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Letter
Nature Genetics  36, 837 - 841 (2004)
Published online: 11 July 2004; | doi:10.1038/ng1391


There is a Corrigendum (September 2004) associated with this Letter.

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

Dehuang Guo1, 13, Manyu Li1, 13, Yan Zhang1, 13, Ping Yang1, Sarah Eckenrode1, Diane Hopkins1, Weipeng Zheng1, Sharad Purohit1, Robert H Podolsky2, Andrew Muir3, Jinzhao Wang4, Zheng Dong4, Todd Brusko5, Mark Atkinson5, Paolo Pozzilli6, Adina Zeidler7, Leslie J Raffel8, Chaim O Jacob7, Yongsoo Park9, Manuel Serrano-Rios10, Maria T Martinez Larrad10, Zixin Zhang11, Henri-Jean Garchon12, Jean-Francois Bach12, Jerome I Rotter8, Jin-Xiong She1 & Cong-Yi Wang1

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

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

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

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

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

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

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

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

9  Hanyang University Hospital, Seoul, Korea.

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

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

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

13  These authors contributed equally to this work.

Correspondence should be addressed to Jin-Xiong She jshe@mail.mcg.edu or Cong-Yi Wang cwang@mail.mcg.edu
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 times 10-7). SUMO4 conjugates to IkappaBalpha and negatively regulates NFkappaB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFkappaB transcriptional activity and approx2 times greater expression of IL12B, an NFkappaB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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