A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.

Abstract

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.

• Authors: Dehuang Guo, Manyu Li, Yan Zhang, Ping Yang, Sarah Eckenrode, Diane Hopkins, Weipeng Zheng, Sharad Purohit, Robert H Podolsky, Andrew Muir, Jinzhao Wang, Zheng Dong, Todd Brusko, Mark Atkinson, Paolo Pozzilli, Adina Zeidler, Leslie J Raffel, Chaim O Jacob, Yongsoo Park, Manuel Serrano-Rios, Maria T Martinez Larrad, Zixin Zhang, Henri-Jean Garchon, Jean-Francois Bach, Jerome I Rotter, Jin-Xiong She, Cong-Yi Wang
• Journal: Nature genetics (Nat Genet) Vol. 36 Issue 8 Pg. 837-41 (Aug 2004) ISSN: 1061-4036 [Print] United States
• PMID: 15247916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• SUMO4 protein, human
• Small Ubiquitin-Related Modifier Proteins

Topics

• Amino Acid Sequence
• Case-Control Studies
• Diabetes Mellitus, Type 1 (genetics)
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Humans
• Molecular Sequence Data
• Physical Chromosome Mapping
• Polymorphism, Single Nucleotide
• Sequence Homology, Amino Acid
• Small Ubiquitin-Related Modifier Proteins (genetics, physiology)