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[PMID]:29178656
[Au] Autor:Wada Y; Ohno S; Aiba T; Horie M
[Ad] Endereço:Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
[Ti] Título:Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
[So] Source:Mol Genet Genomic Med;5(6):639-651, 2017 11.
[Is] ISSN:2324-9269
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy mainly caused by desmosomal gene mutation. More than half of Caucasian probands have desmosomal mutations, which lead to earlier onset of ventricular arrhythmias. Among non-Caucasians, the genetic background of ARVD/C probands and its prognostic impact remain unclear. METHODS AND RESULTS: We genotyped 99 unrelated Japanese ARVD/C probands for plakophilin 2 (PKP2), desmoglein 2 (DSG2), desmoplakin (DSP), and desmocollin 2 (DSC2) between 2005 and 2014. Seventy-five probands who fulfilled "definite" category according to the 2010 Task Force Criteria (TFC) were enrolled and followed up for 6.4 years. Sixty-four percent of probands had desmosomal mutations; DSG2 was predominant (48% of mutations) followed by PKP2 (38%). DSG2 mutations were almost missense, whereas over 90% of PKP2 mutations were truncating mutations. Lethal ventricular arrhythmias (VAs, sustained ventricular tachycardia/fibrillation) occurred in 57% of probands as the first manifestation and 71% at the end of follow-up. Five died during follow-up. Truncating mutation carriers exhibited earlier lethal VAs onset compared to missense mutation carriers or mutation negatives (age at onset 35 ± 12, 49 ± 16, and 50 ± 19 years, respectively, P < 0.05 in each). Cox proportional hazard analysis revealed for the first time that, compared to mutation negatives, truncating mutation carriers had higher risk for lethal VAs, and especially for onset by their 40s, in an age-dependent manner (RR = 4.6, P < 0.01 by their 40s; RR = 2.9, P = 0.01 by their 50s). CONCLUSION: The genetic background of Japanese ARVD/C probands is distinct from that of Caucasian probands, leading to distinct prognosis. The most affected gene mutations in Japanese probands were missense mutations in DSG2 leading to modest outcome, whereas PKP2 truncating mutations were the second most and might be a strong marker for lethal VAs in non-Caucasian Japanese ARVD/C probands.
[Mh] Termos MeSH primário: Displasia Arritmogênica Ventricular Direita/genética
Grupo com Ancestrais do Continente Asiático/genética
[Mh] Termos MeSH secundário: Adulto
Displasia Arritmogênica Ventricular Direita/diagnóstico
Displasia Arritmogênica Ventricular Direita/mortalidade
Estudos de Coortes
Desmocolinas/genética
Desmogleína 2/genética
Desmoplaquinas/genética
Feminino
Seguimentos
Mutação da Fase de Leitura
Estudos de Associação Genética
Patrimônio Genético
Genótipo
Heterozigoto
Seres Humanos
Japão
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Mutação de Sentido Incorreto
Razão de Chances
Fenótipo
Placofilinas/genética
Modelos de Riscos Proporcionais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DSC2 protein, human); 0 (Desmocollins); 0 (Desmoglein 2); 0 (Desmoplakins); 0 (Plakophilins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/mgg3.311


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[PMID]:29253866
[Au] Autor:Klauke B; Gaertner-Rommel A; Schulz U; Kassner A; Zu Knyphausen E; Laser T; Kececioglu D; Paluszkiewicz L; Blanz U; Sandica E; van den Bogaerdt AJ; van Tintelen JP; Gummert J; Milting H
[Ad] Endereço:Erich and Hanna Klessmann Institute for Cardiovascular Research & Development (EHKI), Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
[Ti] Título:High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation.
[So] Source:PLoS One;12(12):e0189489, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the MYH7, MYL2, MYL3, NEXN, TNNC1, TNNI3, DES, LMNA, PKP2, PLN, RBM20, TTN, and CRYAB genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous PKP2-missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age.
[Mh] Termos MeSH primário: Cardiomiopatias/diagnóstico
Cardiomiopatias/genética
Mutação
Placofilinas/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Criança
Estudos de Coortes
Saúde da Família
Feminino
Genótipo
Insuficiência Cardíaca/genética
Transplante de Coração
Sequenciamento de Nucleotídeos em Larga Escala
Homozigoto
Seres Humanos
Recém-Nascido
Masculino
Meia-Idade
Mutação de Sentido Incorreto
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PKP2 protein, human); 0 (Plakophilins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189489


