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Prediction of missense mutation

Mateusz Bujko, Marcin M Machnicki, Emilia Grecka, Natalia Rusetska, Ewa Matyja, Paulina Kober, Tomasz Mandat, Małgorzata Rydzanicz, Rafał Płoski, Romuald Krajewski, Wieslaw Bonicki, Tomasz Stokłosa, Janusz A Siedlecki
BACKGROUND: Rhabdoid meningioma is rare aggressive meningioma histological subtype, which develops predominantly through progression from less malignant tumors. Due to a low incidence the biological background is unknown. The aim of this study was to profile somatic mutations in four meningioma samples from the same patient, derived previously from four subsequent tumor resections. CASE DESCRIPTION: 58-year-old woman suffering from recurrent meningioma progressing from atypical to rhabdoid subtype...
October 15, 2016: World Neurosurgery
Malene Rask Andersen, Muhammad Farooq, Karen Koefoed, Klaus W Kjaer, Ane Simony, Sren Tvorup Christensen, Lars Allan Larsen
STUDY DESIGN: Mutation analysis of a candidate disease gene in a cohort of patients with moderate to severe Adolescent idiopathic scoliosis (AIS). OBJECTIVE: To investigate if damaging mutations in the planar cell polarity gene VANGL1 could be identified in AIS patients. SUMMARY OF BACKGROUND DATA: AIS is a spinal deformity which occurs in 1-3% of the population. The cause of AIS is often unknown, but genetic factors are important in the etiology...
October 17, 2016: Spine
Rose Gelineau-Morel, Marshall Lukacs, K Nicole Weaver, Robert B Hufnagel, Donald L Gilbert, Rolf W Stottmann
Whole exome sequencing continues to end the diagnostic odyssey for a number of patients and expands our knowledge of phenotypes associated with gene mutations. We describe an 11-year-old female patient with a constellation of symptoms including congenital cataracts, gut dysmotility, sensory neuropathy, and bifrontal polymicrogyria. Whole exome sequencing was performed and identified a de novo heterozygous missense mutation in the ATPase motor domain of cytoplasmic dynein heavy chain 1 (DYNC1H1), which is known to be involved in neuronal migration and retrograde axonal transport...
October 14, 2016: Genes
Priyanka Srivastava, Himani Pandey, Divya Agarwal, Kausik Mandal, Shubha R Phadke
We describe three consanguineous Indian families with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). It is an autosomal recessive disorder due to mutation in CHST3 gene. CHST3 gene encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1) which mediates the sulfation of proteoglycans, (chondroitin sulfate), in the extracellular matrix of cartilage. CHST3 gene was sequenced in probands from three different families with SED. In two families missense mutations (c.904G>C predicting the substitution D302H) and c...
October 18, 2016: American Journal of Medical Genetics. Part A
Mark A Corbett, Susannah T Bellows, Melody Li, Renée Carroll, Silvana Micallef, Gemma L Carvill, Candace T Myers, Katherine B Howell, Snezana Maljevic, Holger Lerche, Elena V Gazina, Heather C Mefford, Melanie Bahlo, Samuel F Berkovic, Steven Petrou, Ingrid E Scheffer, Jozef Gecz
OBJECTIVE: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. METHODS: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations...
October 12, 2016: Neurology
Mrinal M Patnaik, Daniela Barraco, Terra L Lasho, Christy M Finke, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Ayalew Tefferi
DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n=261). DNMT3A mutations were seen in 6% (n=16); 56% (n=9) male, with a median age of 64 years. Eighty-one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1-56%, TET2-50%, and ASXL1-25%) were seen in all patients...
October 12, 2016: American Journal of Hematology
Wen-Qing Huang, Cong-Xia Lu, Ya Zhang, Ke-Hui Yi, Liang-Liang Cai, Ming-Li Li, Han Wang, Qing Lin, Chi-Meng Tzeng
Background: Cerebral cavernous malformations (CCMs) are common vascular malformations that predominantly arise in the central nervous system and are mainly characterized by enlarged vascular cavities without intervening brain parenchyma. Familial CCMs (FCCMs) is inherited in an autosomal dominant pattern with incomplete penetrance and variable symptoms. Methods: Mutations of three pathogenic genes, CCM1, CCM2, and CCM3, were investigated by direct DNA sequencing in a Chinese family with multiple CCM lesions...
2016: Frontiers in Aging Neuroscience
J J Xue, J F Xue, H Q Xue, Y Y Guo, Y Liu, N Ouyang
Albinism is a diverse group of hypopigmentary disorders caused by multiple-genetic defects. The genetic diagnosis of patients affected with albinism by Sanger sequencing is often complex, expensive, and time-consuming. In this study, we performed targeted next-generation sequencing to screen for 16 genes in a patient with albinism, and identified 21 genetic variants, including 19 known single nucleotide polymorphisms, one novel missense mutation (c.1456 G>A), and one disease-causing mutation (c.478 G>C)...
September 19, 2016: Genetics and Molecular Research: GMR
Yunhui Peng, Emil Alexov
The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, 13 missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure...
October 1, 2016: Proteins
David A Parry, Claire E L Smith, Walid El-Sayed, James A Poulter, Roger C Shore, Clare V Logan, Chihiro Mogi, Koichi Sato, Fumikazu Okajima, Akihiro Harada, Hong Zhang, Mine Koruyucu, Figen Seymen, Jan C-C Hu, James P Simmer, Mushtaq Ahmed, Hussain Jafri, Colin A Johnson, Chris F Inglehearn, Alan J Mighell
Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation...
