweden)

    Vishnu Chaturvedi

    Full Text Available BACKGROUND: Massive die-offs of little brown bats (Myotis lucifugus have been occurring since 2006 in hibernation sites around Albany, New York, and this problem has spread to other States in the Northeastern United States. White cottony fungal growth is seen on the snouts of affected animals, a prominent sign of White Nose Syndrome (WNS. A previous report described the involvement of the fungus Geomyces destructans in WNS, but an identical fungus was recently isolated in France from a bat that was evidently healthy. The fungus has been recovered sparsely despite plentiful availability of afflicted animals. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated 100 bat and environmental samples from eight affected sites in 2008. Our findings provide strong evidence for an etiologic role of G. destructans in bat WNS. (i Direct smears from bat snouts, Periodic Acid Schiff-stained tissue sections from infected tissues, and scanning electron micrographs of bat tissues all showed fungal structures similar to those of G. destructans. (ii G. destructans DNA was directly amplified from infected bat tissues, (iii Isolations of G. destructans in cultures from infected bat tissues showed 100% DNA match with the fungus present in positive tissue samples. (iv RAPD patterns for all G. destructans cultures isolated from two sites were indistinguishable. (v The fungal isolates showed psychrophilic growth. (vi We identified in vitro proteolytic activities suggestive of known fungal pathogenic traits in G. destructans. CONCLUSIONS/SIGNIFICANCE: Further studies are needed to understand whether G. destructans WNS is a symptom or a trigger for bat mass mortality. The availability of well-characterized G. destructans strains should promote an understanding of bat-fungus relationships, and should aid in the screening of biological and chemical control agents.

  15. Molecular dissection of a contiguous gene syndrome: Frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated island in the Miller-Dieker chromosome region

    International Nuclear Information System (INIS)

    Ledbetter, D.H.; Ledbetter, S.A.; vanTuinen, P.

    1989-01-01

    The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be 100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region

  16. Combining low-molecular-weight heparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: the NICE 3 story. National Investigators Collaborating on Enoxaparin.

    Science.gov (United States)

    Ferguson, J J

    2000-12-01

    In recent years, a number of new therapies have become available that have significantly improved the care of patients with acute coronary syndromes (ACS). A number of studies have documented the significant superiority of the low-molecular-weight heparin (LMWH), enoxaparin, over unfractionated heparin (UFH) in the treatment of ACS. However, there are insufficient data regarding the safety of using LMWH in combination with glycoprotein (GP) IIb/IIIa antagonists. The NICE 3 study is an open-labeled, non-randomized, observational study examining the feasibility, safety, and preliminary efficacy of the LMWH, enoxaparin, in combination with each of the three commercially available GP IIb/IIIa antagonists in ACS patients. Approximately 600 patients at 45 clinical centers in North America will be divided between the three arms of the trial, representing each of the three GP IIb/IIIa antagonists. Once therapy is initiated, patients will receive no UFH (unless they require a coronary artery bypass graft) and will continue treatment even if invasive cath lab procedures are necessary. NICE 3 builds on the previous experiences of NICE 1 and NICE 4 with LMWH in the cath lab (with or without GP IIb/IIIa antagonists) to more aggressively extend the use of LMWHs into the medical management of ACS patients.

  17. Molecular epidemiology of porcine reproductive and respiratory syndrome virus in Central China since 2014: The prevalence of NADC30-like PRRSVs.

    Science.gov (United States)

    Wang, Lin-Jian; Xie, Weitao; Chen, Xin-Xin; Qiao, Songlin; Zhao, Mengmeng; Gu, Yu; Zhao, Bao-Lei; Zhang, Gaiping

    2017-08-01

    Porcine reproductive and respiratory syndrome (PRRS), characterized by respiratory disorders in piglets and reproductive failure in sows, is still the great threat of swine industry. Recently, Emergence of the novel NADC30-like PRRS viruses (PRRSVs) has caused widespread outbreaks of PRRS. To investigate the epidemic characteristics of PRRSVs in Central China since 2014, 6372 clinical serum samples were tested by ELISA, 250 tissue samples were tested by RT-PCR, and among these, 30 ORF5 and 17 Nsp2 genes sequences were analyzed. Phylogenetic tree based on ORF5 revealed that, 17 isolates were clustered into subgroup 1, represented by the NADC30. And for the Nsp2, The strains which had a discontinuous 131-amino-acid deletion in Nsp2, called NADC30-like strains, were clustered into subgroup 2. Our data suggested that the NADC30-like PRRSV strains spread quickly and are now circulating and prevalent in Central China as well as the classical HP-PRRSV strains. In addition, amino acid variation analysis of GP5 revealed that the amino acid sequences of NADC30-like PRRSV strains underwent rapid evolution and contained extensive amino acid substitutions in important motifs, such as potential neutralization epitope and the N-glycosylation sites. In summary, our data would provide a large amount of detailed information on molecular variation and genetic diversity of PRRSV in central China. Copyright © 2017. Published by Elsevier Ltd.

  18. Usher syndrome in Denmark

    DEFF Research Database (Denmark)

    Shzeena, Dad; Rendtorff, Nanna Dahl; Tranebjærg, Lisbeth

    2016-01-01

    BACKGROUND: Usher syndrome (USH) is a genetically heterogeneous deafness-blindness syndrome, divided into three clinical subtypes: USH1, USH2 and USH3. METHODS: Mutations in 21 out of 26 investigated Danish unrelated individuals with USH were identified, using a combination of molecular diagnostic...

  19. Beals Syndrome

    Science.gov (United States)

    ... the syndrome. How does Beals syndrome compare with Marfan syndrome? People with Beals syndrome have many of the ... bone) and aortic enlargement problems as people with Marfan syndrome, and treatments for these problems are the same. ...

  20. Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome.

    Science.gov (United States)

    Chiarelli, Nicola; Carini, Giulia; Zoppi, Nicoletta; Ritelli, Marco; Colombi, Marina

    2018-01-01

    Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures. To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of

  1. Global Liver Gene Expression Analysis on a Murine Metabolic Syndrome Model Treated by Low-molecular-weight Lychee Fruit Polyphenol (Oligonol®).

    Science.gov (United States)

    Uchiyama, Hironobu; Uehara, Kaori; Nagashima, Takayuki; Nakata, Akifumi; Sato, Keisuke; Mihara, Yoshihiro; Komatsu, Ken-Ich; Takanari, Jun; Shimizu, Shigeomi; Wakame, Koji

    2016-07-01

    Oligonol® (OLG) is a low-molecular-weight lychee fruit polyphenol mainly containing catechin-type monomers and oligomers of proanthocyanidins. Dietary OLG supplementation reportedly improves lipid metabolism disorder and lowers the visceral fat level in animal and human studies. Thus, we investigated the mechanism behind the protective and beneficial effects of OLG on a Western diet (WD)-induced metabolic syndrome (MetS) of a murine model. Using the C57BL/6J mouse for the MetS model, mice were divided into three groups: control (normal diet: ND), Western diet (WD) and WD + 0.5% OLG (OLG) groups. The WD group was fed a high-calorie (high fructose plus high fat) diet for 12 weeks to develop MetS. At week 12, all mice were sacrificed and the blood and liver were obtained for histological and biological examinations and RNA sequencing (RNA-Seq). Body weight, liver weight, plasma triglycerides (TG), total cholesterol (T-Cho) and alanine aminotransferase (ATS) levels of both OLG groups were significantly lower than those of the WD group. On histological examination of the liver, the area of fatty deposits was shown to be suppressed by OLG administration. Expression gene analysis in the liver of WD- versus OLG-fed mice by RNA-Seq showed that 464/45,706 genes exhibited a significant change of expression (corrected p-value metabolism-related genes Lpin1, Adig and Cidea were regulated by OLG administration. OLG may function to suppress MetS and the progression of geriatric diseases in WD-fed mice by regulating the expression of lipid metabolism, inflammation and tumor-related genes in the liver. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome.

    Directory of Open Access Journals (Sweden)

    Nicola Chiarelli

    Full Text Available Vascular Ehlers-Danlos syndrome (vEDS is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII, which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures. To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER homeostasis, COLLs folding and extracellular matrix (ECM organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition

  3. High-molecular-weight adiponectin is selectively reduced in women with polycystic ovary syndrome independent of body mass index and severity of insulin resistance.

    LENUS (Irish Health Repository)

    O'Connor, A

    2010-03-01

    Context: High-molecular-weight (HMW) adiponectin contributes to insulin resistance (IR), which is closely associated with the pathophysiology of polycystic ovary syndrome (PCOS). Abnormalities in adipocyte function have been identified in PCOS and potentially contribute to lower adiponectin concentrations. Objective: Our objective was to determine which variables in plasma and adipose tissue influence HMW adiponectin in a well characterized cohort of women with PCOS. Design: This was a cross-sectional study. Settings and Participants: A teaching hospital. Women with PCOS (n = 98) and body mass index (BMI)-matched controls (n = 103) (including 68 age-, BMI-, and IR-matched pairs). Interventions: A standard 75-g oral glucose tolerance test was performed for each participant. Subcutaneous adipose tissue samples were taken by needle biopsy for a subset of PCOS women (n = 9) and controls (n = 8). Main Outcome Measures: Serum levels of HMW adiponectin and their relation to indices of insulin sensitivity, body composition, and circulating androgens as well as adipose tissue expression levels of ADIPOQ, TNFalpha, PPARgamma, and AR were assessed. Results: HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and BMI- and IR-matched controls (P = 0.009 and P = 0.027, respectively). Although BMI and IR were the main predictors of HMW adiponectin, an interaction between waist to hip ratio and plasma testosterone contributed to its variance (P = 0.026). Adipose tissue gene expression analysis demonstrated that AR and TNFalpha (P = 0.008 and P = 0.035, respectively) but not ADIPOQ mRNA levels were increased in PCOS compared with controls. Conclusions: HMW adiponectin is selectively reduced in women with PCOS, independent of BMI and IR. Gene expression analysis suggests that posttranscriptional\\/translational modification contributes to reduced HMW adiponectin in PCOS.

  4. Profiling and functional data on the developing olfactory/GnRH system reveal cellular and molecular pathways essential for this process and potentially relevant for the Kallmann syndrome

    Directory of Open Access Journals (Sweden)

    Giulia eGaraffo

    2013-12-01

    Full Text Available During embryonic development, immature neurons in the olfactory epithelium (OE extend axons through the nasal mesenchyme, to contact projection neurons in the olfactory bulb. Axon navigation is accompanied by migration of the GnRH+ neurons, which enter the anterior forebrain and home in the septo-hypothalamic area. This process can be interrupted at various points and lead to the onset of the Kallmann syndrome (KS, a disorder characterized by anosmia and central hypogonadotropic hypogonadism. Several genes has been identified in human and mice that cause KS or a KS-like phenotype. In mice a set of transcription factors appears to be required for olfactory connectivity and GnRH neuron migration; thus we explored the transcriptional network underlying this developmental process by profiling the OE and the adjacent mesenchyme at three embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene that causes a KS-like phenotype when deleted. We identified 20 interesting genes belonging to the following categories: 1 transmembrane adhesion/receptor, 2 axon-glia interaction, 3 scaffold/adapter for signalling, 4 synaptic proteins. We tested some of them in zebrafish embryos: the depletion of five (of six Dlx5 targets affected axonal extension and targeting, while three (of three affected GnRH neuron position and neurite organization. Thus, we confirmed the importance of cell-cell and cell-matrix interactions and identified new molecules needed for olfactory connection and GnRH neuron migration. Using available and newly generated data, we predicted/prioritized putative KS-disease genes, by building conserved co-expression networks with all known disease genes in human and mouse. The results show the overall validity of approaches based on high-throughput data and predictive bioinformatics to identify genes potentially relevant for the molecular pathogenesis of KS. A number of candidate will be discussed, that should be tested in

  5. Circulating pathogen-associated molecular pattern - binding proteins and High Mobility Group Box protein 1 in nascent metabolic syndrome: implications for cellular Toll-like receptor activity.

    Science.gov (United States)

    Jialal, I; Rajamani, U; Adams-Huet, B; Kaur, H

    2014-09-01

    The Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1). We measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n = 37) and healthy control subjects (n = 32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs). Following adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR. In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α). Thus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD. Published by Elsevier Ireland Ltd.

  6. Novel Nsp2 deletion based on molecular epidemiology and evolution of porcine reproductive and respiratory syndrome virus in Shandong Province from 2013 to 2014.