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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


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[PMID]:28740174
[Au] Autor:Cerrone M; Montnach J; Lin X; Zhao YT; Zhang M; Agullo-Pascual E; Leo-Macias A; Alvarado FJ; Dolgalev I; Karathanos TV; Malkani K; Van Opbergen CJM; van Bavel JJA; Yang HQ; Vasquez C; Tester D; Fowler S; Liang F; Rothenberg E; Heguy A; Morley GE; Coetzee WA; Trayanova NA; Ackerman MJ; van Veen TAB; Valdivia HH; Delmar M
[Ad] Endereço:Leon H Charney Division of Cardiology, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
[Ti] Título:Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm.
[So] Source:Nat Commun;8(1):106, 2017 07 24.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for Ca 1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Coração/fisiologia
Miocárdio/metabolismo
Placofilinas/genética
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Arritmias Cardíacas/genética
Arritmias Cardíacas/fisiopatologia
Western Blotting
Expressão Gênica
Coração/fisiopatologia
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Confocal
Miocárdio/citologia
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/fisiologia
Placofilinas/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Plakophilins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00127-0


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[PMID]:29038103
[Au] Autor:Pilichou K; Lazzarini E; Rigato I; Celeghin R; De Bortoli M; Perazzolo Marra M; Cason M; Jongbloed J; Calore M; Rizzo S; Regazzo D; Poloni G; Iliceto S; Daliento L; Delise P; Corrado D; Van Tintelen JP; Thiene G; Rampazzo A; Basso C; Bauce B; Lorenzon A; Occhi G
[Ad] Endereço:From the Departments of Cardiac, Thoracic, and Vascular Sciences (K.P., E.L., I.R., R.C., M.P.M., M.C., S.R., S.I., L.D., D.C., G. T., C.B., B.B.) and Medicine (D.R.), University of Padua, Italy; Department of Biology, University of Padua, Italy (M.D.B., M.C., G.P., A.R., A.L., G.O.); University Med
[Ti] Título:Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients.
[So] Source:Circ Arrhythm Electrophysiol;10(10), 2017 Oct.
[Is] ISSN:1941-3084
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 ( ) gene, 2 a deletion of only exon 4, 1 a deletion of the exons 6 to 11, 1 a duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 ( ) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both and genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. CONCLUSIONS: Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.
[Mh] Termos MeSH primário: Displasia Arritmogênica Ventricular Direita/genética
Desmossomos/genética
Rearranjo Gênico
[Mh] Termos MeSH secundário: Potenciais de Ação
Adolescente
Adulto
Idoso
Displasia Arritmogênica Ventricular Direita/diagnóstico
Displasia Arritmogênica Ventricular Direita/fisiopatologia
Variações do Número de Cópias de DNA
Análise Mutacional de DNA
Desmocolinas/genética
Desmogleína 2/genética
Desmoplaquinas/genética
Eletrocardiografia
Técnicas Eletrofisiológicas Cardíacas
Feminino
Deleção de Genes
Dosagem de Genes
Duplicação Gênica
Estudos de Associação Genética
Marcadores Genéticos
Predisposição Genética para Doença
Frequência Cardíaca
Hereditariedade
Seres Humanos
Itália
Masculino
Meia-Idade
Reação em Cadeia da Polimerase Multiplex
Linhagem
Fenótipo
Placofilinas/genética
Mutação Puntual
Fatores de Risco
Adulto Jovem
gama Catenina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DSC2 protein, human); 0 (DSG2 protein, human); 0 (DSP protein, human); 0 (Desmocollins); 0 (Desmoglein 2); 0 (Desmoplakins); 0 (Genetic Markers); 0 (JUP protein, human); 0 (PKP2 protein, human); 0 (Plakophilins); 0 (gamma Catenin)
[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:171018
[St] Status:MEDLINE


