(Journal Article): A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.
 
Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY (Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, Georgia 30912, USA.)
 
IN: Nat Genet 2004; 36(8):837-841
Impact Factor(s) of Nat Genet: 25.797 (2005), 24.695 (2004), 26.494 (2003), 26.711 (2002), 29.6 (2001)

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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.

TYPE OF PUBLICATION: Original article

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