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Prediction of missense mutation

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https://www.readbyqxmd.com/read/29343210/prediction-of-structural-consequences-for-disease-causing-variants-in-c21orf2-protein-using-computational-approaches
#1
Shalini Iyer, K Ravi Acharya, Vasanta Subramanian
Amyotrophic lateral sclerosis (ALS), a progressive motor-neurone disease, affects individuals usually aged between 50 and 70 years. C21orf2, recently identified as the new ALS susceptibility gene, harbours rare missense mutations that cause this fatal disease. We used bioinformatics and molecular modelling approaches to study specific ALS-associated mutations in C21orf2. Both native and mutant structures of the protein obtained from homology modelling were analysed in detail to gain insights into the potential impact of these mutations on the protein structure and its function...
January 17, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29342275/hot-spot-kif5a-mutations-cause-familial-als
#2
David Brenner, Rüstem Yilmaz, Kathrin Müller, Torsten Grehl, Susanne Petri, Thomas Meyer, Julian Grosskreutz, Patrick Weydt, Wolfgang Ruf, Christoph Neuwirth, Markus Weber, Susana Pinto, Kristl G Claeys, Berthold Schrank, Berit Jordan, Antje Knehr, Kornelia Günther, Annemarie Hübers, Daniel Zeller, Christian Kubisch, Sibylle Jablonka, Michael Sendtner, Thomas Klopstock, Mamede de Carvalho, Anne Sperfeld, Guntram Borck, Alexander E Volk, Johannes Dorst, Joachim Weis, Markus Otto, Joachim Schuster, Kelly Del Tredici, Heiko Braak, Karin M Danzer, Axel Freischmidt, Thomas Meitinger, Tim M Strom, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt
Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis...
January 12, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29341116/rare-missense-mutations-in-recql-and-polg-associate-with-inherited-predisposition-to-breast-cancer
#3
Anna Tervasmäki, Tuomo Mantere, Jaana M Hartikainen, Saila Kauppila, Hang-Mao Lee, Susanna Koivuluoma, Mervi Grip, Peeter Karihtala, Arja Jukkola-Vuorinen, Arto Mannermaa, Robert Winqvist, Katri Pylkäs
Several known breast cancer susceptibility genes with moderate-to-high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein-truncating variants, and the role of rare missense mutations has remained poorly addressed. In order to identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious...
January 17, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29332214/targeted-next-generation-sequencing-in-patients-with-non-syndromic-congenital-heart-disease
#4
Silvia Pulignani, Cecilia Vecoli, Andrea Borghini, Ilenia Foffa, Lamia Ait-Alì, Maria Grazia Andreassi
Congenital heart disease (CHD) is a genetically heterogeneous disease. Targeted next-generation sequencing (NGS) offers a unique opportunity to sequence multiple genes at lower cost and effort compared to Sanger sequencing. We tested a targeted NGS of a specific gene panel in a relatively large population of non-syndromic CHD patients. The patient cohort comprised 68 CHD patients (45 males; 8.3 ± 1.7 years). Amplicon libraries for 16 CHD-strictly related genes were generated using a TruSeq® Custom Amplicon kit (Illumina, CA) and sequenced using the Illumina MiSeq platform...
January 13, 2018: Pediatric Cardiology
https://www.readbyqxmd.com/read/29319460/polymorphism-of-opioid-receptors-%C3%AE-1-in-highly-hypnotizable-subjects
#5
Silvano Presciuttini, Michele Curcio, Rosalia Sciarrino, Fabrizio Scatena, Mark P Jensen, Enrica L Santarcangelo
The possible cooperation between hypnotizability-related and placebo mechanisms in pain modulation has not been consistently assessed. Here, we investigate possible genetic bases for such cooperation. The OPRM1 gene, which encodes the μ1 opioid receptor-the primary site of action for endogenous and exogenous opioids-is polymorphic in the general population for the missense mutation Asn40Asp (A118G, rs1799971). The minor allele 118G results in decreased levels of OPRM1 mRNA and protein. As a consequence, G carriers are less responsive to opioids...
January 2018: International Journal of Clinical and Experimental Hypnosis
https://www.readbyqxmd.com/read/29317596/rare-loss-of-function-mutations-in-n-methyl-d-aspartate-glutamate-receptors-and-their-contributions-to-schizophrenia-susceptibility
#6
Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki
In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D...
January 10, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29314318/two-novel-cps1-mutations-in-a-case-of-carbamoyl-phosphate-synthetase-1-deficiency-causing-hyperammonemia-and-leukodystrophy
#7
Xihui Chen, Lijuan Yuan, Mao Sun, Qingbo Liu, Yuanming Wu
BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CPS1D can be at any age, and the clinical manifestations are variable and atypical. Genetic tests are indispensable for accurate diagnosis of CPS1D on the basis of biochemical tests. METHODS: Blood tandem mass spectrometric analysis and urea organic acidemia screening were performed on a Chinese neonatal patient with low activity, recurrent seizures, and hyperammonemia...
