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. Epub 2004 Jul 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*
  • Small Ubiquitin-Related Modifier Proteins / physiology*


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