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[PMID]:28767663
[Au] Autor:Fedida J; Fressart V; Charron P; Surget E; Hery T; Richard P; Donal E; Keren B; Duthoit G; Hidden-Lucet F; Villard E; Gandjbakhch E
[Ad] Endereço:INSERM, UMR_S1166, ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
[Ti] Título:Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
[So] Source:PLoS One;12(8):e0181840, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands. RESULTS: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1-7 and exon 1-14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands. CONCLUSION: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes.
[Mh] Termos MeSH primário: Displasia Arritmogênica Ventricular Direita/genética
Redes Reguladoras de Genes
Estudo de Associação Genômica Ampla/métodos
Análise de Sequência de DNA/métodos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Complexo IV da Cadeia de Transporte de Elétrons/genética
Exoma
Feminino
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Linhagem
Placofilinas/genética
Presenilina-1/genética
Proteínas de Ligação a RNA/genética
Deleção de Sequência
Transativadores/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EYA4 protein, human); 0 (PKP2 protein, human); 0 (PSEN1 protein, human); 0 (Plakophilins); 0 (Presenilin-1); 0 (RNA-Binding Proteins); 0 (Trans-Activators); 0 (ribonucleic acid binding motif protein 20, human); EC 1.9.3.1 (COX15 protein, human); EC 1.9.3.1 (Electron Transport Complex IV)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181840


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[PMID]:28507225
[Au] Autor:Lee P; Jiang S; Li Y; Yue J; Gou X; Chen SY; Zhao Y; Schober M; Tan M; Wu X
[Ad] Endereço:Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
[Ti] Título:Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis.
[So] Source:EMBO J;36(13):1963-1980, 2017 Jul 03.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either or impairs skin differentiation and enhances epidermal carcinogenesis Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.
[Mh] Termos MeSH primário: Diferenciação Celular
Queratinócitos/fisiologia
Placofilinas/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas Serina-Treonina Quinases/metabolismo
Pele/citologia
Células-Tronco/fisiologia
[Mh] Termos MeSH secundário: Animais
Carcinogênese
Células Cultivadas
Perfilação da Expressão Gênica
Camundongos
Camundongos Knockout
Fosforilação
Proteoma/análise
Neoplasias Cutâneas
Transplante de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pkp1 protein, mouse); 0 (Plakophilins); 0 (Proteome); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Ripk4 protein, mouse)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201695679


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[PMID]:28253841
[Au] Autor:Bainbridge MN; Li L; Tan Y; Cheong BY; Marian AJ
[Ad] Endereço:Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
[Ti] Título:Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy.
[So] Source:BMC Med Genet;18(1):24, 2017 Mar 03.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Advances in the nucleic acid sequencing technologies have ushered in the era of genetic-based "precision medicine". Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy. CASE PRESENTATION: We report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium. CONCLUSIONS: The patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based "precision medicine".
[Mh] Termos MeSH primário: Cardiomiopatia Hipertrófica/genética
[Mh] Termos MeSH secundário: Cardiomiopatia Hipertrófica/diagnóstico
Cardiomiopatia Hipertrófica/diagnóstico por imagem
DNA/química
DNA/isolamento & purificação
DNA/metabolismo
Análise Mutacional de DNA
Ecocardiografia
Feminino
Coração/diagnóstico por imagem
Ventrículos do Coração/diagnóstico por imagem
Seres Humanos
Imagem por Ressonância Magnética
Meia-Idade
Linhagem
Fenótipo
Placofilinas/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PKP2 protein, human); 0 (Plakophilins); 9007-49-2 (DNA)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0385-8


