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Pesquisa : D08.811.913.696.620.682.324 [Categoria DeCS]
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  1 / 1706 MEDLINE  
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[PMID]:28470860
[Au] Autor:Hong Y; Zisimopoulou P; Trakas N; Karagiorgou K; Stergiou C; Skeie GO; Hao HJ; Gao X; Owe JF; Zhang X; Yue YX; Romi F; Wang Q; Li HF; Gilhus NE; Tzartos SJ
[Ad] Endereço:Department of Clinical Medicine, University of Bergen, Bergen, Norway.
[Ti] Título:Multiple antibody detection in 'seronegative' myasthenia gravis patients.
[So] Source:Eur J Neurol;24(6):844-850, 2017 Jun.
[Is] ISSN:1468-1331
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients. METHODS: Plasma from 81 Chinese MG patients previously found to be seronegative was tested by routine assays for AChR and MuSK antibodies. These samples were screened by (i) a novel, highly sensitive radioimmunoassay for AChR antibodies; (ii) cell-based assays for clustered AChR, MuSK and lipoprotein receptor-related protein 4 (LRP4) antibodies; (iii) a radioimmunoassay for titin antibodies. RESULTS: Antibodies to AChR, MuSK, LRP4 and titin were found in 25% (20/81), 4% (3/81), 7% (6/81) and 6% (5/78) of SNMG patients, respectively. In total, 37% of SNMG patients were found to be positive for at least one of the tested antibodies. AChR antibody positive patients had more severe disease (P = 0.008) and a trend towards fewer remissions/minimal manifestations than AChR antibody negative patients. The four patients with coexistence of antibodies had more severe disease, whilst the seronegative patients had milder MG (P = 0.015). CONCLUSIONS: Detection of multiple muscle antibodies by more sensitive assays provides additional information in diagnosing and subgrouping of MG and may guide MG treatment.
[Mh] Termos MeSH primário: Autoanticorpos/sangue
Conectina/imunologia
Proteínas Relacionadas a Receptor de LDL/imunologia
Miastenia Gravis/imunologia
Receptores Proteína Tirosina Quinases/imunologia
Receptores Colinérgicos/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Feminino
Seres Humanos
Masculino
Meia-Idade
Miastenia Gravis/sangue
Radioimunoensaio
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Connectin); 0 (LDL-Receptor Related Proteins); 0 (LRP4 protein, human); 0 (Receptors, Cholinergic); 0 (TTN protein, human); EC 2.7.10.1 (MUSK protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/ene.13300


  2 / 1706 MEDLINE  
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[PMID]:28469023
[Au] Autor:Tomalka A; Rode C; Schumacher J; Siebert T
[Ad] Endereço:Institute of Sport and Movement Science, University of Stuttgart, Allmandring 28, 70569 Stuttgart, Baden-Württemberg, Germany andre.tomalka@inspo.uni-stuttgart.de.
[Ti] Título:The active force-length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres.
[So] Source:Proc Biol Sci;284(1854), 2017 May 17.
[Is] ISSN:1471-2954
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In contrast to experimentally observed progressive forces in eccentric contractions, cross-bridge and sliding-filament theories of muscle contraction predict that varying myofilament overlap will lead to increases and decreases in active force during eccentric contractions. Non-cross-bridge contributions potentially explain the progressive total forces. However, it is not clear whether underlying abrupt changes in the slope of the nonlinear force-length relationship are visible in long isokinetic stretches, and in which proportion cross-bridges and non-cross-bridges contribute to muscle force. Here, we show that maximally activated single skinned rat muscle fibres behave (almost across the entire working range) like linear springs. The force slope is about three times the maximum isometric force per optimal length. Cross-bridge and non-cross-bridge contributions to the muscle force were investigated using an actomyosin inhibitor. The experiments revealed a nonlinear progressive contribution of non-cross-bridge forces and suggest a nonlinear cross-bridge contribution similar to the active force-length relationship (though with increased optimal length and maximum isometric force). The linear muscle behaviour might significantly reduce the control effort. Moreover, the observed slight increase in slope with initial length is in accordance with current models attributing the non-cross-bridge force to titin.
[Mh] Termos MeSH primário: Contração Muscular
Fibras Musculares Esqueléticas/fisiologia
Músculo Esquelético/fisiologia
[Mh] Termos MeSH secundário: Citoesqueleto de Actina
Actomiosina/fisiologia
Animais
Conectina/fisiologia
Contração Isométrica
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Connectin); 9013-26-7 (Actomyosin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


