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

Dehuang Guo, Manyu Li, Yan Zhang, Ping Yang, Sarah Eckenrode, Diane Hopkins, Weipeng Zheng, Sharad B Purohit, Robert H. Podolsky, Andrew Muir, Jinzhao Wang, Zheng Dong, Todd Brusko, Mark Atkinson, Paolo Pozzilli, Adina Zeidler, Leslie J. Raffel, Chaim O. Jacob, Yongsoo Park, Manuel Serrano-Rios & 7 others Maria T. Martinez Larrad, Zixin Zhang, Henri Jean Garchon, Jean Francois Bach, Jerome I. Rotter, Jin-Xiong She, Cong Yi Wang

Research output: Contribution to journalArticle

288 Citations (Scopus)

Abstract

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)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 T1 D 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 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 NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Original languageEnglish (US)
Pages (from-to)837-841
Number of pages5
JournalNature Genetics
Volume36
Issue number8
DOIs
StatePublished - Aug 1 2004

Fingerprint

Type 1 Diabetes Mellitus
Genes
Ubiquitin
Single Nucleotide Polymorphism
DNA
Proteins
Insulin-Dependent Diabetes Mellitus 5

ASJC Scopus subject areas

  • Genetics

Cite this

Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., ... Wang, C. Y. (2004). A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes. Nature Genetics, 36(8), 837-841. https://doi.org/10.1038/ng1391

A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes. / Guo, Dehuang; Li, Manyu; Zhang, Yan; Yang, Ping; Eckenrode, Sarah; Hopkins, Diane; Zheng, Weipeng; Purohit, Sharad B; Podolsky, Robert H.; Muir, Andrew; Wang, Jinzhao; Dong, Zheng; Brusko, Todd; Atkinson, Mark; Pozzilli, Paolo; Zeidler, Adina; Raffel, Leslie J.; Jacob, Chaim O.; Park, Yongsoo; Serrano-Rios, Manuel; Martinez Larrad, Maria T.; Zhang, Zixin; Garchon, Henri Jean; Bach, Jean Francois; Rotter, Jerome I.; She, Jin-Xiong; Wang, Cong Yi.

In: Nature Genetics, Vol. 36, No. 8, 01.08.2004, p. 837-841.

Research output: Contribution to journalArticle

Guo, D, Li, M, Zhang, Y, Yang, P, Eckenrode, S, Hopkins, D, Zheng, W, Purohit, SB, Podolsky, RH, Muir, A, Wang, J, Dong, Z, Brusko, T, Atkinson, M, Pozzilli, P, Zeidler, A, Raffel, LJ, Jacob, CO, Park, Y, Serrano-Rios, M, Martinez Larrad, MT, Zhang, Z, Garchon, HJ, Bach, JF, Rotter, JI, She, J-X & Wang, CY 2004, 'A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes', Nature Genetics, vol. 36, no. 8, pp. 837-841. https://doi.org/10.1038/ng1391
Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D et al. A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes. Nature Genetics. 2004 Aug 1;36(8):837-841. https://doi.org/10.1038/ng1391
Guo, Dehuang ; Li, Manyu ; Zhang, Yan ; Yang, Ping ; Eckenrode, Sarah ; Hopkins, Diane ; Zheng, Weipeng ; Purohit, Sharad B ; Podolsky, Robert H. ; Muir, Andrew ; Wang, Jinzhao ; Dong, Zheng ; Brusko, Todd ; Atkinson, Mark ; Pozzilli, Paolo ; Zeidler, Adina ; Raffel, Leslie J. ; Jacob, Chaim O. ; Park, Yongsoo ; Serrano-Rios, Manuel ; Martinez Larrad, Maria T. ; Zhang, Zixin ; Garchon, Henri Jean ; Bach, Jean Francois ; Rotter, Jerome I. ; She, Jin-Xiong ; Wang, Cong Yi. / A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes. In: Nature Genetics. 2004 ; Vol. 36, No. 8. pp. 837-841.
@article{dfb934cf8db44bbc883a171f11c17ae2,
title = "A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes",
abstract = "Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)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 T1 D 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 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 NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.",
author = "Dehuang Guo and Manyu Li and Yan Zhang and Ping Yang and Sarah Eckenrode and Diane Hopkins and Weipeng Zheng and Purohit, {Sharad B} and Podolsky, {Robert H.} and Andrew Muir and Jinzhao Wang and Zheng Dong and Todd Brusko and Mark Atkinson and Paolo Pozzilli and Adina Zeidler and Raffel, {Leslie J.} and Jacob, {Chaim O.} and Yongsoo Park and Manuel Serrano-Rios and {Martinez Larrad}, {Maria T.} and Zixin Zhang and Garchon, {Henri Jean} and Bach, {Jean Francois} and Rotter, {Jerome I.} and Jin-Xiong She and Wang, {Cong Yi}",
year = "2004",
month = "8",
day = "1",
doi = "10.1038/ng1391",
language = "English (US)",
volume = "36",
pages = "837--841",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - A functional variant of SUMO4, a new IκBα modifier, is associated with type diabetes

AU - Guo, Dehuang

AU - Li, Manyu

AU - Zhang, Yan

AU - Yang, Ping

AU - Eckenrode, Sarah

AU - Hopkins, Diane

AU - Zheng, Weipeng

AU - Purohit, Sharad B

AU - Podolsky, Robert H.

AU - Muir, Andrew

AU - Wang, Jinzhao

AU - Dong, Zheng

AU - Brusko, Todd

AU - Atkinson, Mark

AU - Pozzilli, Paolo

AU - Zeidler, Adina

AU - Raffel, Leslie J.

AU - Jacob, Chaim O.

AU - Park, Yongsoo

AU - Serrano-Rios, Manuel

AU - Martinez Larrad, Maria T.

AU - Zhang, Zixin

AU - Garchon, Henri Jean

AU - Bach, Jean Francois

AU - Rotter, Jerome I.

AU - She, Jin-Xiong

AU - Wang, Cong Yi

PY - 2004/8/1

Y1 - 2004/8/1

N2 - Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)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 T1 D 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 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 NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

AB - Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1 D)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 T1 D 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 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 NFKB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

UR - http://www.scopus.com/inward/record.url?scp=3543046736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3543046736&partnerID=8YFLogxK

U2 - 10.1038/ng1391

DO - 10.1038/ng1391

M3 - Article

VL - 36

SP - 837

EP - 841

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 8

ER -