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ZFIN ID: ZDB-PUB-160414-17
A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation
Orr, N., Arnaout, R., Gula, L.J., Spears, D.A., Leong-Sit, P., Li, Q., Tarhuni, W., Reischauer, S., Chauhan, V.S., Borkovich, M., Uppal, S., Adler, A., Coughlin, S.R., Stainier, D.Y., Gollob, M.H.
Date: 2016
Source: Nature communications   7: 11303 (Journal)
Registered Authors: Reischauer, Sven, Stainier, Didier
Keywords: Atrial fibrillation, Disease genetics, Mutation
MeSH Terms:
  • Adult
  • Animals
  • Animals, Genetically Modified
  • Atrial Fibrillation/diagnostic imaging
  • Atrial Fibrillation/genetics*
  • Binding Sites
  • Electrocardiography
  • Female
  • Heart Atria/pathology*
  • Humans
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutant Proteins/chemistry
  • Mutant Proteins/genetics
  • Mutation/genetics*
  • Myofibrils/pathology
  • Myosin Light Chains/chemistry
  • Myosin Light Chains/genetics*
  • Pedigree
  • Protein Binding
  • Protein Structure, Secondary
  • Sarcomeres/pathology
  • Ultrasonography
  • Zebrafish
PubMed: 27066836 Full text @ Nat. Commun.
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.