January 4, 2018: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/29304759/a-novel-compound-heterozygous-variant-identified-in-gldc-gene-in-a-chinese-family-with-non-ketotic-hyperglycinemia
#8
Yiming Lin, Zhenzhu Zheng, Wenjia Sun, Qingliu Fu
BACKGROUND: Non-ketotic hyperglycinemia (NKH) is a rare, devastating autosomal recessive disorder of glycine metabolism with a very poor prognosis. Currently, few studies have reported genetic profiling of Chinese NKH patients. This study aimed to identify the genetic mutations in a Chinese family with NKH. METHODS: A Chinese family of Han ethnicity, with three siblings with NKH was studied. Sanger sequencing and multiplex ligation-dependent probe amplification combined with SYBR green real-time quantitative PCR was used to identify potential mutations in the GLDC, AMT and GCSH genes...
January 5, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29302046/p53-status-in-the-primary-tumor-predicts-efficacy-of-subsequent-abiraterone-and-enzalutamide-in-castration-resistant-prostate-cancer
#9
Benjamin L Maughan, Liana B Guedes, Kenneth Boucher, Gaurav Rajoria, Zach Liu, Szczepan Klimek, Roberto Zoino, Emmanuel S Antonarakis, Tamara L Lotan
BACKGROUND: We tested whether tissue-based analysis of p53 and PTEN genomic status in primary tumors is predictive for subsequent sensitivity to abiraterone and enzalutamide in castration-resistant prostate cancer (CRPC). METHODS: We performed a retrospective analysis of 309 consecutive patients with CRPC treated with abiraterone or enzalutamide. Of these, 101 men (33%) had available primary tumor tissue for analysis. We screened for deleterious TP53 missense mutations and PTEN deletions using genetically validated immunohistochemical assays for nuclear accumulation of p53 protein and PTEN protein loss, with sequencing confirmation of TP53 mutations in a subset...
January 4, 2018: Prostate Cancer and Prostatic Diseases
https://www.readbyqxmd.com/read/29300302/splicing-analysis-of-exonic-ocrl-mutations-causing-lowe-syndrome-or-dent-2-disease
#10
Lorena Suarez-Artiles, Ana Perdomo-Ramirez, Elena Ramos-Trujillo, Felix Claverie-Martin
Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some OCRL mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of OCRL exonic mutations on pre-mRNA splicing...
January 4, 2018: Genes
https://www.readbyqxmd.com/read/29290974/sodium-taurocholate-cotransporting-polypeptide-ntcp-deficiency-identification-of-a-novel-slc10a1-mutation-in-two-unrelated-infants-presenting-with-neonatal-indirect-hyperbilirubinemia-and-remarkable-hypercholanemia
#11
Jian-Wu Qiu, Mei Deng, Ying Cheng, Raza-Muhammad Atif, Wei-Xia Lin, Li Guo, Hua Li, Yuan-Zong Song
Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290829/genetic-variation-in-n-and-c-terminal-regions-of-bovine-dnaja1-heat-shock-protein-gene-in-african-asian-and-american-cattle
#12
Oyeyemi O Ajayi, Sunday O Peters, Marcos De Donato, F Denis Mujibi, Waqas A Khan, Tanveer Hussain, Masroor E Babar, Ikhide G Imumorin, Bolaji N Thomas
DNAJA1 or heat shock protein 40 (Hsp40) is associated with heat adaptation in various organisms. We amplified and sequenced a total of 1,142 bp of bovine Hsp40 gene representing the critical N-terminal (NTR) and C-terminal (CTR) regions in representative samples of African, Asian and American cattle breeds. Eleven and 9 different haplotypes were observed in the NTR in Asian and African breeds respectively while in American Brangus, only two mutations were observed resulting in two haplotypes. The CTR appears to be highly conserved between cattle and yak...
2018: Journal of Genomics
https://www.readbyqxmd.com/read/29288420/characterization-of-phenyalanine-hydroxylase-gene-mutations-in-chilean-pku-patients
#13
V Hamilton, L Santa María, K Fuenzalida, P Morales, L R Desviat, M Ugarte, B Pérez, J F Cabello, V Cornejo
Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive disease, caused by mutations in the Phenylalanine Hydroxylase (PAH) gene situated in chromosome 12q22-q24.2. This gene has 13 exons. To date, 991 mutations have been described. The genotype is one of the main factors that determine the phenotype of this disease. OBJECTIVE: Characterize PKU genotype and phenotype seen in Chilean PKU patients. METHODS: We studied the PAH gene by restriction fragment length polymorphism (RFLP) and/or sequencing techniques to identify pathogenic mutations in 71 PKU subjects...
