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J Am Heart Assoc. 2018 Jan 6;7(1). pii: e006320. doi: 10.1161/JAHA.117.006320.

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.

Huang L1, Wu KH2,3,4,5, Zhang L1, Wang Q6, Tang S1, Wu Q1, Jiang PH3,4, Lin JJ7, Guo J8,9, Wang L8,9, Loh SH10,3,5, Cheng J11.

Author information

1
Department of Forensic Pathology, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, Guangdong, China.
2
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
3
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
4
Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
5
Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
6
Department of Biology, University of Iowa, Iowa City, IA Qinchuan.Wang@jhmi.edu shloh@mail.ndmctsgh.edu.tw chengjd@mail.sysu.edu.cn.
7
Department of Biology, University of Iowa, Iowa City, IA.
8
BGI-Shenzhen, Shenzhen, Guangdong, China.
9
China National GeneBank BGI-Shenzhen, Shenzhen, Guangdong, China.
10
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan Qinchuan.Wang@jhmi.edu shloh@mail.ndmctsgh.edu.tw chengjd@mail.sysu.edu.cn.
11
Department of Forensic Pathology, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, Guangdong, China Qinchuan.Wang@jhmi.edu shloh@mail.ndmctsgh.edu.tw chengjd@mail.sysu.edu.cn.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Brugada syndrome; Xirp proteins; cardiac conduction; rare variants; sudden cardiac death; sudden unexplained nocturnal death syndrome

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