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Prediction of missense mutation

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https://www.readbyqxmd.com/read/28306188/protein-modelling-to-understand-fgb-mutations-leading-to-congenital-hypofibrinogenaemia
#1
A Casini, R Vilar, Y Beauverd, D Aslan, K Devreese, V Mondelaers, L Alberio, C Gubert, P de Moerloose, M Neerman-Arbez
INTRODUCTION: Congenital hypofibrinogenaemia is a quantitative fibrinogen disorder characterized by proportionally decreased levels of functional and antigenic fibrinogen. Mutations accounting for quantitative fibrinogen disorders are relatively frequent in the conserved COOH-terminal globular domains of the γ and Bβ chains. The latter mutations are of particular interest since the Bβ-chain is considered the rate-limiting chain in the hepatic production of the fibrinogen hexamer. AIM: The aim of this study was to study the molecular pattern of four patients with congenital hypofibrinogenaemia...
March 17, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28303347/genome-wide-enrichment-of-damaging-de-novo-variants-in-patients-with-isolated-and-complex-congenital-diaphragmatic-hernia
#2
Mauro Longoni, Frances A High, Hongjian Qi, Maliackal P Joy, Regis Hila, Caroline M Coletti, Julia Wynn, Maria Loscertales, Linshan Shan, Carol J Bult, Jay M Wilson, Yufeng Shen, Wendy K Chung, Patricia K Donahoe
Congenital Diaphragmatic Hernia (CDH) is a common and often lethal birth defect characterized by diaphragmatic structural defects and pulmonary hypoplasia. CDH is isolated in 60% of newborns, but may also be part of a complex phenotype with additional anomalies. We performed whole exome sequencing (WES) on 87 individuals with isolated or complex CDH and on their unaffected parents, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify new candidate genes...
March 16, 2017: Human Genetics
https://www.readbyqxmd.com/read/28302169/two-novel-lhx3-mutations-in-patients-with-combined-pituitary-hormone-deficiency-including-cervical-rigidity-and-sensorineural-hearing-loss
#3
Khushnooda Ramzan, Bassam Bin-Abbas, Lolwa Al-Jomaa, Rabab Allam, Mohammed Al-Owain, Faiqa Imtiaz
BACKGROUND: Congenital combined pituitary hormone deficiency (CPHD) is a rare heterogeneous group of conditions. CPHD-type 3 (CPHD3; MIM# 221750) is caused by recessive mutations in LHX3, a LIM-homeodomain transcription factor gene. The isoforms of LHX3 are critical for pituitary gland formation and specification of the anterior pituitary hormone-secreting cell types. They also play distinct roles in the development of neuroendocrine and auditory systems. CASE PRESENTATION: Here, we summarize the clinical, endocrinological, radiological and molecular features of three patients from two unrelated families...
March 16, 2017: BMC Endocrine Disorders
https://www.readbyqxmd.com/read/28297138/a-novel-homozygous-missense-mutation-in-hoxc13-leads-to-autosomal-recessive-pure-hair-and-nail-ectodermal-dysplasia
#4
Xiaoxiao Li, Meredith Lee Orseth, J Michael Smith, Mary Abigail Brehm, Nnenna Gebechi Agim, Donald Alexander Glass
Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family...
