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PMID:19070573

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Citation

Zhang, X, Chen, S, Yoo, S, Chakrabarti, S, Zhang, T, Ke, T, Oberti, C, Yong, SL, Fang, F, Li, L, de la Fuente, R, Wang, L, Chen, Q and Wang, QK (2008) Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 135:1017-27

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.

Links

PubMed Online version:10.1016/j.cell.2008.10.022

Keywords

Amino Acid Sequence; Animals; Atrial Fibrillation/genetics; Death, Sudden, Cardiac; Female; HSP72 Heat-Shock Proteins/genetics; HSP72 Heat-Shock Proteins/metabolism; Humans; Male; Mice; Mice, Knockout; Molecular Sequence Data; Nuclear Envelope/metabolism; Nuclear Pore Complex Proteins/genetics; Nuclear Pore Complex Proteins/metabolism; Pedigree; Sequence Alignment

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NU155

acts_upstream_of_or_within

GO:0006998: nuclear envelope organization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NU155

located_in

GO:0005635: nuclear envelope

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NU155

acts_upstream_of_or_within

GO:0006606: protein import into nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3840086

P

  • occurs_in:(CL:0000746)
  • occurs_in:(EMAPA:32746)

Seeded From UniProt

complete

MOUSE:NU155

acts_upstream_of_or_within

GO:0006406: mRNA export from nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3840086

P

  • occurs_in:(CL:0000746)
  • occurs_in:(EMAPA:32746)

Seeded From UniProt

complete

MOUSE:NU155

acts_upstream_of_or_within

GO:0086014: atrial cardiac muscle cell action potential

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3840086

P

  • occurs_in:(CL:0000746)
  • occurs_in:(EMAPA:32746)

Seeded From UniProt

complete


See also

References

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