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[PMID]:28460066
[Au] Autor:Kim HR; Kang HN; Shim HS; Kim EY; Kim J; Kim DJ; Lee JG; Lee CY; Hong MH; Kim SM; Kim H; Pyo KH; Yun MR; Park HJ; Han JY; Youn HA; Ahn MJ; Paik S; Kim TM; Cho BC
[Ad] Endereço:Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul.
[Ti] Título:Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.
[So] Source:Ann Oncol;28(6):1250-1259, 2017 Jun 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. Results: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. Conclusions: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
[Mh] Termos MeSH primário: Benzimidazóis/uso terapêutico
Biomarcadores/sangue
Carcinoma de Células Escamosas/tratamento farmacológico
Ensaios Clínicos como Assunto
Neoplasias Pulmonares/tratamento farmacológico
Quinolonas/uso terapêutico
Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Carcinoma de Células Escamosas/genética
Seres Humanos
Neoplasias Pulmonares/genética
Mutação
Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
Transdução de Sinais
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one); 0 (Benzimidazoles); 0 (Biomarkers); 0 (Quinolones); 0 (Receptors, Fibroblast Growth Factor)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx098


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[PMID]:28453708
[Au] Autor:Vis DJ; Lewin J; Liao RG; Mao M; Andre F; Ward RL; Calvo F; Teh BT; Camargo AA; Knoppers BM; Sawyers CL; Wessels LFA; Lawler M; Siu LL; Voest E; Clinical Working Group of the Global Alliance for Genomics and Health
[Ad] Endereço:Netherlands Cancer Institute, Amsterdam, The Netherlands.
[Ti] Título:Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.
[So] Source:Ann Oncol;28(5):1145-1151, 2017 May 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community. Methods: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination). Results: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01). Conclusions: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.
[Mh] Termos MeSH primário: Estudos de Associação Genética
Neoplasias/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Bases de Dados Genéticas
Predisposição Genética para Doença
Genoma Humano
Seres Humanos
Anotação de Sequência Molecular
Inquéritos e Questionários
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx037


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[PMID]:29335443
[Au] Autor:Nahar R; Zhai W; Zhang T; Takano A; Khng AJ; Lee YY; Liu X; Lim CH; Koh TPT; Aung ZW; Lim TKH; Veeravalli L; Yuan J; Teo ASM; Chan CX; Poh HM; Chua IML; Liew AA; Lau DPX; Kwang XL; Toh CK; Lim WT; Lim B; Tam WL; Tan EH; Hillmer AM; Tan DSW
[Ad] Endereço:Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, 138672, Singapore.
[Ti] Título:Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.
[So] Source:Nat Commun;9(1):216, 2018 01 15.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Genômica/métodos
Neoplasias Pulmonares/genética
Mutação
Receptor do Fator de Crescimento Epidérmico/genética
Sequenciamento Completo do Exoma/métodos
[Mh] Termos MeSH secundário: Adenocarcinoma/etnologia
Adenocarcinoma/patologia
Grupo com Ancestrais do Continente Asiático/genética
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/genética
Predisposição Genética para Doença/etnologia
Predisposição Genética para Doença/genética
Seres Humanos
Neoplasias Pulmonares/etnologia
Neoplasias Pulmonares/patologia
Inibidores de Proteínas Quinases/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02584-z


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[PMID]:28460482
[Au] Autor:Kim HY; Choi JW; Lee JY; Kong G
[Ad] Endereço:Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
[Ti] Título:Gene-based comparative analysis of tools for estimating copy number alterations using whole-exome sequencing data.
[So] Source:Oncotarget;8(16):27277-27285, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Accurate detection of copy number alterations (CNAs) using next-generation sequencing technology is essential for the development and application of more precise medical treatments for human cancer. Here, we evaluated seven CNA estimation tools (ExomeCNV, CoNIFER, VarScan2, CODEX, ngCGH, saasCNV, and falcon) using whole-exome sequencing data from 419 breast cancer tumor-normal sample pairs from The Cancer Genome Atlas. Estimations generated using each tool were converted into gene-based copy numbers; concordance for gains and losses and the sensitivity and specificity of each tool were compared to validated copy numbers from a single nucleotide polymorphism reference array. The concordance and sensitivity of the tumor-normal pair methods for estimating CNAs (saasCNV, ExomeCNV, and VarScan2) were better than those of the tumor batch methods (CoNIFER and CODEX). SaasCNV had the highest gain and loss concordances (65.0%), sensitivity (69.4%), and specificity (89.1%) for estimating copy number gains or losses. These findings indicate that improved CNA detection algorithms are needed to more accurately interpret whole-exome sequencing results in human cancer.
[Mh] Termos MeSH primário: Biologia Computacional
Variações do Número de Cópias de DNA
Estudo de Associação Genômica Ampla
Neoplasias/genética
[Mh] Termos MeSH secundário: Algoritmos
Biologia Computacional/métodos
Bases de Dados de Ácidos Nucleicos
Estudo de Associação Genômica Ampla/métodos
Seres Humanos
Sensibilidade e Especificidade
Análise de Sequência de DNA
Software
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15932