  3 / 1706 MEDLINE  
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[PMID]:29221435
[Au] Autor:König E; Volpato CB; Motta BM; Blankenburg H; Picard A; Pramstaller P; Casella M; Rauhe W; Pompilio G; Meraviglia V; Domingues FS; Sommariva E; Rossini A
[Ad] Endereço:Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
[Ti] Título:Exploring digenic inheritance in arrhythmogenic cardiomyopathy.
[So] Source:BMC Med Genet;18(1):145, 2017 12 08.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder, characterized by the substitution of heart muscle with fibro-fatty tissue and severe ventricular arrhythmias, often leading to heart failure and sudden cardiac death. ACM is considered a monogenic disorder, but the low penetrance of mutations identified in patients suggests the involvement of additional genetic or environmental factors. METHODS: We used whole exome sequencing to investigate digenic inheritance in two ACM families where previous diagnostic tests have revealed a PKP2 mutation in all affected and some healthy individuals. In family members with PKP2 mutations we determined all genes that harbor variants in affected but not in healthy carriers or vice versa. We computationally prioritized the most likely candidates, focusing on known ACM genes and genes related to PKP2 through protein interactions, functional relationships, or shared biological processes. RESULTS: We identified four candidate genes in family 1, namely DAG1, DAB2IP, CTBP2 and TCF25, and eleven candidate genes in family 2. The most promising gene in the second family is TTN, a gene previously associated with ACM, in which the affected individual harbors two rare deleterious-predicted missense variants, one of which is located in the protein's only serine kinase domain. CONCLUSIONS: In this study we report genes that might act as digenic players in ACM pathogenesis, on the basis of co-segregation with PKP2 mutations. Validation in larger cohorts is still required to prove the utility of this model.
[Mh] Termos MeSH primário: Displasia Arritmogênica Ventricular Direita/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Oxirredutases do Álcool/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Conectina/química
Conectina/genética
Distroglicanas/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Modelos Moleculares
Mutação
Proteínas do Tecido Nervoso/genética
Linhagem
Placofilinas/genética
Domínios Proteicos
Proteínas Repressoras/genética
Sequenciamento Completo do Exoma
Proteínas Ativadoras de ras GTPase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Connectin); 0 (DAB2IP protein, human); 0 (DAG1 protein, human); 0 (Nerve Tissue Proteins); 0 (PKP2 protein, human); 0 (Plakophilins); 0 (Repressor Proteins); 0 (TCF25 protein, human); 0 (TTN protein, human); 0 (ras GTPase-Activating Proteins); 146888-27-9 (Dystroglycans); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.- (CTBP2 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171231
[Lr] Data última revisão:
171231
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171210
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0503-7