March 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28293556/generalized-comedones-acne-and-hidradenitis-suppurativa-in-a-patient-with-an-fgfr2-missense-mutation
#5
Rebecca Higgins, Andrew Pink, Robert Hunger, Nikhil Yawalkar, Alexander A Navarini
Mutations in the fibroblast growth factor-receptor gene 2 (FGFR2) gene have been implicated in numerous diseases, including nevus comedonicus (NC) and naevoid acne that have somatic missense mutations in FGFR2 in the affected tissue. A patient presented in our department with unusual, innumerable large comedones throughout his back reminiscient of NC, as well as multifocal hidradenitis suppurativa and acne. Topical and systemic treatments were unsuccessful. Whole exome sequencing of blood-derived DNA detected a germline mutation in FGFR2 that was predicted to be damaging...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28283438/exome-sequencing-identified-a-novel-smad2-mutation-in-a-chinese-family-with-early-onset-aortic-aneurysms
#6
Wenwen Zhang, Qingfu Zeng, Yingqi Xu, Houqun Ying, Wei Zhou, Qing Cao, Weimin Zhou
Aortic aneurysm remains a devastating disease due to its fatal complications, such as aortic dissection and rupture. A subset of aortic aneurysm is caused by genetic defect and to date more than a dozen of disease-causing genes have been discovered to account for the disease. In this study, by using whole exome sequencing, we identified a novel heterozygous missense mutation (c.833C>T, p.A278V) in the SMAD2 gene in a family with early onset aortic aneurysms. The mutation segregated in this family, was high conserved among species and predicted to be pathogenic by multiple in silico programs...
March 7, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28274275/whole-exome-sequencing-coupled-with-unbiased-functional-analysis-reveals-new-hirschsprung-disease-genes
#7
Hongsheng Gui, Duco Schriemer, William W Cheng, Rajendra K Chauhan, Guillermo Antiňolo, Courtney Berrios, Marta Bleda, Alice S Brooks, Rutger W W Brouwer, Alan J Burns, Stacey S Cherny, Joaquin Dopazo, Bart J L Eggen, Paola Griseri, Binta Jalloh, Thuy-Linh Le, Vincent C H Lui, Berta Luzón-Toro, Ivana Matera, Elly S W Ngan, Anna Pelet, Macarena Ruiz-Ferrer, Pak C Sham, Iain T Shepherd, Man-Ting So, Yunia Sribudiani, Clara S M Tang, Mirjam C G N van den Hout, Herma C van der Linde, Tjakko J van Ham, Wilfred F J van IJcken, Joke B G M Verheij, Jeanne Amiel, Salud Borrego, Isabella Ceccherini, Aravinda Chakravarti, Stanislas Lyonnet, Paul K H Tam, Maria-Mercè Garcia-Barceló, Robert M W Hofstra
BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human...
March 8, 2017: Genome Biology
https://www.readbyqxmd.com/read/28270093/machine-learning-classifier-for-identification-of-damaging-missense-mutations-exclusive-to-human-mitochondrial-dna-encoded-polypeptides
#8
Antonio Martín-Navarro, Andrés Gaudioso-Simón, Jorge Álvarez-Jarreta, Julio Montoya, Elvira Mayordomo, Eduardo Ruiz-Pesini
BACKGROUND: Several methods have been developed to predict the pathogenicity of missense mutations but none has been specifically designed for classification of variants in mtDNA-encoded polypeptides. Moreover, there is not available curated dataset of neutral and damaging mtDNA missense variants to test the accuracy of predictors. Because mtDNA sequencing of patients suffering mitochondrial diseases is revealing many missense mutations, it is needed to prioritize candidate substitutions for further confirmation...
March 7, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28267856/association-of-rare-and-common-variation-in-the-lipoprotein-lipase-gene-with-coronary-artery-disease
#9
Amit V Khera, Hong-Hee Won, Gina M Peloso, Colm O'Dushlaine, Dajiang Liu, Nathan O Stitziel, Pradeep Natarajan, Akihiro Nomura, Connor A Emdin, Namrata Gupta, Ingrid B Borecki, Rosanna Asselta, Stefano Duga, Piera Angelica Merlini, Adolfo Correa, Thorsten Kessler, James G Wilson, Matthew J Bown, Alistair S Hall, Peter S Braund, David J Carey, Michael F Murray, H Lester Kirchner, Joseph B Leader, Daniel R Lavage, J Neil Manus, Dustin N Hartzel, Nilesh J Samani, Heribert Schunkert, Jaume Marrugat, Roberto Elosua, Ruth McPherson, Martin Farrall, Hugh Watkins, Eric S Lander, Daniel J Rader, John Danesh, Diego Ardissino, Stacey Gabriel, Cristen Willer, Gonçalo R Abecasis, Danish Saleheen, Frederick E Dewey, Sekar Kathiresan
Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015...
