RESUMEN
BACKGROUND: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM. METHODS AND RESULTS: A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for alphaMyHC gene (MYH6) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure. CONCLUSIONS: This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.
Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Hipertrófica/genética , Mutación Missense , Cadenas Pesadas de Miosina/genética , Miosinas Ventriculares/genética , Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Hipertrófica/epidemiología , Estudios de Casos y Controles , Secuencia Conservada , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Heterocigoto , Humanos , Masculino , Epidemiología Molecular , Linaje , Sarcómeros/genética , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/genéticaRESUMEN
BACKGROUND: We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenegre syndrome), long-QT syndrome (LQT3), and Brugada syndrome. METHODS AND RESULTS: Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III. CONCLUSIONS: Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.
