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J Am Heart Assoc. 2017 Oct 28;6(11). pii: e007030. doi: 10.1161/JAHA.117.007030.

Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.

Peng W1, Li M2,3,4, Li H1, Tang K1, Zhuang J1, Zhang J5, Xiao J5, Jiang H5, Li D6, Yu Y7, Sham PC2,3, Nattel S8,9,10,11, Xu Y12.

Author information

1
Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
2
Department of Psychiatry, Centre for Genomic Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
3
State Key Laboratory for Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
4
Department of Medical Genetics, Center for Genome Research, Center for Precision Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
5
BGI-Shenzhen, Shenzhen, China.
6
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
7
Shanghai Traditional Chinese Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
8
Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada.
9
Université de Montréal, Montreal, Quebec, Canada.
10
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
11
Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany.
12
Department of Cardiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China xuyawei@tongji.edu.cn.

Abstract

BACKGROUND:

There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (MYL4), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of MYL4 in atrial cardiomyopathy.

METHODS AND RESULTS:

Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of MYL4 (c.31G>A [p.E11K]) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with MYL4 mutation knock-in confirmed the causative role of the mutation. MYL4 knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both MYL4 p.E11K knock-in rats and MYL4 knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of MYL4 p.E11K mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.

CONCLUSIONS:

Loss-of-function MYL4 gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify MYL4 as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.

KEYWORDS:

animal models; arrhythmia; atrial fibrillation; cardiomyopathy; fibrosis; genetics

PMID:
29080865
PMCID:
PMC5721782
DOI:
10.1161/JAHA.117.007030
[Indexed for MEDLINE]
Free PMC Article

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