December 30, 2017: JIMD Reports
https://www.readbyqxmd.com/read/29284740/familial-and-somatic-bap1-mutations-inactivate-asxl1-2-mediated-allosteric-regulation-of-bap1-deubiquitinase-by-targeting-multiple-independent-domains
#14
Hongzhuang Peng, Jeremy Prokop, Jayashree Karar, Kyewon Park, Li Cao, J William Harbour, Anne M Bowcock, S Bruce Malkowicz, Mitchell Cheung, Joseph R Testa, Frank J Rauscher
Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry...
December 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/29282038/the-prognostic-value-of-tp53-mutations-in-hypopharyngeal-squamous-cell-carcinoma
#15
Go Omura, Mizuo Ando, Yasuhiro Ebihara, Yuki Saito, Kenya Kobayashi, Osamu Fukuoka, Ken Akashi, Masafumi Yoshida, Takahiro Asakage, Tatsuya Yamasoba
BACKGROUND: TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC. METHODS: We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014...
December 28, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29279004/insights-into-the-role-of-ribonuclease-4-polymorphisms-in-amyotrophic-lateral-sclerosis
#16
Aditya K Padhi, Priyam Narain, Upma Dave, Rohit Satija, Anirudh Patir, James Gomes
Mutations in certain genes of the Ribonuclease (RNASE) superfamily can cause amyotrophic lateral sclerosis (ALS) through altered RNA processing mechanisms. About 30 of these missense mutations in RNASE5/ANG gene have already been reported in ALS patients. In another gene of the ribonuclease superfamily, ribonuclease 4 (RNASE4), missense mutations and single nucleotide polymorphisms have been identified in patients suffering from ALS. However, their plausible molecular mechanisms of association with ALS are not known...
December 26, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29275168/molecular-analysis-of-thyroglobulin-mutations-found-in-patients-with-goiter-and-hypothyroidism
#17
Sofia Siffo, Ezequiela Adrover, Cintia E Citterio, Mirta B Miras, Viviana A Balbi, Ana Chiesa, Jacques Weill, Gabriela Sobrero, Verónica G González, Patricia Papendieck, Elena Bueno Martinez, Rogelio Gonzalez-Sarmiento, Carina M Rivolta, Héctor M Targovnik
Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG...
December 22, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29260090/a-recurrent-non-penetrant-sequence-variant-p-arg266cys-in-growth-differentiation-factor-3-gdf3-in-a-female-with-unilateral-anophthalmia-and-skeletal-anomalies
#18
Tanya Bardakjian, Max Krall, Di Wu, Richard Lao, Paul Ling-Fung Tang, Eunice Wan, Sarina Kopinsky, Adele Schneider, Pui-Yan Kwok, Anne Slavotinek
Purpose: The genetic causes of anophthalmia, microphthalmia and coloboma remain poorly understood. Missense mutations in Growth/Differentiation Factor 3 (GDF3) gene have previously been reported in patients with microphthalmia, iridial and retinal colobomas, Klippel-Feil anomaly with vertebral fusion, scoliosis, rudimentary 12th ribs and an anomalous right temporal bone. We used whole exome sequencing with a trio approach to study a female with unilateral anophthalmia, kyphoscoliosis and additional skeletal anomalies...
September 2017: American Journal of Ophthalmology Case Reports
https://www.readbyqxmd.com/read/29247561/protein-altering-variants-of-ptpn2-in-childhood-onset-type-1a-diabetes
#19
M Okuno, T Ayabe, I Yokota, I Musha, K Shiga, T Kikuchi, N Kikuchi, A Ohtake, A Nakamura, K Nakabayashi, K Okamura, Y Momozawa, M Kubo, J Suzuki, T Urakami, T Kawamura, S Amemiya, T Ogata, S Sugihara, M Fukami
AIM: To conduct PTPN2 mutation analysis in Japanese people with childhood-onset Type 1A diabetes in order to examine whether PTPN2 variants contribute to the risk of this condition. METHODS: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible...
December 16, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/29242249/acidosis-and-deafness-in-patients-with-recessive-mutations-in-foxi1
#20
Sven Enerbäck, Daniel Nilsson, Noel Edwards, Mikael Heglind, Sumaya Alkanderi, Emma Ashton, Asma Deeb, Feras E B Kokash, Abdulrahim R A Bakhsh, William Van't Hoff, Stephen B Walsh, Felice D'Arco, Arezoo Daryadel, Soline Bourgeois, Carsten A Wagner, Robert Kleta, Detlef Bockenhauer, John A Sayer
Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis...
December 14, 2017: Journal of the American Society of Nephrology: JASN
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