March 7, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28267766/association-of-smad4-mutation-with-patient-demographics-tumor-characteristics-and-clinical-outcomes-in-colorectal-cancer
#10
Amir Mehrvarz Sarshekeh, Shailesh Advani, Michael J Overman, Ganiraju Manyam, Bryan K Kee, David R Fogelman, Arvind Dasari, Kanwal Raghav, Eduardo Vilar, Shanequa Manuel, Imad Shureiqi, Robert A Wolff, Keyur P Patel, Raja Luthra, Kenna Shaw, Cathy Eng, Dipen M Maru, Mark J Routbort, Funda Meric-Bernstam, Scott Kopetz
SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed...
2017: PloS One
https://www.readbyqxmd.com/read/28257692/a-ribosomopathy-reveals-decoding-defective-ribosomes-driving-human-dysmorphism
#11
Nahuel A Paolini, Martin Attwood, Samuel B Sondalle, Carolina Marques Dos Santos Vieira, Anita M van Adrichem, Franca M di Summa, Marie-Françoise O'Donohue, Pierre-Emmanuel Gleizes, Swaksha Rachuri, Joseph W Briggs, Roman Fischer, Peter J Ratcliffe, Marcin W Wlodarski, Riekelt H Houtkooper, Marieke von Lindern, Taco W Kuijpers, Jonathan D Dinman, Susan J Baserga, Matthew E Cockman, Alyson W MacInnes
Ribosomal protein (RP) gene mutations, mostly associated with inherited or acquired bone marrow failure, are believed to drive disease by slowing the rate of protein synthesis. Here de novo missense mutations in the RPS23 gene, which codes for uS12, are reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features. One individual additionally presents with intellectual disability and autism spectrum disorder. The amino acid substitutions lie in two highly conserved loop regions of uS12 with known roles in maintaining the accuracy of mRNA codon translation...
March 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28256248/whole-exome-sequencing-identifies-a-novel-mutation-of-desmocollin-2-in-a-chinese-family-with-arrhythmogenic-right-ventricular-cardiomyopathy
#12
Ji-Shi Liu, Liang-Liang Fan, Jing-Jing Li, Rong Xiang
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare heart disorder characterized by myocyte loss and fibro-fatty tissue replacement. With the progress of ARVC, patient can present serious ventricular arrhythmias, heart failure, and even sudden cardiac death. Previous studies have revealed that the generation and development of ARVC are related to structural changes of desmosomes. To date, at least 5 genes associated with desmosomes have been identified in patients with ARVC, including Desmoplakin, Plakophilin 2, Desmoglein 2, Desmocollin 2, and Junction plakoglobin...
February 10, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/28256214/opposing-effects-on-nav1-2-function-underlie-differences-between-scn2a-variants-observed-in-individuals-with-autism-spectrum-disorder-or-infantile-seizures
#13
Roy Ben-Shalom, Caroline M Keeshen, Kiara N Berrios, Joon Y An, Stephan J Sanders, Kevin J Bender
BACKGROUND: Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear. METHODS: We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry...
January 27, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28249600/identification-of-somatic-mutations-using-whole-exome-sequencing-in-korean-patients-with-acute-myeloid-leukemia
#14
Seong Gu Heo, Youngil Koh, Jong Kwang Kim, Jongsun Jung, Hyung-Lae Kim, Sung-Soo Yoon, Ji Wan Park
BACKGROUND: Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous cancer of the bone marrow that is characterized by the rapid growth of abnormal myeloid cells. METHODS: We performed a mutational analysis to identify AML somatic mutations using the whole-exome sequencing data of 36 tumor-normal sample pairs from Korean patients with de novo AML. We explored the functional impact of the genes identified in the mutational analyses through an integrated Gene Ontology (GO) and pathway analysis...
