title: A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation.
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.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Nathan
authors.initials: N
authors.lastname: Orr
authors.affiliation: Department of Medicine, Cardiovascular Research Institute and Division of Cardiology, University of California San Francisco, San Francisco, California 94158, USA.|Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Arnaout
authors.affiliation: Division of Cardiology, University Hospital, Western University, London, Ontario, Canada N6G 2V4.
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Gula
authors.affiliation: Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Danna A
authors.initials: DA
authors.lastname: Spears
authors.affiliation: Division of Cardiology, University Hospital, Western University, London, Ontario, Canada N6G 2V4.
authors.forename: Peter
authors.initials: P
authors.lastname: Leong-Sit
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Cardiology, University Hospital, Western University, London, Ontario, Canada N6G 2V4.
authors.forename: Wadea
authors.initials: W
authors.lastname: Tarhuni
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.|Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Reischauer
authors.affiliation: Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Chauhan
authors.affiliation: Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Matthew
authors.initials: M
authors.lastname: Borkovich
authors.affiliation: Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Uppal
authors.affiliation: Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Arnon
authors.initials: A
authors.lastname: Adler
authors.affiliation: Department of Medicine, Cardiovascular Research Institute and Division of Cardiology, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.affiliation: Department of Medicine, Cardiovascular Research Institute and Division of Cardiology, University of California San Francisco, San Francisco, California 94158, USA.|Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.|Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Didier Y R
authors.initials: DYR
authors.lastname: Stainier
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.|Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada M5G 2C4.|Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
mesh_terms: D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D001281:Atrial Fibrillation / Q000000981:diagnostic imaging / Q000235:genetics*; D001665:Binding Sites; D004562:Electrocardiography; D005260:Female; D006325:Heart Atria / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009210:Myofibrils / Q000473:pathology; D018994:Myosin Light Chains / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012518:Sarcomeres / Q000473:pathology; D014463:Ultrasonography; D015027:Zebrafish
chemical_list: C000599129:MYL4 protein, human; D050505:Mutant Proteins; D018994:Myosin Light Chains