(Journal Article): Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes.
Kosoy R, Concannon P (Molecular Genetics Program, Benaroya Research Institute and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101, USA.,
patcon@benaroyaresearch.org
)
IN:
Genes Immun
2005; 6(3):231-235
Impact Factor(s) of Genes Immun: 3.718 (2004), 3.637 (2003), 3.06 (2002), 3.787 (2001)
ABSTRACT: Several functional genetic variants that can potentially modulate the activity of NFkappaB have been recently described. As reduced NFkappaB activity has been implicated in risk for autoimmune diabetes in the NOD mouse, these variants were tested for allelic association with type 1 diabetes (T1D) in a family based study. Alleles at markers in the TAB2/SUMO4 locus on chromosome 6q had been previously reported to be associated with T1D in two separate studies, but these studies disagreed on the identity of the risk allele. The current study failed to confirm either of these results. No significant evidence of association with T1D was obtained for three SNP markers in the TAB2/SUMO4 region. An additional functional variant in the promoter of the NFKB1 gene that has been shown to directly affect the expression of NFkappaB was also tested.
TYPE OF PUBLICATION: Original article
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(Journal Article): SUMO wrestling with type 1 diabetes.
Li M, Guo D, Isales CM, Eizirik DL, Atkinson M, She JX, Wang CY (Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, GA, 30912, USA.,
cwang@mcg.edu
)
IN:
J Mol Med
2005; 83(7):504-513
ABSTRACT: Post-translational modification of proteins by phosphorylation, methylation, acetylation, or ubiquitylation represent central mechanisms through which various biological processes are regulated. Reversible covalent modification (i.e., sumoylation) of proteins by the small ubiquitin-like modifier (SUMO) has also emerged as an important mechanism contributing to the dynamic regulation of protein function. Sumoylation has been linked to the pathogenesis of a variety of disorders including Alzheimer's disease (AD), Huntington's disease (HD), and type 1 diabetes (T1D). Advances in our understanding of the role of sumoylation suggested a novel regulatory mechanism for the regulation of immune responsive gene expression. In this review, we first update recent advances in the field of sumoylation, then specifically evaluate its regulatory role in several key signaling pathways for immune response and discuss its possible implication in T1D pathogenesis.
TYPE OF PUBLICATION: Original article
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(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)
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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(Journal Article): A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription fac-tors and is associated with susceptibility to type I diabetes mel-litus.
Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D (Molecular Diabetes and Metabolism Section and the Harry B. and Aileen B. Gordon Diabetes Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.)
IN:
J Biol Chem
2004; 279(26):27233-27238
Impact Factor(s) of J Biol Chem: 6.355 (2004), 6.482 (2003), 7.258 (2001)
ABSTRACT: Three SUMO (small ubiquitin-related modifier) genes have been identified in humans, which tag proteins to modulate subcellular localization and/or enhance protein stability and activity. We report the identification of a novel intronless SUMO gene, SUMO-4, that encodes a 95-amino acid protein having an 86% amino acid homology with SUMO-2. In contrast to SUMO-2, which is highly expressed in all of the tissues examined, SUMO-4 mRNA was detected mainly in the kidney. A single nucleotide polymorphism was detected in SUMO-4, substituting a highly conserved methionine with a valine residue (M55V). In HepG2 (liver carcinoma) cells transiently transfected with SUMO-4 expression vectors, Met-55 was associated with the elevated levels of activated heat shock factor transcription factors as compared with Val-55, whereas the levels of NF-kappaB were suppressed to an identical degree. The SUMO-4M (Met) variant is associated with type I diabetes mellitus susceptibility in families (p = 4.0 x 10(-4)), suggesting that it may be involved in the pathogenesis of type I diabetes.
TYPE OF PUBLICATION: Original article
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(Journal Article): Assessing the validity of the association be-tween the SUMO4 M55V variant and risk of type 1 diabetes.
Smyth DJ, Howson JM, Lowe CE, Walker NM, Lam AC, Nutland S, Hutchings J, Tuomilehto-Wolf E, Tuomilehto J, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Savage D, Dunger DB, Twells RC, McArdle WL, Strachan DP, Todd JA.
IN:
Nat Genet
2005; 37(2):110-111
Impact Factor(s) of Nat Genet: 25.797 (2005), 24.695 (2004), 26.494 (2003), 26.711 (2002), 29.6 (2001)
ABSTRACT: Not available.
TYPE OF PUBLICATION: Letter
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(Journal Article): Additional support for a genetic association between SUMO4 and type 1 diabetes in the Korean population.
Park Y, Park S, Kang J, et al
IN:
Additional support for a ge-netic association between SUMO4 and type 1 diabetes in the Korean population
Nat Genet (in press).:-
TYPE OF PUBLICATION: Original article
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(Journal Article): Genetic heterogeneity of the IDDM5 (SUMO4) locus.
Wang CY, Yang P, She JX
IN:
Nat Genet
:-
Impact Factor(s) of Nat Genet: 25.797 (2005), 24.695 (2004), 26.494 (2003), 26.711 (2002), 29.6 (2001)
TYPE OF PUBLICATION: Original article
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