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
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine, The University of Texas Health Sciences Center, Houston (J.K., Q.Q.Z., R.L., J.T.W., A.J.M.); Texas Heart Institute, Houston (J.T.W., A.J.M.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (C.Y.M., X.H.T.W.); Department of Pediatrics, Texas Children Hospital, Houston (C.Y.M.); Hubrecht Institute, University Medical Center, Utrecht, The Netherlands (K.K., M.B.-H., H.C.); Royal Netherlands Academy of Arts and Sciences and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (H.C.); and École Normale Supérieure de Lyon, France (M.B.-H.).
Circ Res. 2017 Dec 8;121(12):1346-1359. doi: 10.1161/CIRCRESAHA.117.311876. Epub 2017 Oct 10.
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 (desmoplakin) and (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes).
To determine phenotypic consequences of deletion of in a subset of cells common to the heart and skin.
Expression of CSPG4 (chondroitin sulfate proteoglycan 4) was detected in epidermal keratinocytes and the cardiac conduction system. CSPG4 cells constituted ≈5.6±3.3% of the nonmyocyte cells in the mouse heart. Inducible postnatal deletion of under the transcriptional control of the 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 .
Deletion of 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.
致心律失常性心肌病主要由编码桥粒蛋白的基因突变引起。室性心律失常是主要且通常较早出现的表现，而心肌纤维脂肪变性是病理标志。纯合子（桥粒斑蛋白）和（连接蛋白桥粒芯蛋白）突变导致一部分致心律失常性心肌病患者出现心律失常、功能障碍、掌跖角化病和毛发异常（心脏皮肤综合征）。
确定在心脏和皮肤共有的一部分细胞中缺失的表型后果。
在表皮角质形成细胞和心脏传导系统中检测到硫酸软骨素蛋白聚糖4（CSPG4）的表达。CSPG4细胞约占小鼠心脏非心肌细胞的5.6±3.3%。在CSPG4基因座的转录控制下，出生后可诱导性缺失导致室性心律失常、心房颤动、房室传导缺陷，并在4月龄时死亡。心律失常早期出现，且无心脏功能障碍和过多的心脏纤维脂肪细胞，如同人类致心律失常性心肌病。这些小鼠表现出掌跖角化病和进行性脱发，最终导致全秃，这与角质形成细胞的增殖加速和终末分化受损有关。该表型类似于由纯合子突变引起的人类心脏皮肤综合征。
在CSPG4基因座的转录调控下缺失导致在无心脏功能障碍或纤维脂肪变性的情况下出现致命性心律失常、掌跖角化病和脱发，类似于人类心脏皮肤综合征。这些发现为致心律失常性心肌病和心脏皮肤综合征患者早期心律失常提供了细胞基础。