    Science.gov (United States)

    Wang, Feng-Xue; Qin, Li-Ting; Liu, Ying; Liu, Xing; Sun, Na; Yang, Yong; Chen, Ting; Zhu, Hong-Wei; Ren, Jing-Qiang; Sun, Ying-Jun; Cheng, Shi-Peng; Wen, Yong-Jun

    2015-07-01

    Porcine reproductive and respiratory syndrome (PRRS) is an economically important swine disease affecting swine worldwide. In this study, a total of 385 samples were collected from Shandong pig farms during 2013 and 2014, when pigs were not inoculated with any vaccine. Results indicated that, out of 385 samples, 47 (12.21%) were PRRSV-RNA-positive. The gene sequence analysis of 12 ORF5, 12 ORF7, and 8 Nsp2 of these samples was used to determine the molecular epidemiology of PRRSV in different parts of China's Shandong Province. The phylogenetic tree based on these 3 genes indicated that the Chinese PRRSV strains could be divided into five subgroups and two large groups. The 8 study strains were clustered into subgroup IV, another 4 strains into subgroup I. The first 8 strains shared considerable homology with VR-2332 in ORF5 (96-97.5%), the other 4 strains shared considerable homology with JXA1 (94-98%). Phylogenetic tree of GP5 showed that the eight isolates formed a tightly novel clustered branch, subgroup V, which resembled but differed from isolate VR-2332. When examined using Nsp2 alone, the first 8 strains showed considerable homology with a U.S. vaccine strain, Ingelvac MLV (89.6-98.4%). One novel pattern of deletion was observed in Nsp2. The genetic diversity of genotype 2 PRRSV tended to vary in the field. The emergence of novel variants will probably be the next significant branch of PRRSV study. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome Molecular, Cellular, and Clinical Features From a French National Survey

    Science.gov (United States)

    Chandesris, Marie-Olivia; Melki, Isabelle; Natividad, Angels; Puel, Anne; Fieschi, Claire; Yun, Ling; Thumerelle, Caroline; Oksenhendler, Eric; Boutboul, David; Thomas, Caroline; Hoarau, Cyrille; Lebranchu, Yvon; Stephan, Jean-Louis; Cazorla, Celine; Aladjidi, Nathalie; Micheau, Marguerite; Tron, Fran[cedil]cois; Baruchel, Andre; Barlogis, Vincent; Palenzuela, Gilles; Mathey, Catherine; Dominique, Stephane; Body, Gerard; Munzer, Martine; Fouyssac, Fanny; Jaussaud, Rolland; Bader-Meunier, Brigitte; Mahlaoui, Nizar; Blanche, Stephane; Debre, Marianne; Le Bourgeois, Muriel; Gandemer, Virginie; Lambert, Nathalie; Grandin, Virginie; Ndaga, Stephanie; Jacques, Corinne; Harre, Chantal; Forveille, Monique; Alyanakian, Marie-Alexandra; Durandy, Anne; Bodemer, Christine; Suarez, Felipe; Hermine, Olivier; Lortholary, Olivier; Casanova, Jean-Laurent; Fischer, Alain; Picard, Capucine

    2013-01-01

    Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic

  8. Clinical-neurologic, cytogenetic and molecular aspects of the Prader-Willi and Angelman Syndromes Aspectos clínico-neurológicos, citogenéticos e moleculares das síndromes de Prader-Willi e Angelman

    Directory of Open Access Journals (Sweden)

    João M. de Pina-Neto

    1997-06-01

    Full Text Available The Prader-Willi syndrome (PWS and the Angelman syndrome (AS are human neurogenetic disorders involving the imprinting mechanism, at the 15q11-13 chromosome region. The predominant genetic defects in PW are 15q 11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy. In contrast, maternal deletions and paternal chromosome 15 uniparental disomy are associated with a different neurogenetic disorder, the AS. In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q 11-13 loci. We studied 5 patients suspect of PWS and 4 patients suspect of AS who were referred to the Medical Genetics Unit at the University Hospital of Medical School from Ribeirão Preto. Our objective was to establish the correct clinical and etiological diagnosis in these cases. We used conventional cytogenetics, methylation analysis with the probe KB 17 (CpG island of the SNRPN gene by Southern blotting after digestion with the Xba I and Not I restriction enzymes. We studied in patients and their parents the segregation of the (CAn repeats polymorphisms by PCR, using the primers 196 and IR4-3R. All the patients had normal conventional cytogenetical analysis. We confirmed 3 cases of PWS: one by de novo deletion, one by maternal chromosome 15 uniparental disomy and one case with no defined cause determined by the used primers. We confirmed 2 cases of AS, caused by de novo deletion at the 15q 11-13 region, and one case with normal molecular analysis but with strong clinical characteristics.A síndrome de Prader-Willi (SPW e a síndrome de Angelman (SA são doenças neurogenéticas consideradas como exemplos do fenômeno de imprinting em seres humanos, estando relacionadas com alterações envolvendo a região cromossômica 15q11-13. As alterações genéticas predominantes na SPW são deleções na região 15q 11-13 de origem paterna e dissomia uniparental materna. Na SA encontra-se deleções na região 15q

  9. Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome).

    Science.gov (United States)

    Bresler, Scott C; Padwa, Bonnie L; Granter, Scott R

    2016-06-01

    Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy.

  10. Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome.

    Science.gov (United States)

    Agarwal, Rishi; Liebe, Sarah; Turski, Michelle L; Vidwans, Smruti J; Janku, Filip; Garrido-Laguna, Ignacio; Munoz, Javier; Schwab, Richard; Rodon, Jordi; Kurzrock, Razelle; Subbiah, Vivek

    2014-12-01

    Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53).

  11. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: Robust phenotype prediction from the type and position of GLI3 mutations

    NARCIS (Netherlands)

    Johnston, Jennifer J.; Olivos-Glander, Isabelle; Killoran, Christina; Elson, Emma; Turner, Joyce T.; Peters, Kathryn F.; Abbott, Margaret H.; Aughton, David J.; Aylsworth, Arthur S.; Bamshad, Michael J.; Booth, Carol; Curry, Cynthia J.; David, Albert; Dinulos, Mary Beth; Flannery, David B.; Fox, Michelle A.; Graham, John M.; Grange, Dorothy K.; Guttmacher, Alan E.; Hannibal, Mark C.; Henn, Wolfram; Hennekam, Raoul C. M.; Holmes, Lewis B.; Hoyme, H. Eugene; Leppig, Kathleen A.; Lin, Angela E.; Macleod, Patrick; Manchester, David K.; Marcelis, Carlo; Mazzanti, Laura; McCann, Emma; McDonald, Marie T.; Mendelsohn, Nancy J.; Moeschler, John B.; Moghaddam, Billur; Neri, Giovanni; Newbury-Ecob, Ruth; Pagon, Roberta A.; Phillips, John A.; Sadler, Laurie S.; Stoler, Joan M.; Tilstra, David; Walsh Vockley, Catherine M.; Zackai, Elaine H.; Zadeh, Touran M.; Brueton, Louise; Black, Graeme Charles M.; Biesecker, Leslie G.

    2005-01-01

    Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and

  12. Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

    NARCIS (Netherlands)

    Stewart, Douglas R.; Brems, Hilde; Gomes, Alicia G.; Ruppert, Sarah L.; Callens, Tom; Williams, Jennifer; Claes, Kathleen; Bober, Michael B.; Hachen, Rachel; Kaban, Leonard B.; Li, Hua; Lin, Angela; McDonald, Marie; Melancon, Serge; Ortenberg, June; Radtke, Heather B.; Samson, Ignace; Saul, Robert A.; Shen, Joseph; Siqveland, Elizabeth; Toler, Tomi L.; van Maarle, Merel; Wallace, Margaret; Williams, Misti; Legius, Eric; Messiaen, Ludwine

    2014-01-01

    "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of

  13. Rett syndrome: clinical and molecular characterization of two Brazilian patients Síndrome de Rett: caracterização clínica e molecular de dois casos brasileiros

    Directory of Open Access Journals (Sweden)

    Andrea Stachon

    2007-03-01

    Full Text Available BACKGROUND: Rett syndrome (RS is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. OBJECTIVE: To describe two cases of Brazilian patients with identified MECP2 mutations. METHOD: We present two female Brazilian patients with RS. RESULTS: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. CONCLUSION: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.CONTEXTO: Síndrome de Rett (RS é doença pan-étnica de fenótipo bastante variado desde que foram identificadas mutações no gene MECP2 e um número maior de pacientes tem sido diagnosticadas. Existe uma demanda por estudos que investiguem a relação genótipo-fenotipo. OBJETIVO: Descrever dois casos brasileiros de RS com mutações identificadas. MÉTODO: Duas pacientes brasileiras com diagnóstico clínico-molecular de RS foram descritas buscando-se correlacionar genótipo-fenótipo. RESULTADOS: Ambas pacientes apresentaram regressão aos 2-3 anos de idade, movimentos esteriotipados de mãos, retraimento social e desaceleração do crescimento encefálico. Ambas apresentaram déficit de comunicação verbal. Caso 1 também apresentou perda dos movimentos manuais intencionados e crises convulsivas graves. Caso 2 apresentou-se com comprometimento parcial dos movimentos manuais e sem história de crise

  14. Molecular basis of radiation syndrome

    International Nuclear Information System (INIS)

    Romantsev, E.F.; Blokhina, V.D.; Zhulanova, Z I.; Koshcheenko, N.N.; Nikol'skij, A.V.; Filippovich, I.V.

    1984-01-01

    The book is devoted to the analysis of the mechanism of action of ionizing radiation on the most important biochemical processes in the cells and tissues. The postirradiating disturbances of the metabolism of precursors of nucleic acids, biosynthesis of proteins, metabolism of prostaglandins and cyclic nucleotides were examined in detail. The biochemical mechanism of the interphase cell death was discussed. The analysis of the experimental facts about the effect of ionizing radiation with different dose rate upon the cell metabolism was made

  15. Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions.

    Science.gov (United States)

    Simmons, Jon D; Lee, Yann-Leei L; Pastukh, Viktor M; Capley, Gina; Muscat, Cherry A; Muscat, David C; Marshall, Michael L; Brevard, Sidney B; Gillespie, Mark N

    2017-06-01

    Massive transfusions are accompanied by an increased incidence of a particularly aggressive and lethal form of acute lung injury (delayed transfusion-related acute lung injury) which occurs longer than 24 hours after transfusions. In light of recent reports showing that mitochondrial (mt)DNA damage-associated molecular patterns (DAMPs) are potent proinflammatory mediators, and that their abundance in the sera of severely injured or septic patients is predictive of clinical outcomes, we explored the idea that mtDNA DAMPs are present in transfusion products and are associated with the occurrence of delayed transfusion-related acute lung injury. We prospectively enrolled fourteen consecutive severely injured patients that received greater than three units of blood transfusion products and determined if the total amount of mtDNA DAMPs delivered during transfusion correlated with serum mtDNA DAMPs measured after the last transfusion, and whether the quantity of mtDNA DAMPs in the serum-predicted development of acute respiratory distress syndrome (ARDS). We found detectable levels of mtDNA DAMPs in packed red blood cells (3 ± 0.4 ng/mL), fresh frozen plasma (213.7 ± 65 ng/mL), and platelets (94.8 ± 69.2), with the latter two transfusion products containing significant amounts of mtDNA fragments. There was a linear relationship between the mtDNA DAMPs given during transfusion and the serum concentration of mtDNA fragments (R = 0.0.74, p DAMPs in serum measured at 24 hours after transfusion predicted the occurrence of ARDS (9.9 ± 1.4 vs. 3.3 ± 0.9, p DAMPs administered during transfusion may be a determinant of serum mtDNA DAMP levels, and that serum levels of mtDNA DAMPs after multiple transfusions may predict the development of ARDS. Collectively, these findings support the idea that mtDNA DAMPs in transfusion products significantly contribute to the incidence of ARDS after massive transfusions. Prognostic study, level II; therapeutic study, level II.

  16. Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15(q27;q11.2 associated with Prader-Willi syndrome

    Directory of Open Access Journals (Sweden)

    Slater Howard R

    2005-05-01

    Full Text Available Abstract Background Prader-Willi syndrome (MIM #176270; PWS is caused by lack of the paternally-derived copies, or their expression, of multiple genes in a 4 Mb region on chromosome 15q11.2. Known mechanisms include large deletions, maternal uniparental disomy or mutations involving the imprinting center. De novo balanced reciprocal translocations in 5 reported individuals had breakpoints clustering in SNRPN intron 2 or exon 20/intron 20. To further dissect the PWS phenotype and define the minimal critical region for PWS features, we have studied a 22 year old male with a milder PWS phenotype and a de novo translocation t(4;15(q27;q11.2. Methods We used metaphase FISH to narrow the breakpoint region and molecular analyses to map the breakpoints on both chromosomes at the nucleotide level. The expression of genes on chromosome 15 on both sides of the breakpoint was determined by RT-PCR analyses. Results Pertinent clinical features include neonatal hypotonia with feeding difficulties, hypogonadism, short stature, late-onset obesity, learning difficulties, abnormal social behavior and marked tolerance to pain, as well as sticky saliva and narcolepsy. Relative macrocephaly and facial features are not typical for PWS. The translocation breakpoints were identified within SNRPN intron 17 and intron 10 of a spliced non-coding transcript in band 4q27. LINE and SINE sequences at the exchange points may have contributed to the translocation event. By RT-PCR of lymphoblasts and fibroblasts, we find that upstream SNURF/SNRPN exons and snoRNAs HBII-437 and HBII-13 are expressed, but the downstream snoRNAs PWCR1/HBII-85 and HBII-438A/B snoRNAs are not. Conclusion As part of the PWCR1/HBII-85 snoRNA cluster is highly conserved between human and mice, while no copy of HBII-438 has been found in mouse, we conclude that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype.

  17. A de novo duplication of chromosome 21q22.11→qter associated with Down syndrome: Prenatal diagnosis, molecular cytogenetic characterization and fetal ultrasound findings

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2011-12-01

    Conclusion: SKY, FISH and aCGH are useful in prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 21q encompassing the DSCR may present characteristic Down syndrome features on prenatal ultrasound.

  18. Fanconi syndrome

    Science.gov (United States)

    De Toni-Fanconi syndrome ... Fanconi syndrome can be caused by faulty genes, or it may result later in life due to kidney damage. Sometimes the cause of Fanconi syndrome is unknown. Common causes of Fanconi syndrome in ...

  19. Duane Syndrome

    Science.gov (United States)

    ... Frequently Asked Questions Español Condiciones Chinese Conditions Duane Syndrome En Español Read in Chinese What is Duane Syndrome? Duane syndrome, also called Duane retraction syndrome (DRS), ...

  20. Hunter Syndrome

    Science.gov (United States)

    ... in girls. There's no cure for Hunter syndrome. Treatment of Hunter syndrome involves management of symptoms and complications. Symptoms Hunter syndrome is one type of a group of inherited metabolic disorders called mucopolysaccharidoses (MPSs), and Hunter syndrome is ...

  1. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.

    Science.gov (United States)

    Maksimova, N; Hara, K; Miyashia, A; Nikolaeva, I; Shiga, A; Nogovicina, A; Sukhomyasova, A; Argunov, V; Shvedova, A; Ikeuchi, T; Nishizawa, M; Kuwano, R; Onodera, O

    2007-12-01

    In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified. Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut. All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 (Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation. These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.

