Author + information
- Received October 4, 2018
- Revision received November 2, 2018
- Accepted December 3, 2018
- Published online April 29, 2019.
- Nelly Abdelfatah, PHDa,∗,
- Ruping Chen, PHDb,∗,
- Henry J. Duff, MDa,
- Colette M. Seifer, MBc,
- Ilan Buffo, MDd,
- Cathleen Huculak, MSce,
- Stephanie Clarke, MScf,
- Robin Clegg, MDg,
- Davinder S. Jassal, MDc,
- Paul M.K. Gordon, PHDh,
- Carole Ober, PHDi,
- Care4Rare Canada Consortium,
- Patrick Frosk, PHD, MDf,j and
- Brenda Gerull, MDa,b,k,∗ ()
- aDepartment of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- bComprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
- cSection of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- dVariety Children’s Heart Centre, University of Manitoba, Winnipeg, Manitoba, Canada
- eDepartment of Medical Genetics, Alberta Health Services, Calgary, Alberta, Canada
- fDepartment of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- gDepartment of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- hCumming School of Medicine Centre for Health Genomics and Informatics, University of Calgary, Calgary, Alberta, Canada
- iDepartment of Human Genetics, The University of Chicago, Chicago, Illinois
- jDepartment of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- kDepartment of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
- ↵∗Address for correspondence:
Dr. Brenda Gerull, Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.
• The homozygous c.38T>G mutation in the LEMD2 gene causes arrhythmic cardiomyopathy with bilateral juvenile cataract in the Hutterite population.
• The cardiac phenotype is characterized by localized inferior and inferolateral fibrosis of the left ventricle and mild impairment of left ventricular systolic function but severe ventricular arrhythmias leading to sudden cardiac death.
• Affected heart tissue and fibroblasts exhibit abnormally shaped nuclei with condensed peripheral heterochromatin.
• Functional assays on affected fibroblasts show decreased proliferation capacity, cellular senescence, and a prolonged G1 phase, suggesting premature aging and cellular senescence in proliferating cells.
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.
↵∗ Drs. Abdelfatah and Chen contributed equally to this work and are joint first authors.
This research was supported by the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, and the Ontario Genomics Institute with additional funding provided to the predecessor of Care4Rare, FORGE Canada, by Genome Quebec, Genome British Columbia, and the McLaughlin Centre to Dr. Frosk. The study was further supported by Alberta Innovates Health Solutions (grant no. 201200822), the Canadian Institutes of Health Research (FRN: 123351), and the Libin Cardiovascular Institute of Alberta to Drs. Gerull and Abdelfatah. Support was also provided by the German Ministry of Education and Research, Berlin, Germany (grant no. 01EO1504 to Dr. Gerull). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All other authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received October 4, 2018.
- Revision received November 2, 2018.
- Accepted December 3, 2018.
- 2019 The Authors