October 6, 2016: American Journal of Human Genetics
Laura E Mariani, Maarten F Bijlsma, Anna I Ivanova, Sarah K Suciu, Richard A Kahn, Tamara Caspary
The regulatory GTPase Arl13b localizes to primary cilia, where it regulates Sonic hedgehog (Shh) signaling. Missense mutations in ARL13B can cause the ciliopathy Joubert syndrome, while the mouse null allele is embryonic lethal. We used mouse embryonic fibroblasts as a system to determine the effects of Arl13b mutations on Shh signaling. We tested a total of seven different mutants, three JS-causing variants, two point mutants predicted to alter guanine nucleotide handling, one that disrupts cilia localization, and one that prevents palmitoylation and thus membrane binding, in assays of transcriptional and non-transcriptional Shh signaling...
September 28, 2016: Molecular Biology of the Cell
Samiha S Shaikh, Ya-Chun Chen, Sally-Anne Halsall, Michael S Nahorski, Kiyoyuki Omoto, Gareth T Young, Anne Phelan, Christopher Geoffrey Woods
Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. Here, we studied a cohort of seven patients with HSAN IV and describe a comprehensive functional analysis of seven novel NTRK1 missense mutations, c.1550G>A, c.1565G>A, c.1970T>C, c.2096T>C, c.2254T>A, c.2288G>C, c.2311C>T, corresponding to p.G517E, p.G522E, p.L657P, p.I699T, p.C752S, p.C763S and p.R771C, all of which were predicted pathogenic by in-silico analysis...
September 27, 2016: Human Mutation
Siti Aishah Abdul Wahab, Yusnita Yakob, Nor Azimah Abdul Azize, Zabedah Md Yunus, Leong Huey Yin, Mohd Khairul Nizam Mohd Khalid, Ngu Lock Hock
Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp)...
2016: BioMed Research International
Ricardo Faria, Bruno Silva, Catarina Silva, Pedro Loureiro, Ana Queiroz, Sofia Fraga, Jorge Esteves, Diana Mendes, Rita Fleming, Luís Vieira, João Gonçalves, Paula Faustino
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients...
October 2016: Blood Cells, Molecules & Diseases
Edgard Verdura, Dominique Hervé, Françoise Bergametti, Clémence Jacquet, Typhaine Morvan, Carol Prieto-Morin, Alexandre Mackowiak, Eric Manchon, Hassan Hosseini, Charlotte Cordonnier, Isabelle Girard-Buttaz, Sophie Rosenstingl, Christian Hagel, Gregor Kuhlenbaümer, Elena Leca-Radu, Didier Goux, Lauren Fleming, Tom Van Agtmael, Hugues Chabriat, Françoise Chapon, Elisabeth Tournier-Lasserve
OBJECTIVE: Cerebral small vessel disease (cSVD) is an heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in less than 15% of familial cSVD cases. We sought to identify novel causes of cSVD. METHODS: We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including one proband from the first reported Pontine Autosomal Dominant MicroAngiopathy with Leukoencephalopathy (PADMAL) family...
September 26, 2016: Annals of Neurology
E Ullah, D Wu, L Madireddy, R Lao, P Ling-Fung Tang, E Wan, T Bardakjian, S Kopinsky, P-Y Kwok, A Schneider, S Baranzini, M Ansar, A Slavotinek
To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities...
September 23, 2016: Ophthalmic Genetics
J Zhang, R Cheng, J Liang, C Ni, M Li, Z Yao
Pathogenic mutations in genes (SASH1 and PTPN11) can cause a rare genetic disorder associated with pigmentation defects and the well-known LEOPARD syndrome, respectively. Both conditions presented with lentiginous phenotypes. The aim of this study was to arrive at definite diagnoses of three Chinese boys with clinically suspected lentigines-related syndromes. ADAR1, ABCB6, SASH1 and PTPN11 were candidate genes for mutational screening. Sanger sequencing was performed to identify the mutations, whereas bioinformatic analysis was used to predict the pathogenicity of novel missense mutations...
October 2016: Clinical Genetics
Nadia M Al-Wardy, Mohammed N Al-Kindi, Mazin J Al-Khabouri, Yahya Tamimi, Guy Van Camp
OBJECTIVES: To identify genetic defects in an Omani family diagnosed with deafness.  METHODS: A cross-sectional association study was conducted at the Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman and the Centre of Medical Genetics, University of Antwerp, Antwerp, Belgium between August 2010 and September 2014. Microsatellites markers for nine non-syndromic genes were used to genotype the defective locus using the extracted DNA from family members...
October 2016: Saudi Medical Journal
Rebecca A Evans, Mark S Diamond, Andrew J Rech, Timothy Chao, Max W Richardson, Jeffrey H Lin, David L Bajor, Katelyn T Byrne, Ben Z Stanger, James L Riley, Nune Markosyan, Rafael Winograd, Robert H Vonderheide
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy...
September 8, 2016: JCI Insight
Samantha J Spratley, Janet E Deane
Missense mutations in the lysosomal hydrolase β-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics...
November 2016: Journal of Neuroscience Research
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