  2. Mutation analysis of COL4A3 and COL4A4 genes in a Chinese ...

    Indian Academy of Sciences (India)

    Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family.Mutationsin COL4A3 and COL4A4 genes were reported to be associated with ADAS. In this study, clinical ...

  3. Mutation analysis of COL4A3 and COL4A4 genes in a Chinese

    Indian Academy of Sciences (India)

    Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family.Mutationsin COL4A3 and COL4A4 genes were reported to be associated with ADAS. In this study, clinical ...

  4. Mutation analysis of COL4A3 and COL4A4 genes in a Chinese ...

    Indian Academy of Sciences (India)

    Liwei Guo

    2017-06-17

    Jun 17, 2017 ... Department of Forensic Medicine, and Department of Basic Medicine, Xinxiang Medical University, Xinxiang. 453003, People's Republic of China. Abstract. Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising ...

  5. A novel neurofibromin (NF1) interaction with the leucine-rich pentatricopeptide repeat motif-containing protein links neurofibromatosis type 1 and the French Canadian variant of Leigh's syndrome in a common molecular complex.

    Science.gov (United States)

    Arun, Vedant; Wiley, Joseph C; Kaur, Harpreet; Kaplan, David R; Guha, Abhijit

    2013-04-01

    Loss-of-function mutations and deletions in the neurofibromin tumor suppressor gene (NF1) cause neurofibromatosis type 1 (NF-1), the most common inherited syndrome of the nervous system in humans, with a birth incidence of 1:3,000. The most visible features of NF-1 are the neoplastic manifestations caused by the loss of Ras-GTPase-activating protein (Ras-GAP) activity mediated through the GAP-related domain (GRD) of neurofibromin (NF1), the protein encoded by NF1. However, the syndrome is also characterized by cognitive dysfunction and a number of developmental abnormalities. The molecular etiology of many of these nonneoplastic phenotypes remains unknown. Here we show that the tubulin-binding domain (TBD) of NF1 is a binding partner of the leucine-rich pentatricopeptide repeat motif-containing (LRPPRC) protein. These two proteins complex with Kinesin 5B, hnRNP A2, Staufen1, and Myelin Basic Protein (MBP) mRNA, likely in RNA granules. This interaction is of interest in that it links NF-1 with Leigh's syndrome, French Canadian variant (LSFC), an autosomal recessive neurodegenerative disorder that arises from mutations in the LRPPRC gene. Our findings provide clues to how loss or mutation of NF1 and LRPPRC may contribute to the manifestations of NF-1 and LSFC. Copyright © 2013 Wiley Periodicals, Inc.

  6. Hamartomatous polyposis syndromes

    DEFF Research Database (Denmark)

    Jelsig, Anne Marie; Qvist, Niels; Brusgaard, Klaus

    2014-01-01

    Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes such as ......Hamartomatous Polyposis Syndromes (HPS) are genetic syndromes, which include Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumour syndrome (Cowden Syndrom, Bannayan-Riley-Ruvalcaba and Proteus Syndrome) as well as hereditary mixed polyposis syndrome. Other syndromes...

  7. The Marfan syndrome genetics

    Directory of Open Access Journals (Sweden)

    Galina Pungerčič

    2005-05-01

    Full Text Available Background: The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue. It is caused by mutations in the fibrillin-1 gene encoding glycoprotein fibrillin-1, a component of microfibrils of extracellular matrix. Patients with Marfan syndrome show wide spectra of clinical signs, primarily on skeletal, cardiovascular and ocular organ systems. Cardiovascular complications (especially aortic aneurysm and aortic dissection are the most common cause of mortality of Marfan syndrome patients. Discovering genotype-phenotype correlations is complicated because of the large number of mutations reported as well as clinical heterogeneity among individuals with the same mutation. Despite the progress in the knowledge of the molecular nature of Marfan syndrome the diagnosis is still based mainly on the clinical features in the different body systems.Conclusions: Early identification of patient with Marfan syndrome is of considerable importance because of appropriate treatment that can greatly improve life expectancy. Unfortunately, despite the improvement of diagnostic methods, medical and surgical therapy, the mortality due to undiagnosed Marfan syndrome is still high. The present article reviews the molecular genetic studies of Marfan syndrome since the discovery of the mutations in the fibrillin-1 gene.

  8. Mutation in type II procollagen (COL2Al) that substitutes aspartate for glycine [alpha]l-67 and that causes cataracts and retinal detachment: Evidence for molecular heterogeneity in the Wagner Syndrome and the stickler syndrome (Arthro-Ophthalmopathy)

    Energy Technology Data Exchange (ETDEWEB)

    Koerkkoe, J.; Ritvaniemi, P.; Kiviirikko, K.I.; Ala-Kokko, L. (Univ. of Oulu (Finland)); Haataja, L. (Univ. of Turku (Finland)); Kaeaeriaeinen, H. (Univ. of Helsinki (Finland)); Prockop, D.J. (Jefferson Thomas Jefferson Univ., Philadelphia PA (United States))

    1993-07-01

    A search for mutations in the gene for type II procollagen (COL2A1) was carried out in affected members of a family with early-onset cataracts, lattice degeneration of the retina, and retinal detachment. They had no symptoms suggestive of involvement of nonocular tissues, as is typically found in the Stickler syndrome. The COL2A1 gene was amplified with PCR, and the products were analyzed by denaturing gradient gel electrophoresis. The results suggested a mutation in one allele for exon 10. Sequencing of the fragment demonstrated a single-base mutation that converted the codon for glycine at position [alpha]1-67 to aspartate. The mutation was found in three affected members of the family available for study but not in unaffected members or 100 unrelated individuals. Comparison with previously reported mutations suggested that mutations introducing premature termination codons in the COL2A1 gene are a frequent cause of the Stickler syndrome, but mutations in the COL2A1 gene that replace glycine codons with codons for bulkier amino acid can produce a broad spectrum of disorders that range from lethal chondrodysplasias to a syndrome involving only ocular tissues, similar to the syndrome in the family originally described by Wagner in 1938. 38 refs., 4 figs., 3 tabs.

  9. West syndrome in a patient with Schinzel-Giedion syndrome.

    Science.gov (United States)

    Miyake, Fuyu; Kuroda, Yukiko; Naruto, Takuya; Ohashi, Ikuko; Takano, Kyoko; Kurosawa, Kenji

    2015-06-01

    Schinzel-Giedion syndrome is a rare recognizable malformation syndrome defined by characteristic facial features, profound developmental delay, severe growth failure, and multiple congenital anomalies. The causative gene of Schinzel-Giedion syndrome, SETBP1, has been identified, but limited cases have been confirmed by molecular analysis. We present a 9-month-old girl affected by West syndrome with Schinzel-Giedion syndrome. Congenital severe hydronephrosis, typical facial features, and multiple anomalies suggested a clinical diagnosis of Schinzel-Giedion syndrome. Hypsarrhythmia occurred at 7 months of age and was temporarily controlled by adrenocorticotropic hormone (ACTH) therapy during 5 weeks. SETBP1 mutational analysis showed the presence of a recurrent mutation, p.Ile871Thr. The implications in management of Schinzel-Giedion syndrome are discussed. © The Author(s) 2014.

  10. Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Persson, Ulf; juncker, Inger

    2005-01-01

    -by-exon mutation detection strategy such as SSCP analysis or direct sequencing. We have previously reported the results of SSCP analysis of 81 patients suspected of X-linked AS. Genomic DNA from these 81 patients was also analyzed for larger genomic rearrangements, using Southern blotting analysis. Abnormal band...

  11. Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016

    NARCIS (Netherlands)

    Kline, Antonie D.; Krantz, Ian D.; Deardorff, Matthew A.; Shirahige, Katsuhiko; Dorsett, Dale; Gerton, Jennifer L.; Wu, Meng; Mehta, Devanshi; Mills, Jason A.; Carrico, Cheri S.; Noon, Sarah; Herrera, Pamela S.; Horsfield, Julia A.; Bettale, Chiara; Morgan, Jeremy; Huisman, Sylvia A.; Moss, Jo; McCleery, Joseph; Grados, Marco; Hansen, Blake D.; Srivastava, Siddharth; Taylor-Snell, Emily; Kerr, Lynne M.; Katz, Olivia; Calof, Anne L.; Musio, Antonio; Egense, Alena; Haaland, Richard E.

    2017-01-01

    Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are

  12. Molecular characterization of a heterothallic mating system in .i.Pseudogymnoascus destructans./i., the fungus causing white-nose syndrome of bats

    Czech Academy of Sciences Publication Activity Database

    Palmer, J.M.; Kubátová, A.; Nováková, Alena; Minnis, A.M.; Kolařík, M.; Lindner, D.L.

    2014-01-01

    Roč. 4, č. 9 (2014), s. 1755-1763 ISSN 2160-1836 Institutional support: RVO:60077344 Keywords : Genetics of Sex * geomyces * mating type * sexual reproduction * white-nose syndrome Subject RIV: EE - Microbiology, Virology Impact factor: 3.198, year: 2014

  13. Chromosome 15q overgrowth syndrome: Prenatal diagnosis, molecular cytogenetic characterization, and perinatal findings in a fetus with dup(15(q26.2q26.3

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2011-09-01

    Conclusion: The present case provides evidence for prenatal overgrowth, craniosynostosis, and characteristic facial dysmorphism in association with a duplication of 15q26.2→q26.3 and a duplication of the IGF1R gene. Prenatal diagnosis of fetal overgrowth should include a differential diagnosis of the chromosome 15q overgrowth syndrome.

  14. Molecular Screening of "MECP2" Gene in a Cohort of Lebanese Patients Suspected with Rett Syndrome: Report on a Mild Case with a Novel Indel Mutation

    Science.gov (United States)

    Corbani, S.; Chouery, E.; Fayyad, J.; Fawaz, A.; El Tourjuman, O.; Badens, C.; Lacoste, C.; Delague, V.; Megarbane, A.

    2012-01-01

    Background: Rett syndrome (RTT), an X-linked, dominant, neurodevelopment disorder represents 10% of female subjects with profound intellectual disability. Mutations in the "MECP2" gene are responsible for up to 95% of the classical RTT cases, and nearly 500 different mutations distributed throughout the gene have been reported. Methods:…

  15. Caracterización clínica y molecular de individuos con el síndrome frágil X detectados por análisis inmunohistoquímico Clinical and molecular characterization of individuals with fragile X syndrome detected by immunohistochemical analysis

    Directory of Open Access Journals (Sweden)

    Iván Hernández García

    2004-09-01

    Full Text Available Se realizó el estudio de 50 varones con retraso mental y/o autismo de etiología desconocida a fin de detectar individuos afectados con el síndrome frágil X a través del análisis inmunohistoquímico y caracterizarlos clínica y molecularmente. Entre los casos pesquisados se detectaron 3 individuos con baja expresión de la proteína relacionada con el síndrome, a quienes se les realizó la caracterización molecular. La correlación inmunohistoquímica y molecular en 2 de ellos fue positiva. La no correlación de un tercero sugiere que pudiera tratarse de una mutación puntual o una deleción del gen relacionado con la enfermedad. En otro paciente con el fenotipo neuropsicológico y físico característicos de la enfermedad se observó una expresión promedio normal baja, lo que motivó la indicación de la caracterización molecular, que resultó ser positiva. Se discuten los mecanismos genéticos y fisiopatológicos que pudieran explicar la presencia de la proteína en las células analizadas.50 males with mental retardation and/or autism of unknown etiology were studied aimed at detecting individuals affected with the Fragile X syndrome by the immunohistochemical analysis and at characterizing them from the clinical and molecular point of view. Among the screneed subjects, 3 individuals with low expression of the protein related to the syndrome were detected. Molecular characterization was performed in these cases. The immunohistochemical and molecular correlation was positive in 2 of them. The non correlation of the third suggests that it may be a punctual mutation or a deletion of the gene connected with the disease. In another patient with the neuropsychological and physical phenotype characteristic of the disease, it was observed an average normal low expression that led to the indication of the molecular characterization, which proved to be positive. The genetic and physiopathological mechanisms that could explain the presence of

  16. Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients.

    Science.gov (United States)

    Kon, M; Suzuki, E; Dung, V C; Hasegawa, Y; Mitsui, T; Muroya, K; Ueoka, K; Igarashi, N; Nagasaki, K; Oto, Y; Hamajima, T; Yoshino, K; Igarashi, M; Kato-Fukui, Y; Nakabayashi, K; Hayashi, K; Hata, K; Matsubara, Y; Moriya, K; Ogata, T; Nonomura, K; Fukami, M

    2015-03-01

    What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome? Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation. Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias. Systematic mutation screening and genome-wide copy-number analysis of 62 patients. The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization. Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome. The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions. Our data provide evidence that pathogenic mutations can underlie both

  17. Marfan Syndrome

    Science.gov (United States)

    Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood ... fibrillin. A problem with the fibrillin gene causes Marfan syndrome. Marfan syndrome can be mild to severe, and ...

  18. WIEDEMANN SYNDROME

    African Journals Online (AJOL)

    hi-tech

    BILATERAL BENIGN HAEMORRHAGIC ADRENAL CYSTS IN BECKWITH - WIEDEMANN. SYNDROME: CASE REPORT. P. ANOOP and M. A. ANJAY. SUMMARY. Beckwith-Wiedemann syndrome is the most common overgrowth malformation syndrome. The classical features include macrosomia, macroglossia, ...

  19. Tourette syndrome

    Science.gov (United States)

    Gilles de la Tourette syndrome; Tic disorders - Tourette syndrome ... Tourette syndrome is named for Georges Gilles de la Tourette, who first described this disorder in 1885. The disorder is likely passed down through families. ...

  20. Williams syndrome

    Science.gov (United States)

    Williams-Beuren syndrome ... Williams syndrome is caused by not having a copy of several genes. It may be passed down in families. ... history of the condition. However, people with Williams syndrome have a 50% chance of passing the disorder ...

