Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes.
Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes.
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DOI：
10.1161/circresaha.117.311876
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发表时间：
2017-12-08
影响因子：
20.1
通讯作者：
Marian AJ
中科院分区：
文献类型：
--
作者：
Karmouch J;Zhou QQ;Miyake CY;Lombardi R;Kretzschmar K;Bannier-Hélaouët M;Clevers H;Wehrens XHT;Willerson JT;Marian AJ
致心律失常性心肌病 (ACM) 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的、典型的早期表现，而心肌纤维脂肪变性是其病理标志。纯合 DSP（桥粒蛋白）和 JUP（斑球蛋白）突变导致一部分 ACM 患者表现出心律失常和功能障碍、掌跖角化症和毛发异常（心皮肤综合征）。确定心脏和皮肤常见细胞子集中 Dsp 缺失的表型后果。在表皮角质形成细胞和心脏传导系统 (CCS) 中检测到硫酸软骨素蛋白多糖 4 (CSPG4) 的表达。 CSPG4pos 细胞约占小鼠心脏中非肌细胞的 5.6±3.3%。出生后在 Cspg4 位点转录控制下诱导性 Dsp 缺失会导致室性心律失常、心房颤动、房室传导缺陷和 4 个月大时死亡。心律失常发生得很早，并且没有心脏功能障碍和过量的心脏纤维脂肪细胞，如人类 ACM 中那样。小鼠表现出掌跖角化症和进行性脱发，导致全秃，这与角质形成细胞增殖加速和终末分化受损有关。该表型与 DSP 纯合突变引起的人类心皮肤综合征相似。 CSPG4位点转录调控下的Dsp缺失会导致致命性心律失常，但没有心功能障碍或纤维脂肪病、掌跖角化症和脱发，类似于人类心皮肤综合征。这些发现为 ACM 患者早期心律失常和心皮肤综合征提供了细胞基础。
Arrhythmogenic cardiomyopathy (ACM) 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 (plakoglobin) mutations are responsible for a subset of ACM patients that exhibit cardiac arrhythmias and dysfunction, palmo-planter keratosis, and hair abnormalities (cardiocutaneous syndromes). To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. Expression of chondroitin sulfate proteoglycan 4 (CSPG4) was detected in epidermal keratinocytes and the cardiac conduction system (CCS). CSPG4pos cells constituted ~ 5.6±3.3% of the non-myocyte cells in the mouse heart. Inducible post-natal 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 fibro-adipocytes, as in human ACM. The mice exhibited palmo-plantar 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. 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 ACM patients and cardiocutaneous syndromes.