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[PMID]:28154962
[Au] Autor:Hart ML; Rusch E; Kaupp M; Nieselt K; Aicher WK
[Ad] Endereço:Laboratory for Cell & Tissue Engineering, Department of Orthopedics and Trauma Surgery, Medical Center - Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany. melaniehar@gmail.com.
[Ti] Título:Expression of Desmoglein 2, Desmocollin 3 and Plakophilin 2 in Placenta and Bone Marrow-Derived Mesenchymal Stromal Cells.
[So] Source:Stem Cell Rev;13(2):258-266, 2017 Apr.
[Is] ISSN:1558-6804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many controversial results exist when comparing mesenchymal stromal cells (MSCs) derived from different sources. Reasons include not only variables in tissue origin, but also methods of cell preparation or choice of expansion media which can strongly influence the expression and hence, function of the cells. In this short report we aimed to investigate the expression of the cell anchoring proteins desmoglein 2, desmocollin 3 and plakophilin 2 in early passage placenta-derived MSCs of fetal (fetal pMSCs) and maternal (maternal pMSCs) origins versus adult bone marrow-derived MSCs (bmMSCs) that were expanded and cultured under the same good manufacturing practice (GMP) conditions. Comprehensive gene expression microarray analysis profiling indicated differential expression of these genes in the different MSC-derived types with fetal pMSCs expressing the highest levels of PKP2, DSC3 and DSG2, followed by maternal pMSCs, while bmMSCs expressed the lowest levels. A higher expression of PKP2 and DSC3 genes in fetal pMSCs was confirmed by qRT-PCR suggesting neonatal increases in the expression of these desmosomal genes vs. adult MSCs. Intracellular desmocollin 3 and desmoglein 2 expression was observed by flow cytometry and cytoplasmic plakophilin 2 by immunofluorescence in all three MSC sources. These data suggest that fetal pMSCs, maternal pMSCs and bmMSCs may anchor intermediate filaments to the plasma membrane via desmocollin 3, desmoglein 2 and plakophilin 2.
[Mh] Termos MeSH primário: Desmocolinas/genética
Desmogleína 2/genética
Perfilação da Expressão Gênica/métodos
Células Mesenquimais Estromais/metabolismo
Placenta/metabolismo
Placofilinas/genética
[Mh] Termos MeSH secundário: Adulto
Células da Medula Óssea/metabolismo
Diferenciação Celular/genética
Proliferação Celular/genética
Células Cultivadas
Desmocolinas/metabolismo
Desmogleína 2/metabolismo
Feminino
Feto/citologia
Imunofluorescência
Células HeLa
Seres Humanos
Análise de Sequência com Séries de Oligonucleotídeos/métodos
Placenta/citologia
Placofilinas/metabolismo
Gravidez
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DSC3 protein, human); 0 (Desmocollins); 0 (Desmoglein 2); 0 (PKP2 protein, human); 0 (Plakophilins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1007/s12015-016-9710-4


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[PMID]:27030002
[Au] Autor:Ramond F; Janin A; Di Filippo S; Chanavat V; Chalabreysse L; Roux-Buisson N; Sanlaville D; Touraine R; Millat G
[Ad] Endereço:Genetics Department, CHU-Hôpital Nord, Saint-Etienne, France.
[Ti] Título:Homozygous PKP2 deletion associated with neonatal left ventricle noncompaction.
[So] Source:Clin Genet;91(1):126-130, 2017 Jan.
[Is] ISSN:1399-0004
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:Left ventricular noncompaction cardiomyopathy (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. A NGS workflow, based on a panel of 95 genes developed for sequencing most prevalent sudden cardiac death-causing genes, was used to make a rapid and costless molecular diagnosis in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure. For the first time, a total homozygous PKP2 deletion was identified. This molecular defect was further confirmed by MLPA and array-comparative genomic hybridization (CGH). Heterozygous PKP2 mutations are usually reported in a significant proportion of Arrhythmogenic Right Ventricular Cardiomyopathy cases. Our results show, for the first time, the involvement of PKP2 in severe cardiomyopathy with ventricular non compaction.
[Mh] Termos MeSH primário: Cardiomiopatias/genética
Deleção de Genes
Predisposição Genética para Doença/genética
Placofilinas/genética
[Mh] Termos MeSH secundário: Cardiomiopatias/patologia
Hibridização Genômica Comparativa/métodos
Consanguinidade
Saúde da Família
Feminino
Ventrículos do Coração/anormalidades
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Homozigoto
Seres Humanos
Recém-Nascido
Masculino
Linhagem
Irmãos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PKP2 protein, human); 0 (Plakophilins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160401
[St] Status:MEDLINE
[do] DOI:10.1111/cge.12780



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