Dong Tao, Zhao Yan, Zhang Meng, Lang Wei-Ya, Liu Dan-Yang, Zhang Ke-Shuang, Wang Yue-Jing, Li Lin, Lian Jie, Yao Hong-Bo, Zhang Hai-Yan, Jin Hai-Feng, Lu Tong, Shen Lei, Yue Li-Ling, Lin Yan
Department of Anatomy, Histology and Embryology, Basic Medicine School, Qiqihar Medical University, Qiqihar, 161006, Heilongjiang, China.
Heilongjiang Provincial Key Laboratory of Food & Medicine Homology and Metabolic Disease Prevention, Qiqihar, 161006, Heilongjiang, China.
Sci Rep. 2025 Aug 20;15(1):30600. doi: 10.1038/s41598-025-16406-6.
In clinical settings, patients with α-1-syntrophin point mutations are often associated with rare arrhythmias, including Long QT syndrome, Brugada syndrome, and sudden infant death syndrome. Previous studies on α-1-syntrophin have predominantly utilized nonhuman cardiomyocyte models. This study aims to elucidate the phenotype of α-1-syntrophin deficiency using human cardiomyocytes. Using CRISPR/Cas9 technology, we generated SNTA1 knockout (KO) embryonic stem cell line, which were subsequently differentiated into cardiomyocytes using 2D differentiation method. Genotype analysis identified an adenine (A) insertion in the second exon of SNTA1, resulting in a premature stop codon at the 149th amino acid position and truncation within the PDZ domain. SNTA1-deficient cardiomyocytes exhibited a shortened field potential duration (FPD) and slower conduction velocity, as detected by micro electrode array analysis. Immunofluorescence analysis further revealed disorganized distribution of Nav1.5 in SNTA1-deficient cardiomyocytes. SNTA1 is a susceptibility locus for arrhythmias and plays a critical role as an essential auxiliary protein in the proper localization of Nav1.5 in human cardiomyocytes.
在临床环境中，α-1- syntrophin点突变的患者常与罕见的心律失常相关，包括长QT综合征、Brugada综合征和婴儿猝死综合征。先前关于α-1- syntrophin的研究主要使用非人类心肌细胞模型。本研究旨在利用人类心肌细胞阐明α-1- syntrophin缺乏的表型。使用CRISPR/Cas9技术，我们构建了SNTA1基因敲除（KO）胚胎干细胞系，随后使用二维分化方法将其分化为心肌细胞。基因型分析确定在SNTA1的第二个外显子中有一个腺嘌呤（A）插入，导致在第149个氨基酸位置出现过早的终止密码子，并在PDZ结构域内截短。微电极阵列分析检测到，缺乏SNTA1的心肌细胞表现出缩短的场电位持续时间（FPD）和较慢的传导速度。免疫荧光分析进一步揭示了缺乏SNTA1的心肌细胞中Nav1.5的分布紊乱。SNTA1是心律失常的一个易感位点，作为一种重要的辅助蛋白，在人类心肌细胞中Nav1.5的正确定位中起关键作用。