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[PMID]:29386434
[Au] Autor:Watanabe K
[Ad] Endereço:Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences.
[Ti] Título:[From a Ph.D. Thesis: Understanding the Past, Predicting the Future].
[So] Source:Yakugaku Zasshi;138(2):211-219, 2018.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo: Posey et al. have reported multiple molecular diagnoses in 4.5% of cases (101/2076) in which whole-exome sequencing was informative. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. My research projects at the Niigata University of Pharmacy have investigated underlying mechanisms involved in human disease, including fatty acid metabolism, diabetic cardiomyopathy, atopic dermatitis, colitis, hepatitis, etc. Three students from abroad graduated this year from the Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences. These students reported on treatments for heart disease, non-alcoholic steatohepatitis and atopic dermatitis, as well as the underlying mechanisms involved in each. The titles of these reports are "Study of the role of cardiac 14-3-3η protein in cardiac inflammation and adverse cardiac remodeling during heart failure in mice", "Non-alcoholic steatohepatitis: onset of mechanisms under diabetic background and treatment strategies" and "The role of HMGB1 and its cascade signaling pathway in atopic dermatitis". It can be concluded from these three theses that oxidative stress and inflammation are among the principal mechanisms underlying these diseases.
[Mh] Termos MeSH primário: Dermatite Atópica
Proteína HMGB1
Insuficiência Cardíaca
Hepatopatia Gordurosa não Alcoólica
[Mh] Termos MeSH secundário: Proteínas 14-3-3
Proteínas Quinases Ativadas por AMP
Animais
Dermatite Atópica/genética
Complicações do Diabetes
Estresse do Retículo Endoplasmático
Insuficiência Cardíaca/genética
Seres Humanos
Camundongos
Hepatopatia Gordurosa não Alcoólica/etiologia
Hepatopatia Gordurosa não Alcoólica/terapia
Estresse Oxidativo
Patologia Molecular
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (HMGB1 Protein); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180202
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.17-00111


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[PMID]:28749043
[Au] Autor:Cao N; Li W; Li B; Tian Y; Xu D
[Ad] Endereço:Institute of Animal Nutrition, Genetics and Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, China.
[Ti] Título:Transcriptome profiling reveals the immune response of goose T cells under selenium stimuli.
[So] Source:Anim Sci J;88(12):2001-2009, 2017 Dec.
[Is] ISSN:1740-0929
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:The goose is an economically important poultry species and a principal natural host of avian viruses. This study aimed to determine the effects of selenium on the immune response of geese. Under selenium stimulation, gene expression profiling was investigated using transcriptome sequencing. The selenoproteins were promoted by selenium stimulation, while the heat shock proteins, interleukin and interferons were mainly down-regulated. After comparison, 2228 differentially expressed genes were primarily involved in immune and environmental response, and infectious disease and genetic information processing related pathways were identified. Specifically, the enzymes of the lysosomes which acted as a safeguard in preventing pathogens were mostly up-regulated and six randomly selected differentially expressed genes were validated by quantitative polymerase chain reaction. In addition, the most proportional increased transcription factor family basic helix-loop-helix (bHLH) located in the 5' flank of selenoprotein P-like protein for selenium metabolism was identified by response to the selenium stimulation in this study. These analyses show that selenium can promote immune function by activating selenoproteins, transcript factors and lysosome pathway related genes, while weakening cytokine content genes in geese.
[Mh] Termos MeSH primário: Gansos/imunologia
Imunidade Celular/genética
Selênio/imunologia
Linfócitos T/imunologia
Transcriptoma/genética
Transcriptoma/imunologia
[Mh] Termos MeSH secundário: Animais
Fatores de Transcrição Hélice-Alça-Hélice Básicos
Células Cultivadas
Citocinas
Lisossomos/enzimologia
Selenoproteínas
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cytokines); 0 (Selenoproteins); H6241UJ22B (Selenium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1111/asj.12861


