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

• Published in: Cell Vol. 135; no. 6; pp. 1017 - 1027
• Main Authors: Zhang, Xianqin, Chen, Shenghan, Yoo, Shin, Chakrabarti, Susmita, Zhang, Teng, Ke, Tie, Oberti, Carlos, Yong, Sandro L., Fang, Fang, Li, Lin, de la Fuente, Roberto, Wang, Lejin, Chen, Qiuyun, Wang, Qing Kenneth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-12-2008
• Subjects: Amino Acid Sequence; Animals; Atrial Fibrillation - genetics; CELLBIO; Death, Sudden, Cardiac; Female; HSP72 Heat-Shock Proteins - genetics; HSP72 Heat-Shock Proteins - metabolism; Humans; HUMDISEASE; Male; Mice; Mice, Knockout; Molecular Sequence Data; Nuclear Envelope - metabolism; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Pedigree; PROTEINS; Sequence Alignment; CELLBIO; PROTEINS; HUMDISEASE
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2008.10.022

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.