  1. Piriformis Syndrome

    Science.gov (United States)

    ... the National Library of Medicine’s MedlinePlus Piriformis Syndrome Metabolic Syndrome Show More Show Less Search Disorders SEARCH SEARCH Definition Treatment Prognosis Clinical Trials Organizations Publications Definition Piriformis syndrome ...

  2. Hereditary periodic fever syndromes

    NARCIS (Netherlands)

    McDermott, MF; Frenkel, J

    Hereditary periodic fever syndromes are defined by recurrent attacks of generalised inflammation for which no infectious or auto-immune cause can be identified. For most of these disorders, the molecular basis has recently been elucidated. This has opened the prospect of novel therapeutic

  3. Clinical, developmental and molecular update on Cornelia de Lange syndrome and the cohesin complex: abstracts from the 2014 Scientific and Educational Symposium.

    Science.gov (United States)

    Kline, Antonie D; Calof, Anne L; Lander, Arthur D; Gerton, Jennifer L; Krantz, Ian D; Dorsett, Dale; Deardorff, Matthew A; Blagowidow, Natalie; Yokomori, Kyoko; Shirahige, Katsuhiko; Santos, Rosaysela; Woodman, Julie; Megee, Paul C; O'Connor, Julia T; Egense, Alena; Noon, Sarah; Belote, Maurice; Goodban, Marjorie T; Hansen, Blake D; Timmons, Jenni Glad; Musio, Antonio; Ishman, Stacey L; Bryan, Yvon; Wu, Yaning; Bettini, Laura R; Mehta, Devanshi; Zakari, Musinu; Mills, Jason A; Srivastava, Siddharth; Haaland, Richard E

    2015-06-01

    Cornelia de Lange Syndrome (CdLS) is the most common example of disorders of the cohesin complex, or cohesinopathies. There are a myriad of clinical issues facing individuals with CdLS, particularly in the neurodevelopmental system, which also have implications for the parents and caretakers, involved professionals, therapists, and schools. Basic research in developmental and cell biology on cohesin is showing significant progress, with improved understanding of the mechanisms and the possibility of potential therapeutics. The following abstracts are presentations from the 6th Cornelia de Lange Syndrome Scientific and Educational Symposium, which took place on June 25-26, 2014, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting in Costa Mesa, CA. The Research Committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board. In addition to the scientific and clinical discussions, there were educationally focused talks related to practical aspects of behavior and development. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. © 2015 Wiley Periodicals, Inc.

  4. Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Glintborg, D.; Frystyk, J.; Hojlund, K.

    2008-01-01

    OBJECTIVE: Recent studies suggested that the effect of adiponectin on insulin-stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients...... measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Delta-values denoted changes during pioglitazone treatment (16 weeks--basal). RESULTS: Pretreatment adiponectin levels were decreased in PCOS patients vs. controls (P ....89) and Delta-oxidative glucose metabolism (r = 0.71) and inversely with Delta-fasting free fatty acid (FFA) levels (r = -0.69) and Delta-lipid oxidation (r = -0.73) during insulin stimulation (all P

  5. LEOPARD-syndrom

    DEFF Research Database (Denmark)

    Hansen, Lars Kjaersgård; Risby, Kirsten; Bygum, Anette

    2009-01-01

    We describe a 12-year-old boy with a typical phenotype of the LEOPARD syndrome (LS). The diagnosis was confirmed in the boy and his mother, who both had a mutation in the PTPN11 gene at Thr468Met (c.1403C > T). Several other members of the maternal family are suspected also to have the LEOPARD sy...... syndrome. We discuss the clinical characteristics of LS, the need for follow-up and genetic counselling, and the molecular-genetic background as well as the relationship to the allelic disease Noonan syndrome. Udgivelsesdato: 2009-Jan-26......We describe a 12-year-old boy with a typical phenotype of the LEOPARD syndrome (LS). The diagnosis was confirmed in the boy and his mother, who both had a mutation in the PTPN11 gene at Thr468Met (c.1403C > T). Several other members of the maternal family are suspected also to have the LEOPARD...

  6. Hereditary intestinal polyposis syndromes.

    Science.gov (United States)

    Dean, P A

    1996-01-01

    Colorectal cancer is one of the most common cancers in the world, with overall mortality exceeding 40% even with treatment. Effective efforts for screening and prevention are most likely to succeed in patient groups identified as high risk for colorectal cancer, most notably the hereditary intestinal polyposis syndromes. In these syndromes, benign polyps develop throughout the intestinal tract prior to the development of colorectal cancer, marking the patient and associated family for precancer diagnosis followed by either close surveillance or preventive treatment. This review article was undertaken to discuss the most recent developments in the knowledge of hereditary intestinal polyposis syndromes, emphasizing the clinical approach to diagnosis and treatment relative to preventing the development of cancer. The most common of the hereditary polyposis syndromes is familial adenomatous polyposis (FAP), which is characterized by the development of hundreds to thousands of adenomatous polyps in the colon followed at an early age by colorectal cancer. Colorectal cancer can be prevented in this autosomal dominant condition by prophylactic colectomy, though a risk for other tumors, including periampullary cancers, remains throughout life. Variant of FAP associated with fewer and smaller polyps (hereditary flat adenoma syndrome), or even CNS tumors (Turcot's syndrome) also carry this high risk of colorectal cancer. Hereditary hamartomatous polyposis syndromes such as juvenile polyposis and Peutz-Jeghers syndrome (also autosomal dominant) are characterized by less frequent polyps. Though these are generally benign polyps, they are also associated with a significant risk of colorectal and other cancers. Other polyposis syndromes, including neurofibromatosis and Cowden's disease, do not carry this increased risk of colorectal cancer, and therefore affect different treatment strategies. Analysis of genetic factors responsible for these and other hereditary syndromes with

  7. Cornelia de Lange syndrome and molecular implications of the cohesin complex: Abstracts from the 7th biennial scientific and educational symposium 2016.

    Science.gov (United States)

    Kline, Antonie D; Krantz, Ian D; Deardorff, Matthew A; Shirahige, Katsuhiko; Dorsett, Dale; Gerton, Jennifer L; Wu, Meng; Mehta, Devanshi; Mills, Jason A; Carrico, Cheri S; Noon, Sarah; Herrera, Pamela S; Horsfield, Julia A; Bettale, Chiara; Morgan, Jeremy; Huisman, Sylvia A; Moss, Jo; McCleery, Joseph; Grados, Marco; Hansen, Blake D; Srivastava, Siddharth; Taylor-Snell, Emily; Kerr, Lynne M; Katz, Olivia; Calof, Anne L; Musio, Antonio; Egense, Alena; Haaland, Richard E

    2017-05-01

    Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22-23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. © 2017 Wiley Periodicals, Inc.

  8. Pallister–Killian syndrome: Cytogenetics and molecular investigations of mosaic tetrasomy 12p in prenatal chorionic villus and in amniocytes. Strategy of prenatal diagnosis

    Directory of Open Access Journals (Sweden)

    Francesco Libotte

    2016-12-01

    Conclusion: New molecular cytogenetic techniques array comparative genomic hybridization and fluorescence in-situ hybridization in association with conventional karyotype are pivotal innovative tools to search for chromosomic anomalies and for a complete prenatal diagnosis, especially in cases such as PKS where array comparative genomic hybridization analysis alone could not show mosaicism of i(12p.

  9. Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations.

    Science.gov (United States)

    Sen, Ethan S; Dean, Philip; Yarram-Smith, Laura; Bierzynska, Agnieszka; Woodward, Geoff; Buxton, Chris; Dennis, Gemma; Welsh, Gavin I; Williams, Maggie; Saleem, Moin A

    2017-12-01

    There are many single-gene causes of steroid-resistant nephrotic syndrome (SRNS) and the list continues to grow rapidly. Prompt comprehensive diagnostic testing is key to realising the clinical benefits of a genetic diagnosis. This report describes a bespoke-designed, targeted next-generation sequencing (NGS) diagnostic gene panel assay to detect variants in 37 genes including the ability to identify copy number variants (CNVs). This study reports results of 302 patients referred for SRNS diagnostic gene panel analysis. Phenotype and clinical impact data were collected using a standard proforma. Candidate variants detected by NGS were confirmed by Sanger sequencing/Multiplex Ligation-dependent Probe Amplification with subsequent family segregation analysis where possible. Clinical presentation was nephrotic syndrome in 267 patients and suspected Alport syndrome (AS) in 35. NGS panel testing determined a likely genetic cause of disease in 44/220 (20.0%) paediatric and 10/47 (21.3%) adult nephrotic cases, and 17/35 (48.6%) of haematuria/AS patients. Of 71 patients with genetic disease, 32 had novel pathogenic variants without a previous disease association including two with deletions of one or more exons of NPHS1 or NPHS2 . Gene panel testing provides a genetic diagnosis in a significant number of patients presenting with SRNS or suspected AS. It should be undertaken at an early stage of the care pathway and include the ability to detect CNVs as an emerging mechanism for genes associated with this condition. Use of clinical genetic testing after diagnosis of SRNS has the potential to stratify patients and assist decision-making regarding management. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  10. Urinary Metabolomics Identifies a Molecular Correlate of Interstitial Cystitis/Bladder Pain Syndrome in a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP Research Network Cohort

    Directory of Open Access Journals (Sweden)

    Kaveri S. Parker

    2016-05-01

    Full Text Available Interstitial cystitis/bladder pain syndrome (IC/BPS is a poorly understood syndrome affecting up to 6.5% of adult women in the U.S. The lack of broadly accepted objective laboratory markers for this condition hampers efforts to diagnose and treat this condition. To identify biochemical markers for IC/BPS, we applied mass spectrometry-based global metabolite profiling to urine specimens from a cohort of female IC/BPS subjects from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP Research Network. These analyses identified multiple metabolites capable of discriminating IC/BPS and control subjects. Of these candidate markers, etiocholan-3α-ol-17-one sulfate (Etio-S, a sulfoconjugated 5-β reduced isomer of testosterone, distinguished female IC/BPS and control subjects with a sensitivity and specificity >90%. Among IC/BPS subjects, urinary Etio-S levels are correlated with elevated symptom scores (symptoms, pelvic pain, and number of painful body sites and could resolve high- from low-symptom IC/BPS subgroups. Etio-S-associated biochemical changes persisted through 3–6 months of longitudinal follow up. These results raise the possibility that an underlying biochemical abnormality contributes to symptoms in patients with severe IC/BPS.

  11. Clinical and Molecular Genetic Analysis in Three Children with Wolfram Syndrome: A Novel WFS1 Mutation (c.2534T>A).

    Science.gov (United States)

    Çelmeli, Gamze; Türkkahraman, Doğa; Çürek, Yusuf; Houghton, Jayne; Akçurin, Sema; Bircan, İffet

    2017-03-01

    Wolfram syndrome (WS) is an autosomal recessive disorder caused by mutations in WFS1 gene. The clinical features include diabetes insipidus, diabetes mellitus (DM), optic atrophy, deafness, and other variable clinical manifestations. In this paper, we present the clinical and genetic characteristics of 3 WS patients from 3 unrelated Turkish families. Clinical characteristics of the patients and the age of onset of symptoms were quite different in each pedigree. The first two cases developed all symptoms of the disease in their first decade of life. The heterozygous father of case 2 was symptomatic with bilateral deafness. The first ocular finding of one patient (patient 3) was bilateral cataract which was accompanying DM as a first feature of the syndrome. In this patient's family, there were two members with features suggestive of WS. Previously known homozygous mutations, c.460+1G>A in intron 4 and c.1885C>T in exon 8, were identified in these cases. A novel homozygous c.2534T>A mutation was also detected in the exon 8 of WFS1 gene. Because of the rarity and heterogeneity of WS, detection of specific and nonspecific clinical signs including ocular findings and family history in non-autoimmune, insulinopenic diabetes cases should lead to a tentative diagnosis of WS. Genetic testing is required to confirm the diagnosis.

  12. Isolation, Characterization, and Molecular Modeling of a Rheumatoid Factor from a Hepatitis C Virus Infected Patient with Sjögren’s Syndrome

    Directory of Open Access Journals (Sweden)

    Yu-Ching Lee

    2013-01-01

    Full Text Available We have previously isolated several IgG rheumatoid factors (RFs from patients with both rheumatoid arthritis and idiopathic thrombocytopenia purpura using phage display system. To study IgG RFs in patients with other autoimmune diseases, phage display antibody libraries from a hepatitis C virus infected patient with Sjögren’s syndrome were constructed. After panning, a specific clone RFL11 was isolated for characterization in advance. The binding activity and specificity of RFL11 to IgG Fc fragment were comparable to those of RFs previously isolated. The analysis with existed RF-Fc complex structures indicated the homology model of RFL11 is similar to IgM RF61 complex with high binding affinity of about 6×10-8 M. This effect resulted from longer complementarity-determining region (CDR combining key somatic mutations. In the RFL11-Fc interfaces, the CDR-H3 loop forms a finger-like structure extending into the bottom of Fc pocket and resulting in strong ion and cation-pi interactions. Moreover, a process of antigen-driven maturation was proven by somatically mutated VH residues on H2 and H3 CDR loops in the interfaces. Taken together, these results suggested that high affinity IgG RFs can be generated in patients with Sjögren’s syndrome and may play an important role in the pathogenesis of this autoimmune disease.

  13. Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

    Science.gov (United States)

    Zhou, Peng; Zhang, Shilei; Wang, Yewang; Yang, Chao; Huang, Jian

    2016-08-01

    Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3-P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.

  14. A molecular clock dates the common ancestor of European-type porcine reproductive and respiratory syndrome virus at more than 10 years before the emergence of disease

    DEFF Research Database (Denmark)

    Forsberg, Roald; Oleksiewicz, Martin B.; Krabbe Petersen, Anne Mette

    2001-01-01

    an accurate molecular clock for the European PRRSV ORF 3 gene, place the root in the genealogy, estimate the rate of nucleotide substitution, and date the most recent common viral ancestor of the data set to 1979; more than 10 years before the onset of the European epidemic. Based on these findings, we...... conclude that PRRSV virus most likely entered the pig population some time before the epidemic emergence of the virus, and hence, that emergence of European-type PRRSV is not the result of a recent species transmission event. Together, our results show that ORF3 sequencing is a valuable epidemiologic tool...... for examining the emergence and spread of PRRSV in Europe. As such, the panel of well-characterized and highly divergent ORF3 sequences described in this study provides a reference point for future molecular epidemiologic studies....

