RESUMO
Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.
Assuntos
Fibrilação Atrial/genética , Átrios do Coração/patologia , Mutação/genética , Cadeias Leves de Miosina/genética , Adulto , Animais , Animais Geneticamente Modificados , Fibrilação Atrial/diagnóstico por imagem , Sítios de Ligação , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Miofibrilas/patologia , Cadeias Leves de Miosina/química , Linhagem , Ligação Proteica , Estrutura Secundária de Proteína , Sarcômeros/patologia , Ultrassonografia , Peixe-ZebraRESUMO
Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
