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A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes

Nature Genetics volume 36, pages 837–841 (2004)Cite this article

A Corrigendum to this article was published on 01 September 2004

Abstract

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D)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 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 × 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-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

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Figure 1: Physical and transcription map for the IDDM5 interval.
Figure 2: SUMO4 amino acid homology alignment and tissue distribution.
Figure 3: IκBα is a substrate for SUMO4 modification.
Figure 4: SUMO4 expression inhibits NFκB-dependent transcription.
Figure 5: The 163A→G substitution of SUMO4 regulates NFκB-dependent IL12B expression.

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Acknowledgements

We thank R.T. Hay for the NFκB-dependent luciferase reporter (3enh conA luc) and IκBα expression construct, R. McIndoe for suggestions about this project and J. Gu for discussion of manuscript preparation. This study was supported in part by grants from the Combined Intramural Grants Program, the Juvenile Diabetes Research Foundation (C.Y.W.) and the National Institute of Child Health and Development (J.X.S.).

Author information

Author notes

  1. Dehuang Guo, Manyu Li and Yan Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, 30912, Georgia, USA

    Dehuang Guo, Manyu Li, Yan Zhang, Ping Yang, Sarah Eckenrode, Diane Hopkins, Weipeng Zheng, Sharad Purohit, Jin-Xiong She & Cong-Yi Wang

  2. Office of Biostatistics and Bioinformatics, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, 30912, Georgia, USA

    Robert H Podolsky

  3. Children's Medical Center, Medical College of Georgia, 1446 Harper Street, BG-1020, Augusta, 30912, Georgia, USA

    Andrew Muir

  4. Department of Cellular Biology and Anatomy, Medical College of Georgia, 1120 15th Street, Augusta, 30912, Georgia, USA

    Jinzhao Wang & Zheng Dong

  5. Department of Pathology, College of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, 32610, Florida, USA

    Todd Brusko & Mark Atkinson

  6. Endocrinologia, Istituto Clinica Medica II, University of Rome “La Sapienza”, Rome, Italy

    Paolo Pozzilli

  7. Department of Medicine, University of Southern California School of Medicine, Los Angeles, California, USA

    Adina Zeidler & Chaim O Jacob

  8. Departments of Pediatrics and Medicine, Cedars-Sinai Medical Center and University of California Los Angeles, Los Angeles, California, USA

    Leslie J Raffel & Jerome I Rotter

  9. Hanyang University Hospital, Seoul, Korea

    Yongsoo Park

  10. Facultad de Medicina, Universidad Complutense, Madrid, Spain

    Manuel Serrano-Rios & Maria T Martinez Larrad

  11. HLA laboratory, Beijing Red Cross Blood Center, Beijing, China

    Zixin Zhang

  12. Unite de Recherches de l'INSERM U580, Centre de l'Association Claude Bernard, Paris, France

    Henri-Jean Garchon & Jean-Francois Bach

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Correspondence to Jin-Xiong She or Cong-Yi Wang.

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Supplementary information

Supplementary Fig. 1

LD of SNPs flanking the IDDM5 interval. (PDF 92 kb)

Supplementary Fig. 2

Pooled DNA sequencing results for the M55V of SUMO4. (PDF 103 kb)

Supplementary Fig. 3

Semi-quantitative Western analysis of IL-p40 in stimulated/unstimulated PBMC lysates from individuals studied in Figure 4. (PDF 123 kb)

Supplementary Table 1

Case-control association results for 001Msp. (PDF 53 kb)

Supplementary Table 2

Family-based association results for 001Msp. (PDF 90 kb)

Supplementary Table 3

Family-based association results for 268Hha. (PDF 89 kb)

Supplementary Table 4

Family-based association results for 012Taq. (PDF 89 kb)

Supplementary Table 5

Case-control association results for M55V. (PDF 44 kb)

Supplementary Table 6

Family-based association results for M55V. (PDF 89 kb)

Supplementary Methods (PDF 84 kb)

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Guo, D., Li, M., Zhang, Y. et al. A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes. Nat Genet 36, 837–841 (2004). https://doi.org/10.1038/ng1391

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