  4 / 1706 MEDLINE  
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[PMID]:29073955
[Au] Autor:Tayal U; Newsome S; Buchan R; Whiffin N; Halliday B; Lota A; Roberts A; Baksi AJ; Voges I; Midwinter W; Wilk A; Govind R; Walsh R; Daubeney P; Jarman JWE; Baruah R; Frenneaux M; Barton PJ; Pennell D; Ware JS; Prasad SK; Cook SA
[Ad] Endereço:National Heart Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre, Royal Brompton Hospital, London, United Kingdom.
[Ti] Título:Phenotype and Clinical Outcomes of Titin Cardiomyopathy.
[So] Source:J Am Coll Cardiol;70(18):2264-2274, 2017 Oct 31.
[Is] ISSN:1558-3597
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. OBJECTIVES: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. METHODS: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. RESULTS: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m reduction; p = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). CONCLUSIONS: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.
[Mh] Termos MeSH primário: Cardiomiopatia Dilatada/diagnóstico por imagem
Cardiomiopatia Dilatada/genética
Conectina/genética
Fenótipo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Criança
Estudos de Coortes
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Estudos Prospectivos
Método Simples-Cego
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Connectin); 0 (TTN protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171028
[St] Status:MEDLINE


  5 / 1706 MEDLINE  
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[PMID]:28968385
[Au] Autor:Heidlauf T; Klotz T; Rode C; Siebert T; Röhrle O
[Ad] Endereço:Institute of Applied Mechanics (CE), University of Stuttgart, Stuttgart, Germany.
[Ti] Título:A continuum-mechanical skeletal muscle model including actin-titin interaction predicts stable contractions on the descending limb of the force-length relation.
[So] Source:PLoS Comput Biol;13(10):e1005773, 2017 Oct.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Contractions on the descending limb of the total (active + passive) muscle force-length relationship (i. e. when muscle stiffness is negative) are expected to lead to vast half-sarcomere-length inhomogeneities. This is however not observed in experiments-vast half-sarcomere-length inhomogeneities can be absent in myofibrils contracting in this range, and initial inhomogeneities can even decrease. Here we show that the absence of half-sarcomere-length inhomogeneities can be predicted when considering interactions of the semi-active protein titin with the actin filaments. Including a model of actin-titin interactions within a multi-scale continuum-mechanical model, we demonstrate that stability, accurate forces and nearly homogeneous half-sarcomere lengths can be obtained on the descending limb of the static total force-length relation. This could be a key to durable functioning of the muscle because large local stretches, that might harm, for example, the transverse-tubule system, are avoided.
[Mh] Termos MeSH primário: Actinas/metabolismo
Fenômenos Biomecânicos/fisiologia
Conectina/metabolismo
Modelos Biológicos
Contração Muscular/fisiologia
Músculo Esquelético/fisiologia
[Mh] Termos MeSH secundário: Animais
Biologia Computacional
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Connectin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005773


  6 / 1706 MEDLINE  
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[PMID]:28866075
[Au] Autor:Gerull B
[Ad] Endereço:Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany; Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Electronic address: gerull_b@ukw.de.
[Ti] Título:Between Disease-Causing and an Innocent Bystander: The Role of Titin as a Modifier in Hypertrophic Cardiomyopathy.
[So] Source:Can J Cardiol;33(10):1217-1220, 2017 10.
[Is] ISSN:1916-7075
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica
Conectina/genética
[Mh] Termos MeSH secundário: Cardiomiopatia Dilatada
Seres Humanos
Mutação
[Pt] Tipo de publicação:EDITORIAL; RESEARCH SUPPORT, NON-U.S. GOV'T; COMMENT
[Nm] Nome de substância:
0 (Connectin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170904
[St] Status:MEDLINE


