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 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; Maria T. Martinez Larrad; Zixin Zhang; Henri Jean Garchon; Jean Francois Bach; Jerome I. Rotter; Jin Xiong She; Cong Yi Wang

doi:10.1038/ng1391

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 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

Maria T. Martinez Larrad, Zixin Zhang, Henri Jean Garchon, Jean Francois Bach, Jerome I. Rotter, Jin Xiong She^*, Cong Yi Wang

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

374 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 language	English
Pages (from-to)	837-841
Number of pages	5
Journal	Nature Genetics
Volume	36
Issue number	8
DOIs	https://doi.org/10.1038/ng1391
Publication status	Published - Aug 2004
Externally published	Yes

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Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S., Podolsky, R. H., Muir, A., Wang, J., Dong, Z., Brusko, T., Atkinson, M., Pozzilli, P., Zeidler, A., Raffel, L. J., Jacob, C. O., Park, Y., ... 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

@article{f1508ee3df3f4efeb6e51100488e96c8,

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 Sharad Purohit 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 She, \{Jin Xiong\} and Wang, \{Cong Yi\}",

year = "2004",

month = aug,

doi = "10.1038/ng1391",

language = "English",

volume = "36",

pages = "837--841",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Guo, D, Li, M, Zhang, Y, Yang, P, Eckenrode, S, Hopkins, D, Zheng, W, Purohit, S, 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, JX & 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

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

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

Y1 - 2004/8

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 - https://www.scopus.com/pages/publications/3543046736

U2 - 10.1038/ng1391

DO - 10.1038/ng1391

M3 - Article

C2 - 15247916

AN - SCOPUS:3543046736

SN - 1061-4036

VL - 36

SP - 837

EP - 841

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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