  15. [Pearson syndrome. Case report].

    Science.gov (United States)

    Cammarata-Scalisi, Francisco; López-Gallardo, Ester; Emperador, Sonia; Ruiz-Pesini, Eduardo; Da Silva, Gloria; Camacho, Nolis; Montoya, Julio

    2011-09-01

    Among the etiologies of anemia in the infancy, the mitochondrial cytopathies are infrequent. Pearson syndrome is diagnosed principally during the initial stages of life and it is characterized by refractory sideroblastic anemia with vacuolization of marrow progenitor cells, exocrine pancreatic dysfunction and variable neurologic, hepatic, renal and endocrine failures. We report the case of a 14 month-old girl evaluated by a multicentric study, with clinic and molecular diagnosis of Pearson syndrome, with the 4,977-base pair common deletion of mitochondrial DNA. This entity has been associated to diverse phenotypes within the broad clinical spectrum of mitochondrial disease.

  16. 46,XX Male Syndrome

    Directory of Open Access Journals (Sweden)

    Bekir Uçan

    2013-06-01

    Full Text Available 46, XX male syndrome – testicular disorder of sexual differentiation (DSD is a rare condition characterized by a spectrum of clinical presentations, ranging from ambiguous to normal male genitalia. These cases are diagnosed more easily in childhood. In adults, the diagnosis can be difficult due to the current normal gender development. Here, we report hormonal, molecular and cytogenetic results in an adult male patient with primary hypogonadism who was diagnosed with 46, XX male syndrome in our clinic. Turk Jem 2013; 17: 46-8

  17. Low-molecular-weight heparin and aspirin use in relation to pregnancy outcome in women with systemic lupus erythematosus and antiphospholipid syndrome: A cohort study.

    Science.gov (United States)

    Abheiden, Carolien N H; Blomjous, Birgit S; Kroese, Sylvia J; Bultink, Irene E M; Fritsch-Stork, Ruth D E; Lely, A Titia; de Boer, Marjon A; de Vries, Johanna I P

    2017-02-01

    To relate anticoagulant use to pregnancy complications in women with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). All ongoing pregnancies, 184, in two Dutch tertiary centers between 2000 and 2015. LMWH and aspirin was prescribed in 15/109 SLE women without antiphospholipid antibodies (aPL), 5/14 with aPL, 11/13 with APS, 45/48 with primary APS. Main complications in the four treatment groups (no anticoagulant treatment, aspirin, LMWH, aspirin and LMWH) included hypertensive disorders of pregnancy (9.4%, 23.3%, 50%, 18.4%, respectively, p = 0.12) and preterm birth (16.7%, 34.3%, 75%, 36.8%, respectively, p < 0.001). Maternal and perinatal complications occurred frequently, despite LMWH and aspirin use.

  18. Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1 in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion.

    Directory of Open Access Journals (Sweden)

    Thierry Vilboux

    Full Text Available Smith-Magenis syndrome (SMS is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1 is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion, were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.

  19. Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion.

    Science.gov (United States)

    Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K; Cox, Gerald F; Deshpande, Charu; Introne, Wendy J; Gahl, William A; Smith, Ann C M; Huizing, Marjan

    2011-01-01

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.

  20. Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome

    Directory of Open Access Journals (Sweden)

    Sargent Carole A

    2010-02-01

    Full Text Available Abstract Background X monosomic mice (39,XO have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO. The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. Results We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. Conclusions Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for

  1. The Greig cephalopolysyndactyly syndrome

    Directory of Open Access Journals (Sweden)

    Biesecker Leslie G

    2008-04-01

    Full Text Available Abstract The Greig cephalopolysyndactyly syndrome (GCPS is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of incidence are difficult to determine, as ascertainment is erratic (estimated range 1–9/1,000,000. The primary findings include hypertelorism, macrocephaly with frontal bossing, and polysyndactyly. The polydactyly is most commonly preaxial of the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS anomalies, hernias, and cognitive impairment. GCPS is caused by loss of function mutations in the GLI3 transcription factor gene and is inherited in an autosomal dominant pattern. The disorder is allelic to the Pallister-Hall syndrome and one form of the acrocallosal syndrome. Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical have been delineated. For this reason, we have proposed a combined clinical-molecular definition for the syndrome. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Patients with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above and a GLI3 mutation may be diagnosed definitively with GCPS. In addition, persons with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may be diagnosed definitively as well. Antenatal molecular diagnosis is technically straightforward to perform. Differential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. Treatment of the disorder is symptomatic, with plastic or

  2. Improved molecular diagnosis of unparental disomy 15 in Prader-Willi and Angelman syndromes utilizing new short tandem repeats (STRs) mapped to chromosome 15q11.2-q12

    Energy Technology Data Exchange (ETDEWEB)

    Christian, S.L.; Kubota, T.; Ledbetter, D.H. [National Institutes of Health, Bethesda, MD (United States)] [and others

    1994-09-01

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by paternal (PWS) or maternal (AS) deficiencies of chromosome 15q11.2-q12. Three STRs (D15S11, GABRB3, and D15S113) were previously developed utilizing YACs from this region as a molecular diagnostic test for PWS/AS. Since then twenty-three new STRs have been developed by several groups which map to 15q11.2-q12. Fine mapping of some of these markers was accomplished utilizing a 3.5 Mb YAC contig of this region. Three new CEPH-Genethon markers, D15S122, D15S128, and D15S210 were mapped within the smallest PWS/AS critical regions. D15S122 mapped to YACs 230H12 and 132D4, D15S128 mapped to YACs 457B4, 11H11, and B58C7, and D15S210 mapped to 132D4 and B230E3. To improve molecular diagnosis of uniparental disomy in PWS/AS, D15S122 and D15S128 with >70% hetrozygosities were placed in a new multiplex PCR reaction with D15S11. Additionally, three CEPH-Genethon markers with high heterozygosities from distal 15q, D15S123, D15S125, and D15S131, were used establish a second multiplex to increase the total number of markers analyzed to six. Twenty-three patients with uniparental disomy 15 were compared using the original multiplex and the two new multiplexes. The results indicated that 16/23 had at least one fully informative marker with the original multiplex and 23/23 using the two new multiplexes. Using a more rigorous diagnostic criterion of two fully informative markers, only 8/23 were informative with the original multiplex and 21/23 with the two new multiplexes. These results demonstrate that these two new multiplexes composed of a total of six polymorphic STRs provide an improved diagnostic test for uniparental disomy 15.

  3. Myelodysplastic Syndromes

    Science.gov (United States)

    ... blood cells, and the cells have a specific mutation in their DNA. Myelodysplastic syndrome with excess blasts — ... Chemicals linked to myelodysplastic syndromes include tobacco smoke, pesticides and industrial chemicals, such as benzene. Exposure to ...

  4. Moebius Syndrome

    Science.gov (United States)

    ... and supports a broad range of research on neurogenetic disorders, including Moebius syndrome. The goals of these ... and supports a broad range of research on neurogenetic disorders, including Moebius syndrome. The goals of these ...

  5. Pendred Syndrome

    Science.gov (United States)

    ... scan) to look for two characteristics of Pendred syndrome. One characteristic might be a cochlea with too few turns. ... Inner Ear Credit: NIH Medical Arts A second characteristic of Pendred syndrome is an enlarged vestibular aqueduct (see figure). The ...

  6. Rett Syndrome

    Science.gov (United States)

    Rett syndrome is a rare genetic disease that causes developmental and nervous system problems, mostly in girls. It's related to autism spectrum disorder. Babies with Rett syndrome seem to grow and ...

  7. Ohtahara Syndrome

    Science.gov (United States)

    ... but be profoundly handicapped. As they grow, some children will progress into other epileptic disorders such as West syndrome and Lennox-Gestaut syndrome. What research is being done? The NINDS conducts and supports an extensive research program on seizures ...

  8. Gardner's syndrome

    International Nuclear Information System (INIS)

    Sobrado Junior, C.W.; Bresser, A.; Cerri, G.G.; Habr-Gama, A.; Pinotti, H.W.; Magalhaes, A.

    1988-01-01

    A case of familiar poliposis of colon related to a right mandibular osteoma is reported (this association is usually called Gardner's syndrome). Radiologic pictures ae shown and some commentaries about this syndrome concerning the treatment are made. (author) [pt

  9. Turner Syndrome

    Science.gov (United States)

    Turner syndrome is a genetic disorder that affects a girl's development. The cause is a missing or incomplete X ... work properly. Other physical features typical of Turner syndrome are Short, "webbed" neck with folds of skin ...

  10. Metabolic Syndrome

    Science.gov (United States)

    Metabolic syndrome is a group of conditions that put you at risk for heart disease and diabetes. These conditions ... agree on the definition or cause of metabolic syndrome. The cause might be insulin resistance. Insulin is ...

  11. Felty syndrome

    Science.gov (United States)

    Seropositive rheumatoid arthritis (RA); Felty's syndrome ... The cause of Felty syndrome is unknown. It is more common in people who have had rheumatoid arthritis (RA) for a long time. People with ...

  12. Cushing's Syndrome

    Science.gov (United States)

    Cushing's syndrome is a hormonal disorder. The cause is long-term exposure to too much cortisol, a hormone that ... your body to make too much cortisol. Cushing's syndrome is rare. Some symptoms are Upper body obesity ...

  13. Usher Syndrome

    Science.gov (United States)

    Usher syndrome is an inherited disease that causes serious hearing loss and retinitis pigmentosa, an eye disorder that causes ... and vision. There are three types of Usher syndrome: People with type I are deaf from birth ...

  14. Piriformis syndrome

    Science.gov (United States)

    Pseudosciatica; Wallet sciatica; Hip socket neuropathy; Pelvic outlet syndrome; Low back pain - piriformis ... Sciatica is the main symptom of piriformis syndrome. Other symptoms include: Tenderness or a dull ache in ...

  15. Dressler's Syndrome

    Science.gov (United States)

    ... syndrome Overview Dressler's syndrome is a type of pericarditis — inflammation of the sac surrounding the heart (pericardium). ... reducing its ability to pump blood efficiently. Constrictive pericarditis. Recurring or chronic inflammation can cause the pericardium ...

  16. Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 22 associated with cat eye syndrome.

    Science.gov (United States)

    Chen, Chih-Ping; Ko, Tsang-Ming; Chen, Yi-Yung; Su, Jun-Wei; Wang, Wayseen

    2013-09-15

    We present prenatal diagnosis of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 22 associated with cat eye syndrome (CES) using cultured amniocytes in a pregnancy with fetal microcephaly, intrauterine growth restriction, left renal hypoplasia, total anomalous pulmonary venous return with dominant right heart and right ear deformity. The sSMC was bisatellited and dicentric, and was characterized by multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). The SALSA MLPA P250-B1 DiGeorge Probemix showed duplication of gene dosage in the CES region. aCGH showed a 1.26-Mb duplication at 22q11.1-q11.21 encompassing CECR1-CECR7. The sSMC was likely inv dup(22) (q11.21). Prenatal diagnosis of an sSMC(22) at amniocentesis should alert CES. MLPA, aCGH and fetal ultrasound are useful for rapid diagnosis of CES in case of prenatally detected sSMC(22). Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature.

    Science.gov (United States)

    Dietze, Ilona; Fritz, Barbara; Huhle, Dagmar; Simoens, Wouter; Piecha, Ernestine; Rehder, Helga

    2004-01-01

    Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal. Copyright 2004 S. Karger AG, Basel

  18. A molecular deletion of distal chromosome 4p in two families with a satellited chromosome 4 lacking the Wolf-Hirschhorn syndrome phenotype.

    Science.gov (United States)

    Estabrooks, L L; Lamb, A N; Kirkman, H N; Callanan, N P; Rao, K W

    1992-11-01

    We report two families with a satellited chromosome 4 short arm (4ps). Satellites and stalks normally occur on the short arms of acrocentric chromosomes; however, the literature cites several reports of satellited nonacrocentric chromosomes, which presumably result from a translocation with an acrocentric chromosome. This is the first report of 4ps chromosomes. Our families are remarkable in that both unaffected and affected individuals carry the 4ps chromosome. The phenotypes observed in affected individuals, although dissimilar, were sufficient to encourage a search for a deletion of chromosome 4p. By Southern blot analysis and fluorescence in situ hybridization, a deletion of material mapping approximately 150 kb from chromosome 4pter was discovered. This deletion is notable because it does not result in the Wolf-Hirschhorn syndrome and can result in an apparently normal phenotype. We speculate that homology between subterminal repeat sequences on 4p and sequences on the acrocentric short arms may explain the origin of the rearrangement and that position effect may play a role in the expression of the abnormal phenotype.

  19. Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs.

    Science.gov (United States)

    Kumari, Daman; Bhattacharya, Aditi; Nadel, Jeffrey; Moulton, Kristen; Zeak, Nicole M; Glicksman, Anne; Dobkin, Carl; Brick, David J; Schwartz, Philip H; Smith, Carolyn B; Klann, Eric; Usdin, Karen

    2014-12-01

    Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2, and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). The treatment with small molecules that inhibit S6K1 and a known FMRP target, phosphoinositide 3-kinase (PI3K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches. © 2014 WILEY PERIODICALS, INC.

  20. Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea.

    Science.gov (United States)

    Jang, Mi-Ae; Lee, Taeheon; Lee, Junnam; Cho, Eun-Hae; Ki, Chang-Seok

    2015-05-01

    Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea.

  1. Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.

