Mutation in Nuclear Pore Component NUP155 Leads to Atrial Fibrillation and Early Sudden Cardiac Death

Xianqin Zhang, Shenghan Chen, Shin Yoo, Susmita Chakrabarti, Teng Zhang, Tie Ke, Carlos Oberti, Sandro L. Yong, Fang Fang, Lin Li, Roberto de la Fuente, Lejin Wang, Qiuyun Chen, Qing Kenneth Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

Atrial fibrillation (AF) is the most common form of sustained clinical arrhythmia. We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood. Here we show that the specific AF gene underlying this linkage is NUP155, which encodes a member of the nucleoporins, the components of the nuclear pore complex (NPC). We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability. Homozygous NUP155-/- knockout mice die before E8.5, but heterozygous NUP155+/- mice show the AF phenotype. The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein. These human and mouse studies indicate that loss of NUP155 function causes AF by altering mRNA and protein transport and link the NPC to cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)1017-1027
Number of pages11
JournalCell
Volume135
Issue number6
DOIs
StatePublished - Dec 12 2008

Keywords

  • CELLBIO
  • HUMDISEASE
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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