Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.
Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.
复制标题
Xirp 蛋白在心脏传导中的关键作用及其在中国汉族人群不明原因夜间死亡综合征和布鲁格达综合征中鉴定的罕见变异。
DOI：
10.1161/jaha.117.006320
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发表时间：
2018-01-06
影响因子：
5.4
通讯作者：
Cheng J
中科院分区：
文献类型：
--
作者：
Huang L;Wu KH;Zhang L;Wang Q;Tang S;Wu Q;Jiang PH;Lin JJ;Guo J;Wang L;Loh SH;Cheng J
不明原因夜间猝死综合征（SUNDS）是一种病因不明的尸检阴性疾病。心律失常与SUNDS有关。已证明椎间盘组件的突变/缺陷会导致心律失常。人心肌病相关1（XIRP 1）和3（XIRP 2）是嵌入盘相关的，含Xin重复序列的蛋白质。小鼠Xirp 1是必需的闰盘的完整性和瞬时外向和延迟整流钾离子通道的表面表达，而小鼠Xirp 2是必需的Xirp 1闰盘定位。因此，XIRP 1和XIRP 2可能是SUNDS的潜在致病基因。我们在中国汉族人群中对134例散发性SUNDS患者和22例Brugada综合征（BrS）患者进行了XIRP基因筛查。我们在SUNDS受害者中发现了16种罕见变体（其中6种通过计算机模拟预测为有害），包括一种新型变体XIRP 2-E215 K。在BrS病例中还检测到4种罕见变异（2种经计算机模拟预测为有害），包括一种新型变异XIRP 2-L2718 P。有趣的是，在这20种变异中，我们检测到了2种可能的致病变异：一种无义变异（XIRP 2-Q2875*）和一种移码变异（XIRP 2-T2238 QfsX 7）。分析可用的Xirp 2敲除小鼠，我们进一步发现没有Xirp 2的小鼠心脏表现出延长的PR和QT间期、缓慢的传导速度、房室传导阻滞和异常的结下心室传导系统。全细胞膜片钳检测到Xirp 2 −/−心肌细胞中离子电流的改变，与免疫共沉淀中观察到的Xirp 2和Nav1.5/Kv1.5之间的相关性一致。这是第一份报告，确定了可能致病XIRP罕见变异的致炎性疾病，如SUNDS和Brugada综合征，并显示了Xirp 2在心脏传导中的关键作用。
Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy‐associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc–associated, Xin repeats‐containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS. We genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2‐E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2‐L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2‐Q2875*) and a frameshift variant (XIRP2‐T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole‐cell patch‐clamp detected altered ionic currents in Xirp2 −/− cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co‐immunoprecipitation. This is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction.
影响因子：
3.7
作者：
Grosskurth, Shaun E.;Bhattacharya, Debashish;Wang, Qinchuan;Lin, Jim Jung-Ching
通讯作者：
Lin, Jim Jung-Ching