A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus

被引：99

作者：

Orru, Valeria ^{[1
]}

Tsai, Sophia J.

Rueda, Blanca ^{[2
]}

Fiorillo, Edoardo ^{[1
]}

Stanford, Stephanie M. ^{[1
]}

Dasgupta, Jhimli

Hartiala, Jaana ^{[1
,3
]}

Zhao, Lei ^{[1
]}

Ortego-Centeno, Norberto ^{[4
]}

D'Alfonso, Sandra ^{[5
,6
]}

Arnett, Frank C. ^{[7
]}

Wu, Hui ^{[8
]}

Gonzalez-Gay, Miguel A. ^{[9
]}

Tsao, Betty P. ^{[8
]}

Pons-Estel, Bernardo ^{[10
]}

Alarcon-Riquelme, Marta E. ^{[11
]}

He, Yantao ^{[12
]}

Zhang, Zhong-Yin ^{[12
]}

Allayee, Hooman ^{[1
,3
]}

Chen, Xiaojiang S.

Martin, Javier ^{[2
]}

Bottini, Nunzio ^{[1
]}

机构：

[1] Univ So Calif, Inst Med Genet, Keck Sch Med, Los Angeles, CA 90033 USA

[2] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

[3] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[4] Hosp Clin San Cecilio, Dept Internal Med, Granada, Spain

[5] Univ Piemonte Orientale, Dept Med Sci, Novara, Italy

[6] Univ Piemonte Orientale, Interdisciplinary Res Ctr Autoimmune Dis, Novara, Italy

[7] Univ Texas Houston, Sch Med, Dept Rheumatol, Houston, TX USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[9] Hosp Xeral Calde, Rheumatol Unit, Lugo, Spain

[10] Sanatorio Parque, Rosario, Santa Fe, Argentina

[11] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, Uppsala, Sweden

[12] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

LYMPHOID TYROSINE PHOSPHATASE; CELL ANTIGEN RECEPTOR; GENETIC-VARIATION; POLYMORPHISM; IDENTIFICATION; ANTIBODIES; TOLERANCE; HAPLOTYPE; KINASE;

D O I：

10.1093/hmg/ddn363

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

引用

页码：569 / 579

页数：11

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