Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.
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.
Zhang
Xianqin
X
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Chen
Shenghan
S
Yoo
Shin
S
Chakrabarti
Susmita
S
Zhang
Teng
T
Ke
Tie
T
Oberti
Carlos
C
Yong
Sandro L
SL
Fang
Fang
F
Li
Lin
L
de la Fuente
Roberto
R
Wang
Lejin
L
Chen
Qiuyun
Q
Wang
Qing Kenneth
QK
D000595:Amino Acid Sequence; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D005260:Female; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009685:Nuclear Envelope / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016415:Sequence Alignment
D050884:HSP72 Heat-Shock Proteins; C080427:NUP155 protein, human; C533999:NUP155 protein, mouse; D028861:Nuclear Pore Complex Proteins