    Science.gov (United States)

    Novara, Francesca; Groeneweg, Stefan; Freri, Elena; Estienne, Margherita; Reho, Paolo; Matricardi, Sara; Castellotti, Barbara; Visser, W Edward; Zuffardi, Orsetta; Visser, Theo J

    2017-03-01

    Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected V max and K m values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype. © 2016 WILEY PERIODICALS, INC.

  2. International Rett Syndrome Foundation

    Science.gov (United States)

    ... Newsletters & Reports About Rett Syndrome What is Rett Syndrome? Rett Syndrome Diagnosis Boys with MECP2 Clinics FAQs Glossary ... Newsletters & Reports About Rett Syndrome What is Rett Syndrome? Rett Syndrome Diagnosis Boys with MECP2 Clinics FAQs Glossary ...

  3. [Capgras syndrome].

    Science.gov (United States)

    Alcoverro Fortuny, O; Sierra Acín, A C

    2001-01-01

    The authors report a case of Capgras' syndrome in a 16-years-old child, who had been hospitalized for psychotic disorder. A review of the literature is performed. Most authors state that Capgras' syndrome would represent a symptom of underlying medical o functional disorders, although the term syndrome is used. The main etiopathogenic hypothesis of this syndrome are put forward (psychodynamic, disconnection, neuropsychological and medical).

  4. Renal-skin syndromes.

    Science.gov (United States)

    Has, Cristina; He, Yinghong

    2017-07-01

    Renal-skin syndroms are a group of genetic disorders with renal and cutaneous manifestations that target molecular components present in both organs. Inherited renal-skin syndromes are mainly associated with defects of cell-matrix adhesion. We provide a non-exhaustive overview of the main molecular players at cell-matrix adhesions in mouse models and in human genetic disorders affecting kidney and skin. Renal and urinary tract involvement is described in all four major epidermolysis bullosa types and, in particular, in junctional subtypes and in recessive dystrophic epidermolysis bullosa. Here, we describe in detail those subtypes for which reno-urinary involvement is a constant and primary feature. Furthermore, complex multiorgan disorders with a predisposition to malignancies or attributable to metabolic defects that involve both kidney and skin are briefly summarized.

  5. Prenatal diagnosis and molecular cytogenetic characterization of a 1.07-Mb microdeletion at 5q35.2–q35.3 associated with NSD1 haploinsufficiency and Sotos syndrome

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2014-12-01

    Conclusion: Fetuses with Sotos syndrome may present macrocephaly, polyhydramnios, ventriculomegaly, and pyelectasis in the third trimester. aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome.

  6. Genetic syndromes associated with overgrowth in childhood

    Directory of Open Access Journals (Sweden)

    Jung Min Ko

    2013-09-01

    Full Text Available Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians' ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.

  7. Axenfeld-Rieger anomaly and Axenfeld-Rieger syndrome: clinical, molecular-cytogenetic, and DNA array analyses of three patients with chromosomal defects at 6p25.

    Science.gov (United States)

    Tonoki, Hidefumi; Harada, Naoki; Shimokawa, Osamu; Yosozumi, Ayako; Monzaki, Kadomi; Satoh, Kohei; Kosaki, Rika; Sato, Atsushi; Matsumoto, Naomichi; Iizuka, Susumu

    2011-12-01

    Clinical phenotypes of and genetic aberrations in three unrelated Japanese patients with Axenfeld-Rieger anomalies and various accompanying malformations of systemic organs are described. GTG-banded chromosome analysis showed terminal deletions of the short arm of chromosome 6 in two patients and an inversion, inv(6)(p25q14), in the other. FISH and DNA array analyses revealed that the two patients with deletions had 5.0-5.7 Mb and 6.6 Mb 6p terminal deletions, respectively, and FOXC1 was apparently deleted in both patients. In the other patient, the inversion breakpoint at 6p25 was estimated to be in or very close to the FOXC1 locus, but DNA array analysis did not reveal a deletion around the breakpoint. Common extraocular findings in these patients included broad forehead, brachycephaly, hypertelorism, downslanting palpebral fissures, small anteverted nose, and cardiac defects. Two patients also exhibited autistic characteristics. The two patients with deletions exhibited poor muscle tone and developmental delays. Most of these extraocular findings were similar to those found in previous patients with FOXC1 mutations and distinct from those found in patients with PITX2 mutations, who frequently develop umbilical and dental anomalies. We suggest that the psychomotor retardation is a clinical manifestation associated with a deletion of multiple contiguous genes in the 6p terminus and that this phenomenon is similar to the 6p25 deletion syndrome. Understanding the relationship between genetic lesions and the spectrum of extraocular findings in patients with Axenfeld-Rieger anomalies may lead to better clinical management. Copyright © 2011 Wiley Periodicals, Inc.

  8. Brachmann-Cornelia de Lange syndrome with a papilloma of the choroid plexus: analyses of molecular genetic characteristics of the patient and the tumor. A single-case study.

    Science.gov (United States)

    de León, Fernando Chico-Ponce; Gordillo-Domínguez, Luis F; González-Carranza, Vicente; Torres-García, Samuel; García-Delgado, Constanza; Sánchez-Boiso, Adriana; Arenas-Huertero, Francisco; Perezpeña-Diazconti, Mario; Eguía-Aguilar, Pilar; Baqueiro-Hernández, César; Buenrostro-Márquez, Guillermo; Martínez-Rodríguez, Sonia; Dhellemmes, Patrick; Castro-Sierra, Eduardo

    2015-01-01

    A 10-month-old girl with a Brachmann-Cornelia de Lange syndrome and a choroid plexus papilloma of the brain was studied at the Hospital Infantil de México Federico Gómez (HIMFG) in Mexico City. Presumptive papilloma of the third ventricle was evidenced on CT and MR images and removed. Pathological analysis confirmed its origin. A posterior radiosurgery was required due to a tumor relapse. Karyotypes (GTG bands) of the patient and her parents undertaken at HIMFG were normal. Array comparative genomic hybridization (array CGH) analyses of blood DNA of the patient and her parents carried out at BlueGnome's Laboratory in Cambridge, UK, set in evidence amplification of genes SPNS2, GGT6, SMTNL2, PELP1, MYBBP1A, and ALOX15 in chromosome 17p of the patient. Since MYBBP1A is a proto-oncogene and ALOX15 participates in the development of cancer and metastases of tumors, further fluorescent in situ hybridization (FISH) analyses of these two genes were implemented at HIMFG. Amplification of the two genes was found in the tumor of the case under study but not in an unrelated papilloma of the choroid plexus. Further analyses of the association of choroid plexus papillomas with disorders of psycho-neural development and its relationship to molecular genetic modifications at chromosome 17p are now under way at HIMFG.

  9. Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

    Science.gov (United States)

    Hyman, B T; West, H L; Rebeck, G W; Buldyrev, S V; Mantegna, R N; Ukleja, M; Havlin, S; Stanley, H E

    1995-04-11

    The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

  10. Diagnosis in Prader-Willi syndrome.

    OpenAIRE

    Chu, C E; Cooke, A; Stephenson, J B; Tolmie, J L; Clarke, B; Parry-Jones, W L; Connor, J M; Donaldson, M D

    1994-01-01

    Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.

  11. Genetics Home Reference: arterial tortuosity syndrome

    Science.gov (United States)

    ... Barrow M, Dekens R, Loeys BL, Coucke PJ, De Paepe AM. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified ... R, Dietz HC, Barlati S, Colombi M, Loeys B, De Paepe A. Mutations in the ... and cause arterial tortuosity syndrome. Nat Genet. 2006 Apr;38(4):452-7. ...

  12. Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation.

    Science.gov (United States)

    Earley, Christopher J; Uhl, George R; Clemens, Stefan; Ferré, Sergi

    2017-03-01

    Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these

  13. ADULT VARIANT BARTTER’S SYNDROME- A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Ishwar Sidappa Hasabi

    2017-02-01

    Full Text Available BACKGROUND Bartter syndrome is a group of channelopathies with different genetic origins and molecular pathophysiologies, but sharing common feature of decreased tubular transport of sodium chloride in thick ascending loop of Henle (TAL, 1 although more common in antenatal group. Classic adult variant of Bartter syndrome is a rare entity. We hereby present a rare adult variant of classic Bartter syndrome.

  14. Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms.

    Science.gov (United States)

    Blum, Kenneth; Oscar-Berman, Marlene; Stuller, Elizabeth; Miller, David; Giordano, John; Morse, Siobhan; McCormick, Lee; Downs, William B; Waite, Roger L; Barh, Debmalya; Neal, Dennis; Braverman, Eric R; Lohmann, Raquel; Borsten, Joan; Hauser, Mary; Han, David; Liu, Yijun; Helman, Manya; Simpatico, Thomas

    2012-11-27

    In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the "Brain Reward Cascade" (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications.

  15. Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms

    Science.gov (United States)

    Blum, Kenneth; Oscar-Berman, Marlene; Stuller, Elizabeth; Miller, David; Giordano, John; Morse, Siobhan; McCormick, Lee; Downs, William B; Waite, Roger L; Barh, Debmalya; Neal, Dennis; Braverman, Eric R; Lohmann, Raquel; Borsten, Joan; Hauser, Mary; Han, David; Liu, Yijun; Helman, Manya; Simpatico, Thomas

    2013-01-01

    In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the “Brain Reward Cascade” (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications. PMID:23926462

  16. Guillain-Barré syndrome- and Miller Fisher syndrome-associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b Antibodies in rabbits.

    NARCIS (Netherlands)

    M.A. de Klerk; H.P. Endtz (Hubert); B.C. Jacobs (Bart); J.D. Laman (Jon); F.G.A. van der Meché (Frans); P.A. van Doorn (Pieter); C.W. Ang (Wim)

    2001-01-01

    textabstractCampylobacter jejuni infections are thought to induce antiganglioside antibodies in patients with Guillain-Barre syndrome (GBS) and Miller Fisher syndrome (MFS) by molecular mimicry between C. jejuni lipopolysaccharides (LPS) and gangliosides. We used

  17. Revesz syndrome

    Directory of Open Access Journals (Sweden)

    Dayane Cristine Issaho

    2015-04-01

    Full Text Available Revesz syndrome is a rare variant of dyskeratosis congenita and is characterized by bilateral exudative retinopathy, alterations in the anterior ocular segment, intrauterine growth retardation, fine sparse hair, reticulate skin pigmentation, bone marrow failure, cerebral calcification, cerebellar hypoplasia and psychomotor retardation. Few patients with this syndrome have been reported, and significant clinical variations exist among patients. This report describes the first Brazilian case of Revesz syndrome and its ocular and clinical features.

  18. Gorlin syndrome

    Directory of Open Access Journals (Sweden)

    Basanti Devi

    2013-01-01

    Full Text Available Gorlin Syndrome, a rare genodermatosis, otherwise known as Nevoid basal cell carcinoma syndrome (NBCCS is a multisystem disease affecting skin, nervous system, eyes, endocrine glands, and bones. It is characterized by multiple basal cell carcinomas, palmoplantar pits, jaw cysts, and bony deformities like kyphoscoliosis and frontal bossing. We would like to report a case of Gorlin syndrome with classical features, as this is a rare genodermatosis.

  19. Urofacial syndrome

    Directory of Open Access Journals (Sweden)

    Kamal F Akl

    2012-01-01

    Full Text Available The urofacial syndrome is characterized by functional obstructive uropathy asso-ciated with an inverted smile. The importance of the subject is that it sheds light, not only on the muscles of facial expression, but also on the inheritance of voiding disorders and lower urinary tract malformations. We report a 10-year-old-male patient who had the urofacial syndrome. Early diagnosis of the urofacial syndrome is important to avoid upper urinary tract damage and renal failure.

  20. Joubert Syndrome

    Science.gov (United States)

    ... syndrome is inherited in an autosomal recessive manner (meaning both parents must have a copy of ... physical, occupational, and speech therapy may benefit some children. Infants with abnormal ...

  1. Reye's Syndrome

    Science.gov (United States)

    ... that contain aspirin. Some hospitals and medical facilities conduct newborn screenings for fatty acid oxidation disorders to determine which children are at greater risk of developing Reye's syndrome. ...

  2. Angelman Syndrome

    Science.gov (United States)

    ... See More About Research The NINDS supports and conducts research on neurogenetic disorders such as Angelman syndrome, to develop techniques to diagnose, treat, ... Publications Definition Angelman ...

  3. Russell-Silver syndrome

    Science.gov (United States)

    Silver-Russell syndrome; Silver syndrome; RSS; Russell-Silver syndrome ... One in 10 children with this syndrome has a problem involving chromosome 7. In other people with the syndrome, it may affect chromosome 11. Most of the time, it ...

  4. [Ballantyne syndrome or mirror syndrome].

    Science.gov (United States)

    Torres-Gómez, Luis Guillermo; Silva-González, María Eugenia; González-Hernández, Rigoberto

    2010-11-01

    Ballantyne syndrome or mirror syndrome is a triad consisting of the presence of fetal hydrops, generalized edema placentomegaly mother. May be related to any cause of fetal hydrops. The fetal prognosis is poor in untreated cases, the mother has reference to be the cause or the termination of pregnancy. Present the case of a 26-year-old who developed mirror syndrome secondary to non-immune fetal hydrops of unknown origin, accompanied by preeclampsia.

  5. Glomerular Diseases

    Science.gov (United States)

    ... is called a glomerulus , which comes from the Greek word meaning filter. The plural form of the ... primary indicator of Alport syndrome is a family history of chronic glomerular disease, although it may also ...

  6. NIDCD Glossary

    Science.gov (United States)

    ... the sense of taste. Albinism - lack of normal pigment in the skin, eyes, and hair. Alport Syndrome - ... throat) that is the primary organ of voice production. Learning Disabilities - childhood disorders characterized by difficulty with ...

  7. Familial neurofibromatosis type 1 associated with an overgrowth syndrome resembling Weaver syndrome

    NARCIS (Netherlands)

    van Asperen, C. J.; Overweg-Plandsoen, W. C.; Cnossen, M. H.; van Tijn, D. A.; Hennekam, R. C.

