Characterization of a Unique Form of Arrhythmic Cardiomyopathy Caused by Recessive Mutation in LEMD2

Nelly Abdelfatah; Ruping Chen; Henry J Duff; Colette M Seifer; Ilan Buffo; Cathleen Huculak; Stephanie Clarke; Robin Clegg; Davinder S Jassal; Paul M K Gordon; Carole Ober; Care4Rare Canada Consortium; Patrick Frosk; Brenda Gerull

doi:10.1016/j.jacbts.2018.12.001

Characterization of a Unique Form of Arrhythmic Cardiomyopathy Caused by Recessive Mutation in LEMD2

JACC Basic Transl Sci. 2019 Apr 29;4(2):204-221. doi: 10.1016/j.jacbts.2018.12.001. eCollection 2019 Apr.

Authors

Affiliations

¹ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
² Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
³ Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁴ Variety Children's Heart Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
⁵ Department of Medical Genetics, Alberta Health Services, Calgary, Alberta, Canada.
⁶ Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
⁷ Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
⁸ Cumming School of Medicine Centre for Health Genomics and Informatics, University of Calgary, Calgary, Alberta, Canada.
⁹ Department of Human Genetics, The University of Chicago, Chicago, Illinois.
¹⁰ Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
¹¹ Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.

Abstract

Nuclear envelope proteins have been shown to play an important role in the pathogenesis of inherited dilated cardiomyopathy. Here, we present a remarkable cardiac phenotype caused by a homozygous LEMD2 mutation in patients of the Hutterite population with juvenile cataract. Mutation carriers develop arrhythmic cardiomyopathy with mild impairment of left ventricular systolic function but severe ventricular arrhythmias leading to sudden cardiac death. Affected cardiac tissue from a deceased patient and fibroblasts exhibit elongated nuclei with abnormal condensed heterochromatin at the periphery. The patient fibroblasts demonstrate cellular senescence and reduced proliferation capacity, which may suggest an involvement of LEM domain containing protein 2 in chromatin remodeling processes and premature aging.

Keywords: ACM, arrhythmogenic cardiomyopathy; BANF, barrier to autointegration factor; CMR, cardiac magnetic resonance; DAPI, 4′,6′-diamidino-2-phenylindole; DCM, dilated cardiomyopathy; DNA, deoxyribonucleic acid; EMD, emerin; ICD, implantable cardioverter-defibrillator; LEMD2; LEMD2, LEM domain containing protein 2; LGE, late gadolinium enhancement; LMNA, lamin A/C; LV, left ventricular; NE, nuclear envelope; P, passage; PBS, phosphate-buffered saline; SAHF, senescence-associated heterochromatin foci; SNV, single nucleotide variant; chromatin remodeling; dilated cardiomyopathy; eGFP, enhanced green fluorescent protein; inner nuclear membrane; sudden death.