  7 / 1706 MEDLINE  
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[PMID]:28822653
[Au] Autor:Zhang C; Zhang H; Wu G; Luo X; Zhang C; Zou Y; Wang H; Hui R; Wang J; Song L
[Ad] Endereço:State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of
[Ti] Título:Titin-Truncating Variants Increase the Risk of Cardiovascular Death in Patients With Hypertrophic Cardiomyopathy.
[So] Source:Can J Cardiol;33(10):1292-1297, 2017 Oct.
[Is] ISSN:1916-7075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Titin-truncating variants (TTNtv) have been detected in a variety of cardiomyopathies and represent the most common cause of dilated cardiomyopathy. However, their significance in hypertrophic cardiomyopathy (HCM) is still unclear. METHODS: The titin gene (TTN) was sequenced for truncating variants in a cohort of 529 Chinese patients with HCM and 307 healthy controls. Baseline and follow-up clinical data (for 4.7 ± 3.2 years) from these patients were obtained. RESULTS: We identified 13 and 8 TTNtv in patients with HCM (13 of 529 [2.5%]) and controls (8 of 307 [2.6%]), respectively. The prevalence of TTNtv in patients with HCM and in healthy controls was comparable (P = 0.895). There were no significant differences in baseline characteristics between patients with and those without TTNtv. However, during follow-up, patients with TTNtv (3 of 13 [23.1%]) were more likely to experience cardiovascular death compared with those without TTNtv (39 of 516 [7.6%]) [adjusted hazard ratio, 6.88; 95% confidence interval, 2.04-23.20; P = 0.002). CONCLUSIONS: Our study suggests that TTNtv might be a genetic modifier of HCM and confer an increased risk for cardiovascular death.
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/genética
Conectina/genética
DNA/genética
Mutação
[Mh] Termos MeSH secundário: Adulto
Cardiomiopatia Hipertrófica/metabolismo
Cardiomiopatia Hipertrófica/mortalidade
China/epidemiologia
Conectina/metabolismo
Análise Mutacional de DNA
Bases de Dados Genéticas
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Reação em Cadeia da Polimerase
Estudos Retrospectivos
Taxa de Sobrevida/tendências
Fatores de Tempo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Connectin); 0 (TTN protein, human); 9007-49-2 (DNA)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170821
[St] Status:MEDLINE


  8 / 1706 MEDLINE  
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[PMID]:28811266
[Au] Autor:Tan H; Su W; Wang P; Zhang W; Sattler M; Zou P
[Ad] Endereço:Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
[Ti] Título:Expression and purification of a difficult sarcomeric protein: Telethonin.
[So] Source:Protein Expr Purif;140:74-80, 2017 Dec.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Telethonin anchors the N-terminal region of titin in the Z-disk of the sarcomere by binding to two immunoglobulin-like (Ig) domains (Z1 and Z2) of titin (Z1Z2). Thereby telethonin plays an important role in myofibril assembly and in muscle development and functional regulation. The expression and purification of recombinant telethonin is very challenging. In previous studies, recombinant telethonin expressed from E. coli was refolded in the presence of Z1Z2. Here, we report various strategies to establish a reliable and efficient protocol for the preparation of telethonin and titin Z1Z2 protein. First, a co-expression strategy was designed to obtain soluble Z1Z2/telethonin complexes. The concentration of antibiotics and the type of expression vector were found to be important for achieving high yields of purified complex. Second, the five cysteine residues of telethonin were mutated to serine to avoid severe problems with cysteine oxidation. Third, a short version of telethonin (telethonin ) was designed to avoid the proteolytic degradation observed for longer constructs of the protein. The short telethonin formed a highly stable complex with Z1Z2 with no degradation being observed for 30 days at 4 °C. Fourth, an improved refolding protocol was developed to achieve high yields of Z1Z2/telethonin complex. Finally, based on the crystal structure in which Z1Z2 and telethonin assemble into a 2:1 complex, a single chain fusion protein was designed, comprising two Z1Z2 modules that are connected by flexible linkers N- and C-terminally of the telethonin . Expression of this fusion protein, named ZTZ, affords high yields of soluble expressed and purified protein.
[Mh] Termos MeSH primário: Conectina/isolamento & purificação
Complexos Multiproteicos/isolamento & purificação
Proteínas Recombinantes/isolamento & purificação
[Mh] Termos MeSH secundário: Conectina/biossíntese
Conectina/química
Conectina/genética
Escherichia coli/genética
Seres Humanos
Complexos Multiproteicos/química
Complexos Multiproteicos/genética
Proteínas Musculares/química
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Sarcômeros/química
Sarcômeros/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Connectin); 0 (Multiprotein Complexes); 0 (Muscle Proteins); 0 (Recombinant Proteins); 0 (TCAP protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171011
[Lr] Data última revisão:
171011
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE


