A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes

Dehuang Guo, Manyu Li, Yan Zhang, Ping Yang, Sarah Eckenrode, Diane Hopkins, Weipeng Zheng, Sharad B 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-RiosMaria T. Martinez Larrad, Zixin Zhang, Henri Jean Garchon, Jean Francois Bach, Jerome I. Rotter, Jin-Xiong She, Cong Yi Wang

Research output: Contribution to journalArticle

299 Scopus citations

Abstract

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)1,2, but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1 D 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 IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B, an NFκB NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Original languageEnglish (US)
Pages (from-to)837-841
Number of pages5
JournalNature Genetics
Volume36
Issue number8
DOIs
StatePublished - Aug 1 2004

ASJC Scopus subject areas

  • Genetics

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    Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S. B., Podolsky, R. H., Muir, A., Wang, J., Dong, Z., Brusko, T., Atkinson, M., Pozzilli, P., Zeidler, A., Raffel, L. J., Jacob, C. O., Park, Y., ... Wang, C. Y. (2004). A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes. Nature Genetics, 36(8), 837-841. https://doi.org/10.1038/ng1391