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Copyright 2008 Elsevier Inc.. All rights reserved.
Cell, Volume 135, Issue 6, 1017-1027, 12 December 2008
doi:10.1016/j.cell.2008.10.022
Article
Mutation in Nuclear Pore Component NUP155 Leads to Atrial Fibrillation and Early Sudden Cardiac Death
Xianqin Zhang1,2,5,Shenghan Chen1,5,Shin Yoo1,5,Susmita Chakrabarti1,5,Teng Zhang1,5,Tie Ke1,2,5,Carlos Oberti1,3,5,Sandro L. Yong1,Fang Fang1,4,Lin Li1,Roberto de la Fuente3,Lejin Wang1,2,Qiuyun Chen1andQing Kenneth Wang1,2,4,,
1 Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Taussig Cancer Center, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA
2 Key Laboratory of Molecular Biophysics, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, China
3 Department of Cardiology, Ospedale Italiano Umberto I, Montevideo 11600, Uruguay
4 Department of Chemistry, Cleveland State University, Cleveland, OH 44107, USA
Corresponding author
5 These authors contributed equally to this work
Summary
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.