  9 / 1706 MEDLINE  
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[PMID]:28797094
[Au] Autor:Mendes de Almeida R; Tavares J; Martins S; Carvalho T; Enguita FJ; Brito D; Carmo-Fonseca M; Lopes LR
[Ad] Endereço:Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
[Ti] Título:Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with hypertrophic cardiomyopathy.
[So] Source:PLoS One;12(8):e0182946, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: High throughput sequencing technologies have revolutionized the identification of mutations responsible for genetic diseases such as hypertrophic cardiomyopathy (HCM). However, approximately 50% of individuals with a clinical diagnosis of HCM have no causal mutation identified. This may be due to the presence of pathogenic mutations located deep within the introns, which are not detected by conventional sequencing analysis restricted to exons and exon-intron boundaries. OBJECTIVE: The aim of this study was to develop a whole-gene sequencing strategy to prioritize deep intronic variants that may play a role in HCM pathogenesis. METHODS AND RESULTS: The full genomic DNA sequence of 26 genes previously associated with HCM was analysed in 16 unrelated patients. We identified likely pathogenic deep intronic variants in VCL, PRKAG2 and TTN genes. These variants, which are predicted to act through disruption of either splicing or transcription factor binding sites, are 3-fold more frequent in our cohort of probands than in normal European populations. Moreover, we found a patient that is compound heterozygous for a splice site mutation in MYBPC3 and the deep intronic VCL variant. Analysis of family members revealed that carriers of the MYBPC3 mutation alone do not manifest the disease, while family members that are compound heterozygous are clinically affected. CONCLUSION: This study provides a framework for scrutinizing variation along the complete intronic sequence of HCM-associated genes and prioritizing candidates for mechanistic and functional analysis. Our data suggest that deep intronic variation contributes to HCM phenotype.
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/genética
Variação Genética
Íntrons
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/genética
Proteínas de Transporte/genética
Criança
Conectina/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Linhagem
Polimorfismo de Nucleotídeo Único
Análise de Sequência de DNA
Vinculina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Connectin); 0 (TTN protein, human); 0 (VCL protein, human); 0 (myosin-binding protein C); 125361-02-6 (Vinculin); EC 2.7.11.1 (PRKAG2 protein, human); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182946


  10 / 1706 MEDLINE  
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[PMID]:28771489
[Au] Autor:Mademont-Soler I; Mates J; Yotti R; Espinosa MA; Pérez-Serra A; Fernandez-Avila AI; Coll M; Méndez I; Iglesias A; Del Olmo B; Riuró H; Cuenca S; Allegue C; Campuzano O; Picó F; Ferrer-Costa C; Álvarez P; Castillo S; Garcia-Pavia P; Gonzalez-Lopez E; Padron-Barthe L; Díaz de Bustamante A; Darnaude MT; González-Hevia JI; Brugada J; Fernandez-Aviles F; Brugada R
[Ad] Endereço:Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
[Ti] Título:Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.
[So] Source:PLoS One;12(8):e0181465, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. METHODS: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. RESULTS: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. CONCLUSIONS: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/genética
Variações do Número de Cópias de DNA
Testes Genéticos
Sequenciamento de Nucleotídeos em Larga Escala
[Mh] Termos MeSH secundário: Sequência de Bases
Proteínas de Ligação ao Cálcio/genética
Cardiomiopatia Hipertrófica/diagnóstico
Proteínas de Transporte/genética
Estudos de Coortes
Conectina/genética
Feminino
Heterozigoto
Seres Humanos
Masculino
Meia-Idade
Sarcômeros/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Carrier Proteins); 0 (Connectin); 0 (TTN protein, human); 0 (myosin-binding protein C); 0 (phospholamban)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181465



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