    1998-01-01

    The simultaneous occurrence of familial neurofibromatosis type 1 (NF1) and an overgrowth syndrome resembling Weaver syndrome was observed in two related cases (a mother and her son). NF1 was confirmed by molecular genetic analysis showing a large deletion at 17q11.2, encompassing the entire NF1

  8. Antiphospholipid syndrome

    DEFF Research Database (Denmark)

    Cervera, Ricard; Piette, Jean-Charles; Font, Josep

    2002-01-01

    To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression.......To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression....

  9. Ascher syndrome

    Directory of Open Access Journals (Sweden)

    Zhifang Zhai

    2015-03-01

    Full Text Available Ascher syndrome is a rare, benign skin disorder characterized by a double upper lip, blepharochalasis, and nontoxic enlargement of the thyroid gland. The exact cause is unknown, but it is considered to be a hereditary disease with an autosomal dominant trait. We report here a case of forme fruste Ascher syndrome in a 29-year-old man.

  10. Passwell syndrome

    Directory of Open Access Journals (Sweden)

    Muhammed K

    2003-03-01

    Full Text Available There is an expanding list of syndromes that combine ichthyosis with neuroectodermal and mesodermal defects. We report a syndrome of congenital ichthyosis with atrophy, mental retardation, dwarfism, aminoaciduria, primary amenorrhoea and underdeveloped secondary sexual characters in a 38-year-old woman of non consanguinous parentage.

  11. Proteus syndrome

    Directory of Open Access Journals (Sweden)

    George Renu

    1993-01-01

    Full Text Available A case of proteus syndrome in a 20 year old male is repoted. Hemihypertrophy, asymmetric megalodactyly, linear epidermal naevus, naevus flammeus, angiokeratoma, lymphangioma circumscriptum, thickening of the palms and soles, scoliosis and varicose veins were present. There are only few reports of these cases in adults. The syndrome has not been reported from India.

  12. Lemierre's syndrome

    DEFF Research Database (Denmark)

    Johannesen, Katrine; Bødtger, Uffe; Heltberg, Ole

    2014-01-01

    Lemierre's syndrome is an often un-diagnosed disease seen in previously healthy young subjects, presenting with symptoms of pharyngitis, fever and elevated markers of inflammation. The syndrome is characterised by infectious thrombosis of the jugular vein due to infection with Fusobacteria, causing...

  13. Tourette Syndrome

    Science.gov (United States)

    If you have Tourette syndrome, you make unusual movements or sounds, called tics. You have little or no control over them. Common tics are throat- ... spin, or, rarely, blurt out swear words. Tourette syndrome is a disorder of the nervous system. It ...

  14. Fahr's Syndrome

    Science.gov (United States)

    ... or 50s, although it can occur at any time in childhood or adolescence. × Definition Fahr's Syndrome is a rare, genetically dominant, inherited ... or 50s, although it can occur at any time in childhood or adolescence. View Full Definition Treatment There is no cure for Fahr's Syndrome, ...

  15. Old and new syndromes

    Directory of Open Access Journals (Sweden)

    Giovanni Corsello

    2015-10-01

    Full Text Available What is a genetic syndrome? For a long time this definition was reserved to those patients with a set of features recurrent together, in which a genetic origin was certain or highly presuntive. Dysmorphic features, multiple malformations and mental retardations (MCA/MR were main clinical elements in most of the patients. The authors of the first description frequently gave the eponimic name to these syndromes.The application of new molecular and cytogenetics technologies, such as FISH and array-CGH, has amplified in the last two decades the opportunity to identify new genetic conditions in patients with a clinical spectrum MCA/MR. Microdeletions and microduplications syndromes, telomeric rearrangements defects, genomic imprinting abnormalities, uniparental disomies,  are some examples of the so called “new genetic” syndromes. Proceedings of the 11th International Workshop on Neonatology and Satellite Meetings · Cagliari (Italy · October 26th-31st, 2015 · From the womb to the adultGuest Editors: Vassilios Fanos (Cagliari, Italy, Michele Mussap (Genoa, Italy, Antonio Del Vecchio (Bari, Italy, Bo Sun (Shanghai, China, Dorret I. Boomsma (Amsterdam, the Netherlands, Gavino Faa (Cagliari, Italy, Antonio Giordano (Philadelphia, USA

  16. Sheldon-Hall syndrome

    Directory of Open Access Journals (Sweden)

    Bamshad Michael J

    2009-03-01

    Full Text Available Abstract Sheldon-Hall syndrome (SHS is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate. Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature. Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive. SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic. Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers. The diagnosis of SHS is based on clinical criteria. Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome. Prenatal diagnosis by ultrasonography is feasible at 18–24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible. There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery. Life expectancy and cognitive abilities are normal.

  17. [Familial Wolfram syndrome].

    Science.gov (United States)

    Bessahraoui, M; Paquis, V; Rouzier, C; Bouziane-Nedjadi, K; Naceur, M; Niar, S; Zennaki, A; Boudraa, G; Touhami, M

    2014-11-01

    Wolfram syndrome (WS) is a rare autosomal recessive progressive neurodegenerative disorder, and it is mainly characterized by the presence of diabetes mellitus and optic atrophy. Other symptoms such as diabetes insipidus, deafness, and psychiatric disorders are less frequent. The WFS1 gene, responsible for the disease and encoding for a transmembrane protein called wolframin, was localized in 1998 on chromosome 4p16. In this report, we present a familial observation of Wolfram syndrome (parents and three children). The propositus was a 6-year-old girl with diabetes mellitus and progressive visual loss. Her family history showed a brother with diabetes mellitus, optic atrophy, and deafness since childhood and a sister with diabetes mellitus, optic atrophy, and bilateral hydronephrosis. Thus, association of these familial and personal symptoms is highly suggestive of Wolfram syndrome. The diagnosis was confirmed by molecular analysis (biology), which showed the presence of WFS1 homozygous mutations c.1113G>A (p.Trp371*) in the three siblings and a heterozygote mutation in the parents. Our observation has demonstrated that pediatricians should be aware of the possibility of Wolfram syndrome when diagnosing optic atrophy in diabetic children. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  18. TAFRO Syndrome.

    Science.gov (United States)

    Igawa, Takuro; Sato, Yasuharu

    2018-02-01

    TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS). Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular-type CD. TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

    NARCIS (Netherlands)

    Cullup, Thomas; Kho, Ay Lin; Dionisi-Vici, Carlo; Brandmeier, Birgit; Smith, Frances; Urry, Zoe; Simpson, Michael A.; Yau, Shu; Bertini, Enrico; McClelland, Verity; Al-Owain, Mohammed; Koelker, Stefan; Koerner, Christian; Hoffmann, Georg F.; Wijburg, Frits A.; ten Hoedt, Amber E.; Rogers, R. Curtis; Manchester, David; Miyata, Rie; Hayashi, Masaharu; Said, Elizabeth; Soler, Doriette; Kroisel, Peter M.; Windpassinger, Christian; Filloux, Francis M.; Al-Kaabi, Salwa; Hertecant, Jozef; del Campo, Miguel; Buk, Stefan; Bodi, Istvan; Goebel, Hans-Hilmar; Sewry, Caroline A.; Abbs, Stephen; Mohammed, Shehla; Josifova, Dragana; Gautel, Mathias; Jungbluth, Heinz

    2013-01-01

    Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18

  20. Medulloblastoma: Molecular Genetics and Animal Models

    Directory of Open Access Journals (Sweden)

    Corey Raffel

    2004-07-01

    Full Text Available Medulloblastoma is a primary brain tumor found in the cerebellum of children. The tumor occurs in association with two inherited cancer syndromes: Turcot syndrome and Gorlin syndrome. Insights into the molecular biology of the tumor have come from looking at alterations in the genes altered in these syndromes, PTC and APC, respectively. Murine models of medulloblastoma have been constructed based on these alterations. Additional murine models that, while mimicking the appearance of the human tumor, seem unrelated to the human tumor's molecular alterations have been made. In this review, the clinical picture, origin, molecular biology, murine models of medulloblastoma are discussed. Although a great deal has been discovered about this tumor, the genetic alterations responsible for tumor development in a majority of patients have yet to be described.

  1. CHARGE syndrome

    Directory of Open Access Journals (Sweden)

    Prasad Chitra

    2006-09-01

    Full Text Available Abstract CHARGE syndrome was initially defined as a non-random association of anomalies (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness. In 1998, an expert group defined the major (the classical 4C's: Choanal atresia, Coloboma, Characteristic ears and Cranial nerve anomalies and minor criteria of CHARGE syndrome. Individuals with all four major characteristics or three major and three minor characteristics are highly likely to have CHARGE syndrome. However, there have been individuals genetically identified with CHARGE syndrome without the classical choanal atresia and coloboma. The reported incidence of CHARGE syndrome ranges from 0.1–1.2/10,000 and depends on professional recognition. Coloboma mainly affects the retina. Major and minor congenital heart defects (the commonest cyanotic heart defect is tetralogy of Fallot occur in 75–80% of patients. Choanal atresia may be membranous or bony; bilateral or unilateral. Mental retardation is variable with intelligence quotients (IQ ranging from normal to profound retardation. Under-development of the external genitalia is a common finding in males but it is less apparent in females. Ear abnormalities include a classical finding of unusually shaped ears and hearing loss (conductive and/or nerve deafness that ranges from mild to severe deafness. Multiple cranial nerve dysfunctions are common. A behavioral phenotype for CHARGE syndrome is emerging. Mutations in the CHD7 gene (member of the chromodomain helicase DNA protein family are detected in over 75% of patients with CHARGE syndrome. Children with CHARGE syndrome require intensive medical management as well as numerous surgical interventions. They also need multidisciplinary follow up. Some of the hidden issues of CHARGE syndrome are often forgotten, one being the feeding adaptation of these children, which needs an early aggressive approach from a feeding team. As the child

  2. Bouveret's syndrome

    International Nuclear Information System (INIS)

    Rehman, A.; Hasan, Z.; Saeed, A.; Abdullah, K.

    2008-01-01

    Gastric Outlet Obstruction (GOO) due to impaction of a gallstone in the duodenum after migration through a bilioduodenal fistula is known as Bouveret's syndrome. Its clinical symptoms are entirely vague and nonspecific. Because of its rarity, insidiousness and unpredictable symptomatology. Bouveret's syndrome is never thought of in the differential diagnosis as aetiology of gastric outlet obstruction. Recent advances in fiberoptics technology, advent of modern imaging modalities and minimally-invasive techniques like endoscopy and laparoscopy has brought a great revolution in the management of Bouveret's syndrome and have tremendously decreased morbidity and mortality associated with this rare clinical entity. (author)

  3. Neuroacanthocytosis Syndromes

    Directory of Open Access Journals (Sweden)

    Walker Ruth H

    2011-10-01

    Full Text Available Abstract Neuroacanthocytosis (NA syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington´s disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes

  4. Cowden syndrome

    Directory of Open Access Journals (Sweden)

    Ravi Prakash S

    2010-01-01

    Full Text Available Cowden syndrome or multiple hamartoma syndrome is an autosomal dominant condition with variable expressions that result mainly from mutation in the PTEN gene on arm 10q. It is characterized by multiple hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal tract, bones, CNS, eyes, and genitourinary tract. Mucocutaneous features include trichilemmomas, oral mucosal papillomatosis, acral keratosis, and palmoplantar keratosis. Here we present a case of Cowden syndrome in a 14-year-old female patient with the chief complaint of multiple oral papillomatous lesions.

  5. Premenstrual Syndrome (PMS) FAQ

    Science.gov (United States)

    ... Search FAQs Premenstrual Syndrome (PMS) Page Navigation ▼ ACOG Pregnancy Book Premenstrual Syndrome (PMS) Patient Education FAQs Premenstrual Syndrome (PMS) Patient Education Pamphlets - Spanish ...

  6. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  7. Molecular pathology of colorectal cancer predisposing syndromes

    NARCIS (Netherlands)

    Puijenbroek, Marjo van

    2008-01-01

    Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the

  8. Reye's Syndrome

    Science.gov (United States)

    ... vomiting Diarrhea Reye's syndrome Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  9. Turner Syndrome

    Science.gov (United States)

    ... girls and women with TS may have low self- esteem, anxiety, or depression. How is Turner syndrome diagnosed? ... to active partners in their health care. This fact sheet is also available in Spanish at www. ...

  10. Sotos Syndrome

    Science.gov (United States)

    ... and social development; hypotonia (low muscle tone), and speech impairments. Clumsiness, an awkward gait, and unusual aggressiveness or irritability may also occur. Although most cases of Sotos syndrome occur sporadically (meaning they are not known to be inherited), familial ...

  11. Potter syndrome

    Science.gov (United States)

    Potter phenotype ... In Potter syndrome, the primary problem is kidney failure. The kidneys fail to develop properly as the baby is ... kidneys normally produce the amniotic fluid (as urine). Potter phenotype refers to a typical facial appearance that ...

  12. Gilbert's Syndrome

    Science.gov (United States)

    ... doctor before taking new medications. Also, having certain types of Gilbert's syndrome may increase your risk of ... of Nondiscrimination Advertising Mayo Clinic is a not-for-profit organization ...

  13. Compartment syndrome

    Science.gov (United States)

    ... term (chronic) compartment syndrome can be caused by repetitive activities, such as running. The pressure in a compartment ... or loosened to relieve the pressure Stopping the repetitive activity or exercise, or changing the way it's done ...

  14. Aicardi Syndrome

    Science.gov (United States)

    ... See More About Research The NINDS supports and conducts research on neurogenetic disorders such as Aicardi syndrome. The goals of this research are to locate and understand ... Publications Definition Aicardi ...

  15. Zellweger Syndrome

    Science.gov (United States)

    ... swallow. Some babies will be born with glaucoma, retinal degeneration, and impaired hearing. Jaundice and gastrointestinal bleeding also may occur. Treatment There is no cure for Zellweger syndrome, nor ...

