Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes
Karmouch, Jennifer; Zhou, Qiong Q.; Miyake, Christina Y.; Lombardi, Raffaella; Kretzschmar, Kai; Bannier-Hélaouët, Marie; Clevers, Hans; Wehrens, Xander H.T.; Willerson, James T.; Marian, Ali J.
(2017) Circulation Research, volume 121, issue 12, pp. 1346 - 1359
(Article)
Abstract
Rationale: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit
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cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes). Objective: To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. Methods and Results: Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4pos cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibroadipocytes, as in human arrhythmogenic cardiomyopathy. The mice exhibited palmoplantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. Conclusions: Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in patients with arrhythmogenic cardiomyopathy and cardiocutaneous syndromes.
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Keywords: arrhythmogenic right ventricular dysplasia, death, sudden, desmoplakins, desmosomes, neuroglia, Physiology, Cardiology and Cardiovascular Medicine
ISSN: 0009-7330
Publisher: Lippincott Williams & Wilkins
Note: Funding Information: We wish to acknowledge Alon R. Azares for his technical support with fluorescence-activated cell sorting. Q.Q. Zhou was supported by a scholarship from the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Funding Information: This work was supported, in part, by grants from National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (R01 HL088498 and 1R01HL132401), Leducq Foundation (14 CVD 03), George and Mary Josephine Hamman Foundation, and American Heart Association Beginning Grant in Aid (15BGIA25080008 to R. Lombardi). X.H.T. Wehrens was supported by grants from NIH (R01-HL089598, R01-HL091947, R01-HL117641, and R41-HL129570) and American Heart Association (13EIA14560061). K. Kretzschmar is supported by a VENI grant from the Netherlands Organisation for Scientific Research (NWO-ZonMW, 016.166.140) and a fellowship from the Human Frontier Science Program Organization (HFSPO, LT771/2015). Publisher Copyright: © 2017 American Heart Association, Inc.
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