A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.
Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
Guo
Dehuang
D
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, Georgia 30912, USA.
Li
Manyu
M
Zhang
Yan
Y
Yang
Ping
P
Eckenrode
Sarah
S
Hopkins
Diane
D
Zheng
Weipeng
W
Purohit
Sharad
S
Podolsky
Robert H
RH
Muir
Andrew
A
Wang
Jinzhao
J
Dong
Zheng
Z
Brusko
Todd
T
Atkinson
Mark
M
Pozzilli
Paolo
P
Zeidler
Adina
A
Raffel
Leslie J
LJ
Jacob
Chaim O
CO
Park
Yongsoo
Y
Serrano-Rios
Manuel
M
Larrad
Maria T Martinez
MT
Zhang
Zixin
Z
Garchon
Henri-Jean
HJ
Bach
Jean-Francois
JF
Rotter
Jerome I
JI
She
Jin-Xiong
JX
Wang
Cong-Yi
CY
D000595:Amino Acid Sequence; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics* / Q000502:physiology*
C489647:SUMO4 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins