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

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

  • Nat Genet. 2004 Aug;36(8):837-41. doi: 10.1038/ng1391.
Dehuang Guo 1,  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
Affiliations

Affiliation

  • 1 Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, Georgia 30912, USA.
PMID: 15247916 DOI: 10.1038/ng1391
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.

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