  16. Gerstmann's Syndrome

    Science.gov (United States)

    ... drawings. Frequently, there is also an impairment in reading. Children with a high level of intellectual functioning as well as those with brain damage may be affected with the disorder. × Definition Gerstmann's syndrome is a cognitive impairment that results ...

  17. Usher Syndrome

    Science.gov (United States)

    ... with age. Decline in hearing and vision varies. Children with type 3 Usher syndrome often develop hearing loss by adolescence, requiring hearing aids by mid-to-late adulthood. Night blindness also usually begins during adolescence. Blind spots appear ...

  18. Piriformis Syndrome

    Science.gov (United States)

    ... may order additional tests. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans cannot diagnose piriformis syndrome, ... you are sitting, driving or standing. Don’t lift by bending over. Lift an object by bending ...

  19. Turner Syndrome

    Science.gov (United States)

    ... have an increased risk of an underactive thyroid (hypothyroidism) due to the autoimmune disorder Hashimoto's thyroiditis. They also have an increased risk of diabetes. Some women with Turner syndrome have gluten intolerance (celiac disease) or inflammatory bowel disease. Skeletal ...

  20. Reye Syndrome

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now What Is Reye’s Syndrome? ...

  1. Alagille Syndrome

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Alagille Syndrome Back Alagille ...

  2. Cushing syndrome

    Science.gov (United States)

    ... mellitus High blood pressure (hypertension) Increased cholesterol and triglycerides (hyperlipidemia) Women with Cushing syndrome may have: Excess ... Wisse, MD, Associate Professor of Medicine, Division of Metabolism, Endocrinology & Nutrition, University of Washington School of Medicine, ...

  3. Autosomal dominant syndrome resembling Coffin-Siris syndrome.

    Science.gov (United States)

    Flynn, Maureen A; Milunsky, Jeff M

    2006-06-15

    Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

  4. The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism

    Directory of Open Access Journals (Sweden)

    Yi Wang

    2016-02-01

    Full Text Available Most of the intracellular pattern recognition receptors (PRRs reside in either the endolysosome or the cytoplasm to sense pathogen-derived RNAs, DNAs, or synthetic analogs of double-stranded RNA (dsRNA, such as poly(I:C. However, it remains elusive whether or not a pathogen-derived protein can function as a cytosolic pathogen-associated molecular pattern (PAMP. In this study, we demonstrate that delivering the membrane gene of severe acute respiratory syndrome coronavirus (SARS-CoV into HEK293T, HEK293ET, and immobilized murine bone marrow-derived macrophage (J2-Mφ cells significantly upregulates beta interferon (IFN-β production. Both NF-κB and TBK1-IRF3 signaling cascades are activated by M gene products. M protein rather than M mRNA is responsible for M-mediated IFN-β induction that is preferentially associated with the activation of the Toll-like receptor (TLR adaptor proteins MyD88, TIRAP, and TICAM2 but not the RIG-I signaling cascade. Blocking the secretion of M protein by brefeldin A (BFA failed to reverse the M-mediated IFN-β induction. The antagonist of both TLR2 and TLR4 did not impede M-mediated IFN-β induction, indicating that the driving force for the activation of IFN-β production was generated from inside the cells. Inhibition of TRAF3 expression by specific small interfering RNA (siRNA did not prevent M-mediated IFN-β induction. SARS-CoV pseudovirus could induce IFN-β production in an M rather than M(V68A dependent manner, since the valine-to-alanine alteration at residue 68 in M protein markedly inhibited IFN-β production. Overall, our study indicates for the first time that a pathogen-derived protein is able to function as a cytosolic PAMP to stimulate type I interferon production by activating a noncanonical TLR signaling cascade in a TRAF3-independent manner.

  5. What is Metabolic Syndrome?

    Science.gov (United States)

    ... Research Home / Metabolic Syndrome Metabolic Syndrome What Is Metabolic syndrome is the name for a group of risk ... three metabolic risk factors to be diagnosed with metabolic syndrome. A large waistline. This also is called abdominal ...

  6. Obesity Hypoventilation Syndrome

    Science.gov (United States)

    ... Home / Obesity Hypoventilation Syndrome Obesity Hypoventilation Syndrome Also known as Pickwickian Syndrome What ... your neck is larger than normal. Complications of Obesity Hypoventilation Syndrome When left untreated, OHS can cause ...

  7. Learning about WAGR Syndrome

    Science.gov (United States)

    ... children who have WAGR syndrome may have normal intelligence. Other symptoms of WAGR syndrome may also include: ... mild. Some individuals with WAGR syndrome have normal intelligence. Children with WAGR syndrome should be referred for ...

  8. Toxic Shock Syndrome

    Science.gov (United States)

    ... may also be caused by toxins produced by group A streptococcus (strep) bacteria. Toxic shock syndrome has been associated ... syndrome. The syndrome can also be caused by group A streptococcus (strep) bacteria. Risk factors Toxic shock syndrome can ...

  9. Milk-alkali syndrome

    Science.gov (United States)

    Calcium-alkali syndrome; Cope syndrome; Burnett syndrome; Hypercalcemia; Calcium metabolism disorder ... Milk-alkali syndrome is almost always caused by taking too many calcium supplements, usually in the form of calcium ...

  10. What Causes Down Syndrome?

    Science.gov (United States)

    ... it? Share Facebook Twitter Pinterest Email Print What causes Down syndrome? Down syndrome is caused by a random error ... The Down Syndrome Registry . Chromosomal Changes That Can Cause Down Syndrome Research shows that three types of chromosomal changes ...

  11. Molecular hematology

    National Research Council Canada - National Science Library

    Provan, Drew; Gribben, John

    2010-01-01

    ... The molecular basis of hemophilia, 219 Paul LF Giangrande 4 The genetics of acute myeloid leukemias, 42 Carolyn J Owen & Jude Fitzgibbon 19 The molecular basis of von Willebrand disease, 233 Luciano Baronc...

  12. Applying molecular epidemiology in pediatric leukemia.

    Science.gov (United States)

    Schiffman, Joshua D

    2016-02-01

    Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members. Copyright © 2016 American Federation for Medical Research.

  13. [Myelodysplastic syndrome classification].

    Science.gov (United States)

    Ghariani, Ines; Braham, Najia; Hassine, Mohsen; Kortas, Mondher

    2013-01-01

    Myelodysplastic syndromes (MDS) are myeloid disorders with various clinical and biological presentations. The French-American-British (FAB-1982) classification included five categories basing on morphology and bone marrow blast count. Three criteria are taken into account: 1) the percentage of blasts in peripheral blood and bone marrow, 2) the percentage of ringed sideroblasts, and 3) the number of monocytes in peripheral blood. The World Health Organization classification (WHO 2001, 2008) modifies the FAB system by also taking cytogenetic characteristics and molecular biology into consideration. The last classification (WHO-2008) takes into account: 1) the number of peripheral cytopenia, 2) the percentage of blasts in peripheral blood and bone marrow, 3) the percentage of ringed sideroblasts, 4) the possible presence of Auer Rods, and 5) the detection of a cytogenetic abnormality (the isolated 5q deletion). The following subgroups are defined: refractory cytopenia with unilineage dysplasia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, myelodysplastic syndrome unclassifiable and myelodysplastic syndrome with isolated del(5q).

  14. Pericentrin expression in Down's syndrome.

    Science.gov (United States)

    Salemi, Michele; Barone, Concetta; Romano, Carmelo; Salluzzo, Roberto; Caraci, Filippo; Cantarella, Rita Anna; Salluzzo, Maria Grazia; Drago, Filippo; Romano, Corrado; Bosco, Paolo

    2013-11-01

    Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.

  15. Compartment syndromes

    Science.gov (United States)

    Mubarak, S. J.; Pedowitz, R. A.; Hargens, A. R.

    1989-01-01

    The compartment syndrome is defined as a condition in which high pressure within a closed fascial space (muscle compartment) reduces capillary blood perfusion below the level necessary for tissue viability'. This condition occurs in acute and chronic (exertional) forms, and may be secondary to a variety of causes. The end-result of an extended period of elevated intramuscular pressure may be the development of irreversible tissue injury and Volkmann's contracture. The goal of treatment of the compartment syndrome is the reduction of intracompartmental pressure thus facilitating reperfusion of ischaemic tissue and this goal may be achieved by decompressive fasciotomy. Controversy exists regarding the critical pressure-time thresholds for surgical decompression and the optimal diagnostic methods of measuring intracompartmental pressures. This paper will update and review some current knowledge regarding the pathophysiology, aetiology, diagnosis, and treatment of the acute compartment syndrome.

  16. Fraser syndrome

    DEFF Research Database (Denmark)

    Barisic, Ingeborg; Odak, Ljubica; Loane, Maria

    2013-01-01

    Fraser syndrome is a rare autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, laryngeal, and urogenital malformations. We present a population-based epidemiological study using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network...... of birth defect registries. Between January 1990 and December 2008, we identified 26 cases of Fraser syndrome in the monitored population of 12,886,464 births (minimal estimated prevalence of 0.20 per 100,000 or 1:495,633 births). Most cases (18/26; 69%) were registered in the western part of Europe, where...... was particularly high (42%). Most cases of Fraser syndrome (85%) are suspected prenatally, often due to the presence of the association of renal agenesis and cryptophthalmos. In the European population, a high proportion (82%) of pregnancies is terminated, thus reducing the live birth prevalence to a third...

  17. Dressler Syndrome

    Directory of Open Access Journals (Sweden)

    Erkan Ceylan

    2016-02-01

    Full Text Available Dressler Syndrome (DS is a febrile illness secondary to an inflammatory reaction involving the pleura and pericardium. It is more common in patients who have undergone surgery that involves opening the pericardium. However, DS has also been described following myocardial infarction and as an unusual complication after percutaneous procedures such as coronary stent implantation, after implantation of epicardial pacemaker leads and transvenous pacemaker leads, and following blunt trauma, stab wounds, and heart puncture. Pericardial effusions often accompany the syndrome and may develop into early or late postoperative cardiac tamponade and even recurrent cardiac tamponade. The syndrome is also characterized by pericardial or pleuritic pain, pleural effusions, pneumonitis, and abnormal ECG and radiography findings.

  18. BRUGADA SYNDROME

    Directory of Open Access Journals (Sweden)

    Tomislav Kostić

    2015-06-01

    Full Text Available In 1992, Brugada syndrom was introduced as a new clinical entity linking typical but variable ST segment changes in the right precordial leads to an increased vulnerability for lethal ventricular arrhythmias. The diagnosis of Brugada syndrome is based on clinical and electrocardiographic features. Recent studies illustrate the dynamic character of these ECG patterns. Whenever a large number of baseline ECGs was available during a follow-up, the diagnostic pattern could be documented only in approximately 25% of the tracings. Because the presence of the spontaneous coved type I ECG pattern is thought to be a useful predictor of future arrhythmic events in asymptomatic patients, these findings are of great clinical importance. ICD implantation is an option for the patients with Brugada syndrome and ventricular tachycardia or fibrillation. Extensive research is ongoing to find alternative pharmacological options for these patients, especially for patients in whom ICD implantation is contraindicated for various reasons.

  19. A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: Clinical and molecular analysis.

    Science.gov (United States)

    Mimouni-Bloch, Aviva; Yeshaya, Josepha; Kahana, Sarit; Maya, Idit; Basel-Vanagaite, Lina

    2015-11-01

    Microdeletions of various sizes in the 2p16.1-p15 chromosomal region have been grouped together under the 2p16.1-p15 microdeletion syndrome. Children with this syndrome generally share certain features including microcephaly, developmental delay, facial dysmorphism, urogenital and skeletal abnormalities. We present a child with a de-novo interstitial 1665 kb duplication of 2p16.1-p15. Clinical features of this child are distinct from those of children with the 2p16.1-p15 microdeletion syndrome, specifically the head circumference which is within the normal range and mild intellectual disability with absence of autistic behaviors. Microduplications many times bear milder clinical phenotypes in comparison with corresponding microdeletion syndromes. Indeed, as compared to the microdeletion syndrome patients, the 2p16.1-p15 microduplication seems to have a milder cognitive effect and no effect on other body systems. Limited information available in genetic databases about cases with overlapping duplications indicates that they all have abnormal developmental phenotypes. The involvement of genes in this location including BCL11A, USP34 and PEX13, affecting fundamental developmental processes both within and outside the nervous system may explain the clinical features of the individual described in this report. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  20. Eagle's Syndrome

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    Pinheiro, Thaís Gonçalves

    2014-01-01

    Full Text Available Introduction: Eagle's syndrome is characterized by cervicopharyngeal signs and symptoms associated with elongation of the styloid apophysis. This elongation may occur through ossification of the stylohyoid ligament, or through growth of the apophysis due to osteogenesis triggered by a factor such as trauma. Elongation of the styloid apophysis may give rise to intense facial pain, headache, dysphagia, otalgia, buzzing sensations, and trismus. Precise diagnosis of the syndrome is difficult, and it is generally confounded by other manifestations of cervicopharyngeal pain. Objective: To describe a case of Eagle's syndrome. Case Report: A 53-year-old man reported lateral pain in his neck that had been present for 30 years. Computed tomography (CT of the neck showed elongation and ossification of the styloid processes of the temporal bone, which was compatible with Eagle's syndrome. Surgery was performed for bilateral resection of the stylohyoid ligament by using a transoral and endoscopic access route. The patient continued to present pain laterally in the neck, predominantly on his left side. CT was performed again, which showed elongation of the styloid processes. The patient then underwent lateral cervicotomy with resection of the stylohyoid process, which partially resolved his painful condition. Final Comments: Patients with Eagle's syndrome generally have a history of chronic pain. Appropriate knowledge of this disease is necessary for adequate treatment to be provided. The importance of diagnosing this uncommon and often unsuspected disease should be emphasized, given that correct clinical-surgical treatment is frequently delayed. The diagnosis of Eagle's syndrome is clinical and radiographic, and the definitive treatment in cases of difficult-to-control pain is surgical.