March 1, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28240010/pik3ca-mutations-in-her2-positive-breast-cancer-patients-frequency-and-clinicopathological-perspective-in-egyptian-patients
#15
Fatma Elwy, Reham Helwa, Asmaa A El Leithy, Zeinab Shehab El din, Magda M Assem, Nagwa H A Hassan
Missense mutations in PIK3CA are common in breast cancers. They mostly involve exons 9 and 20 which encode kinase and helical domains of the protein and may result in its activation. PIK3CA activating mutations were previously shown to predict lower pathologic complete response (pCR) in HER2-positive breast cancer cases undergoing neoadjuvant human epidermal growth factor receptor 2-targeting therapy. Hence, the present work was conducted to estimate the mutation frequency in PIK3CA in 51 HER2-positive patients by direct sequencing...
January 1, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28236339/mutations-of-the-aminoacyl-trna-synthetases-sars-and-wars2-are-implicated-in-the-aetiology-of-autosomal-recessive-intellectual-disability
#16
Luciana Musante, Lucia Püttmann, Kimia Kahrizi, Masoud Garshasbi, Hao Hu, Henning Stehr, Bettina Lipkowitz, Sabine Otto, Lars R Jensen, Andreas Tzschach, Payman Jamali, Thomas Wienker, Hossein Najmabadi, Hans Hilger Ropers, Andreas W Kuss
Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA(Ser) concentrations...
February 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28236338/summary-of-mutations-underlying-autosomal-recessive-congenital-ichthyoses-arci-in-arabs-with-four-novel-mutations-in-arci-related-genes-from-the-united-arab-emirates
#17
Fatma Bastaki, Madiha Mohamed, Pratibha Nair, Fatima Saif, Ethar M Mustafa, Sami Bizzari, Mahmoud T Al-Ali, Abdul Rezzak Hamzeh
BACKGROUND: Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. METHODS: In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates...
February 24, 2017: International Journal of Dermatology
https://www.readbyqxmd.com/read/28236226/nmr-resonance-assignments-of-the-fkbp-domain-of-human-aryl-hydrocarbon-receptor-interacting-protein-like-1-aipl1-in-complex-with-a-farnesyl-ligand
#18
Liping Yu, Ravi P Yadav, Nikolai O Artemyev
Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a specialized chaperone of phosphodiesterase 6, a key effector enzyme in the phototransduction cascade. The FKBP domain of AIPL1 is known to bind the farnesyl moiety of PDE6. Mutations in AIPL1, including many missense mutations in the FKBP domain, have been associated with Leber congenital amaurosis, a severe blinding disease. Here, we report the backbone and sidechain assignments of the N-terminal FKBP(Δloop) (with a loop deletion) of AIPL1 in complex with a farnesyl ligand...
February 24, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28229249/adcy5-related-dyskinesia-presenting-as-familial-myoclonus-dystonia
#19
Andrew G L Douglas, Gaia Andreoletti, Kevin Talbot, Simon R Hammans, Jaspal Singh, Andrea Whitney, Sarah Ennis, Nicola C Foulds
We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c...
February 22, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28228528/clinical-genetic-and-structural-basis-of-congenital-adrenal-hyperplasia-due-to-11%C3%AE-hydroxylase-deficiency
#20
Ahmed Khattab, Shozeb Haider, Ameet Kumar, Samarth Dhawan, Dauood Alam, Raquel Romero, James Burns, Di Li, Jessica Estatico, Simran Rahi, Saleel Fatima, Ali Alzahrani, Mona Hafez, Noha Musa, Maryam Razzghy Azar, Najoua Khaloul, Moez Gribaa, Ali Saad, Ilhem Ben Charfeddine, Berenice Bilharinho de Mendonça, Alicia Belgorosky, Katja Dumic, Miroslav Dumic, Javier Aisenberg, Nurgun Kandemir, Ayfer Alikasifoglu, Alev Ozon, Nazli Gonc, Tina Cheng, Ursula Kuhnle-Krahl, Marco Cappa, Paul-Martin Holterhus, Munier A Nour, Daniele Pacaud, Assaf Holtzman, Sun Li, Mone Zaidi, Tony Yuen, Maria I New
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
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