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[PMID]:29355681
[Au] Autor:Fan LL; Huang H; Jin JY; Li JJ; Chen YQ; Zhao SP; Xiang R
[Ad] Endereço:Department of Cell Biology, The School of Life Sciences, Central South University, Changsha 410013, China.
[Ti] Título:Whole exome sequencing identifies a novel mutation (c.333 + 2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease.
[So] Source:Gene;648:63-67, 2018 Mar 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dilated Cardiomyopathy (DCM) and cardiac conduction disease (CCD) are two kinds if diseases that can induce heart failure, syncope and even sudden cardiac death (SCD). DCM patients can experience CCD at the same time. In recent research, some disease-causing genes and variants have been identified in patients with DCM and CCD, such as Alpha-Actinin-2 and TNNI3 Interacting Kinase (TNNI3K). In this study, we employed whole-exome sequencing (WES) to explore the potential causative genes in a Chinese family with DCM and CCD. A novel splice site mutation (c.333 + 2 T > C) of TNNI3K was identified and co-segregated with the affected family members. This novel mutation was also absent in 200 healthy local controls and predicted to be disease-causing by Mutationtaster. The splice site mutation (c.333 + 2 T > C) may result in a premature stop codon in exon 4 of the TNNI3K gene and can induce nonsense-mediated mRNA decay. Real-time qPCR also confirmed that the level of TNNI3K mRNA expression was decreased significantly compared with the controls, which may lead to myocardial structural disorder and arrhythmia. In this study we reported the third novel mutation of TNNI3K in DCM and CCD patients which further supported the important role of TNNI3K in heart development and expanded the spectrum of TNNI3K mutations. The results may contribute to the genetic diagnosis and counseling of families with DCM and CCD.
[Mh] Termos MeSH primário: Doença do Sistema de Condução Cardíaco/genética
Cardiomiopatia Dilatada/genética
MAP Quinase Quinase Quinases/genética
Mutação
Sequenciamento Completo do Exoma/métodos
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático/genética
Sequência de Bases
Doença do Sistema de Condução Cardíaco/etnologia
Cardiomiopatia Dilatada/etnologia
China
Saúde da Família
Feminino
Seres Humanos
Masculino
Degradação do RNAm Mediada por Códon sem Sentido/genética
Linhagem
Sítios de Splice de RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Splice Sites); EC 2.7.11.1 (TNNI3K protein, human); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29193015
[Au] Autor:Zamò A; Pischimarov J; Horn H; Ott G; Rosenwald A; Leich E
[Ad] Endereço:Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
[Ti] Título:The exomic landscape of t(14;18)-negative diffuse follicular lymphoma with 1p36 deletion.
[So] Source:Br J Haematol;180(3):391-394, 2018 02.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Predominantly diffuse t(14;18) negative follicular lymphoma (FL) with 1p36 deletion shows distinctive clinical, morphological and molecular features that distinguish it from classical FL. In order to investigate whether it possesses a unique mutation profile, we performed whole exome sequencing of six well-characterised cases. Our analysis showed that the mutational landscape of this subtype is largely distinct from classical FL. It appears to harbour several recurrent mutations, affecting STAT6, CREBBP and basal membrane protein genes with high frequency. Our data support the view that this FL subtype should be considered a separate entity from classical FL.
[Mh] Termos MeSH primário: Deleção Cromossômica
Cromossomos Humanos Par 1
Exoma
Predisposição Genética para Doença
Linfoma Folicular/genética
Linfoma Folicular/patologia
Translocação Genética
[Mh] Termos MeSH secundário: Cromossomos Humanos Par 14
Cromossomos Humanos Par 18
Seres Humanos
Mutação
Polimorfismo de Nucleotídeo Único
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.15041


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[PMID]:29220678
[Au] Autor:Falkenberg KD; Braverman NE; Moser AB; Steinberg SJ; Klouwer FCC; Schlüter A; Ruiz M; Pujol A; Engvall M; Naess K; van Spronsen F; Körver-Keularts I; Rubio-Gozalbo ME; Ferdinandusse S; Wanders RJA; Waterham HR
[Ad] Endereço:Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
[Ti] Título:Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.
[So] Source:Am J Hum Genet;101(6):965-976, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
[Mh] Termos MeSH primário: Regiões 3´ não Traduzidas/genética
ATPases Associadas a Diversas Atividades Celulares/genética
Desequilíbrio Alélico/genética
Síndrome de Zellweger/genética
[Mh] Termos MeSH secundário: Alelos
Células Cultivadas
Feminino
Regulação da Expressão Gênica/genética
Predisposição Genética para Doença
Seres Humanos
Masculino
Peroxissomos/genética
Peroxissomos/patologia
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities); EC 3.6.4.- (PEX6 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:29198720
[Au] Autor:Luscan R; Mechaussier S; Paul A; Tian G; Gérard X; Defoort-Dellhemmes S; Loundon N; Audo I; Bonnin S; LeGargasson JF; Dumont J; Goudin N; Garfa-Traoré M; Bras M; Pouliet A; Bessières B; Boddaert N; Sahel JA; Lyonnet S; Kaplan J; Cowan NJ; Rozet JM; Marlin S; Perrault I
[Ad] Endereço:Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
[Ti] Título:Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
[So] Source:Am J Hum Genet;101(6):1006-1012, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in ß-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the ß-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αß-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αß-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.
[Mh] Termos MeSH primário: Amaurose Congênita de Leber/genética
Microtúbulos/genética
Tubulina (Proteína)/genética
[Mh] Termos MeSH secundário: Adulto
Sítios de Ligação/genética
Células Cultivadas
Criança
Análise Mutacional de DNA
Feminino
Seres Humanos
Masculino
Microtúbulos/metabolismo
Meia-Idade
Mutação de Sentido Incorreto/genética
Células Fotorreceptoras/metabolismo
Tubulina (Proteína)/metabolismo
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tubulin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE



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