RESUMO
Restrictive cardiomyopathy (RCM) is one of the rarest cardiac disorders, with a very poor prognosis, and heart transplantation is the only long-term treatment of choice. We reported that a Korean family presented different cardiomyopathies, such as idiopathic RCM and hypertrophic cardiomyopathy (HCM), caused by the same MYBPC3 mutation in different individuals. A 74-year-old male was admitted for the evaluation of exertional dyspnea, palpitations, and pitting edema in both legs for several months. Transthoracic echocardiography (TTE) showed RCM with biatrial enlargement and pericardial effusion. Cardiac magnetic resonance (CMR) images revealed normal left ventricular chamber size, borderline diffuse left ventricular hypertrophy and very large atria. In contrast to the proband, CMR images showed asymmetric septal hypertrophy of the left ventricle, consistent with a diagnosis of HCM in the proband's two daughters. Of the five heterozygous variants identified as candidate causes of inherited cardiomyopathy by whole exome sequencing in the proband, Sanger sequencing confirmed the presence of a heterozygous frameshift mutation (NM_000256.3:c.3313_3314insGG; p.Ala1105Glyfs*85) in MYBPC3 in the proband and his affected daughters, but not in his unaffected granddaughter. There is clinical and genetic overlap of HCM with restrictive physiology and RCM, especially when HCM is combined with severe myocardial fibrosis. Family screening with genetic testing and CMR imaging could be excellent tools for the evaluation of idiopathic RCM.
Assuntos
Cardiomiopatia Hipertrófica Familiar , Mutação da Fase de Leitura , Idoso , Proteínas de Transporte/genética , Humanos , Masculino , Mutação , Linhagem , Fenótipo , República da CoreiaRESUMO
BACKGROUND: Mutations in MYBPC3 are the most common cause of hypertrophic cardiomyopathy (HCM). These mutations produce dysfunctional protein that is quickly degraded and not incorporated in the myofilaments. Most patients are heterozygous and allelic expression differs between cells. We hypothesized that this would lead to cell-to-cell variation in cardiac myosin binding protein-C (cMyBP-C, encoded by MYBPC3 gene) protein levels. METHODS: Twelve HCM patients were included (six had no sarcomere mutations (HCMsmn) and served as the control group and six harbored mutations in the MYBPC3 gene (MYBPC3mut). Western blot and RNA sequencing analysis of cardiac tissue lysates were performed to detect overall cMyBP-C protein and mRNA levels. Cellular expression of cMyBP-C and α-actin was obtained by immunofluorescence staining. Quantification of cell-to-cell variation of cMyBP-C expression between cardiomyocytes was measured by determining the ratio of cMyBP-C:α-actin stained area of each cell. RESULTS: Protein and mRNA analysis revealed significantly reduced cMyBP-C levels in MYBPC3mut patients compared with HCMsmn patients (0.73⯱â¯0.09 vs. 1.0⯱â¯0.15, pâ¯<â¯.05; 162.3⯱â¯16.4 vs. 326.2⯱â¯41.9 RPKM, pâ¯=â¯.002), without any sign of truncated proteins. Immunofluorescence staining of individual cardiomyocytes in HCMsmn patients demonstrated homogenous and equal cMyBP-C:α-actin staining ratio. In contrast, MYBPC3mut patients demonstrated inhomogeneous staining patterns with a large intercellular variability per patient. Coefficient of variance for cMyBP-C/α-actin staining for each patient showed a significant difference between both groups (17.30⯱â¯4.08 vs. 5.18⯱â¯0.65% in MYBPC3mut vs. HCMsmn, pâ¯=â¯.02). CONCLUSION: This is the first study to demonstrate intercellular variation of myofilament cMyBP-C protein expression within the myocardium from HCM patients with heterozygous MYBPC3 mutations.
Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Regulação da Expressão Gênica , Mutação , Miofibrilas/genética , Idoso , Alelos , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/metabolismo , Proteínas de Transporte/metabolismo , Feminino , Imunofluorescência , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). METHODS: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. RESULTS: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. CONCLUSIONS: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age.