A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation

Nat Commun. 2016 Apr 12;7:11303. doi: 10.1038/ncomms11303.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Mutant Proteins
  • Myosin Light Chains
  • myosin light chain 4, human