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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adolescent
  • Adult
  • Animals
  • Asian Continental Ancestry Group / genetics
  • Atrioventricular Block / genetics
  • Atrioventricular Block / metabolism
  • Atrioventricular Block / physiopathology
  • Brugada Syndrome / ethnology*
  • Brugada Syndrome / genetics
  • Brugada Syndrome / metabolism
  • Brugada Syndrome / physiopathology
  • China / epidemiology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Death, Sudden, Cardiac / ethnology
  • Female
  • Genetic Predisposition to Disease
  • Heart Conduction System / metabolism
  • Heart Conduction System / physiopathology
  • Heart Rate
  • Humans
  • Kv1.5 Potassium Channel / metabolism
  • LIM Domain Proteins / genetics*
  • LIM Domain Proteins / metabolism
  • Male
  • Mice, Knockout
  • Middle Aged
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism
  • Risk Factors
  • Young Adult


  • DNA-Binding Proteins
  • Kcna5 protein, mouse
  • Kcne3 protein, mouse
  • Kv1.5 Potassium Channel
  • LIM Domain Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • Nuclear Proteins
  • Potassium Channels, Voltage-Gated
  • Scn5a protein, mouse
  • XIRP1 protein, human
  • XIRP2 protein, human