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

Valeria Orrú, Sophia J. Tsai, Blanca Rueda, Edoardo Fiorillo, Stephanie M. Stanford, Jhimli Dasgupta, Jaana Hartiala, Lei Zhao, Norberto Ortego-Centeno, Sandra D'Alfonso, Frank C. Arnett, Hui Wu, Miguel A. Gonzalez-Gay, Betty P. Tsao, Bernardo Pons-Estel, Marta E. Alarcon-Riquelme, Yantao He, Zhong-Yin Zhang, Hooman Allayee, Xiaojiang S. ChenJavier Martin, Nunzio Bottini, Giovanna Danieli, Mauro Galeazzi, Maria Grazia, Sergio Migliaresi, Gian Domenico

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)569-579
Number of pages11
JournalHuman Molecular Genetics
Volume18
Issue number3
DOIs
StatePublished - 2009

Fingerprint

Systemic Lupus Erythematosus
Autoimmunity
Non-Receptor Type 22 Protein Tyrosine Phosphatase
Phosphoric Monoester Hydrolases
Tyrosine
Catalytic Domain
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Orrú, V., Tsai, S. J., Rueda, B., Fiorillo, E., Stanford, S. M., Dasgupta, J., ... Domenico, G. (2009). A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Human Molecular Genetics, 18(3), 569-579. https://doi.org/10.1093/hmg/ddn363

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. / Orrú, Valeria; Tsai, Sophia J.; Rueda, Blanca; Fiorillo, Edoardo; Stanford, Stephanie M.; Dasgupta, Jhimli; Hartiala, Jaana; Zhao, Lei; Ortego-Centeno, Norberto; D'Alfonso, Sandra; Arnett, Frank C.; Wu, Hui; Gonzalez-Gay, Miguel A.; Tsao, Betty P.; Pons-Estel, Bernardo; Alarcon-Riquelme, Marta E.; He, Yantao; Zhang, Zhong-Yin; Allayee, Hooman; Chen, Xiaojiang S.; Martin, Javier; Bottini, Nunzio; Danieli, Giovanna; Galeazzi, Mauro; Grazia, Maria; Migliaresi, Sergio; Domenico, Gian.

In: Human Molecular Genetics, Vol. 18, No. 3, 2009, p. 569-579.

Research output: Contribution to journalArticle

Orrú, V, Tsai, SJ, Rueda, B, Fiorillo, E, Stanford, SM, Dasgupta, J, Hartiala, J, Zhao, L, Ortego-Centeno, N, D'Alfonso, S, Arnett, FC, Wu, H, Gonzalez-Gay, MA, Tsao, BP, Pons-Estel, B, Alarcon-Riquelme, ME, He, Y, Zhang, Z-Y, Allayee, H, Chen, XS, Martin, J, Bottini, N, Danieli, G, Galeazzi, M, Grazia, M, Migliaresi, S & Domenico, G 2009, 'A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus', Human Molecular Genetics, vol. 18, no. 3, pp. 569-579. https://doi.org/10.1093/hmg/ddn363
Orrú, Valeria ; Tsai, Sophia J. ; Rueda, Blanca ; Fiorillo, Edoardo ; Stanford, Stephanie M. ; Dasgupta, Jhimli ; Hartiala, Jaana ; Zhao, Lei ; Ortego-Centeno, Norberto ; D'Alfonso, Sandra ; Arnett, Frank C. ; Wu, Hui ; Gonzalez-Gay, Miguel A. ; Tsao, Betty P. ; Pons-Estel, Bernardo ; Alarcon-Riquelme, Marta E. ; He, Yantao ; Zhang, Zhong-Yin ; Allayee, Hooman ; Chen, Xiaojiang S. ; Martin, Javier ; Bottini, Nunzio ; Danieli, Giovanna ; Galeazzi, Mauro ; Grazia, Maria ; Migliaresi, Sergio ; Domenico, Gian. / A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 3. pp. 569-579.
@article{93831d15963345a2958a3cf7974fe93d,
title = "A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus",
abstract = "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.",
author = "Valeria Orr{\'u} and Tsai, {Sophia J.} and Blanca Rueda and Edoardo Fiorillo and Stanford, {Stephanie M.} and Jhimli Dasgupta and Jaana Hartiala and Lei Zhao and Norberto Ortego-Centeno and Sandra D'Alfonso and Arnett, {Frank C.} and Hui Wu and Gonzalez-Gay, {Miguel A.} and Tsao, {Betty P.} and Bernardo Pons-Estel and Alarcon-Riquelme, {Marta E.} and Yantao He and Zhong-Yin Zhang and Hooman Allayee and Chen, {Xiaojiang S.} and Javier Martin and Nunzio Bottini and Giovanna Danieli and Mauro Galeazzi and Maria Grazia and Sergio Migliaresi and Gian Domenico",
year = "2009",
doi = "10.1093/hmg/ddn363",
language = "English",
volume = "18",
pages = "569--579",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus

AU - Orrú, Valeria

AU - Tsai, Sophia J.

AU - Rueda, Blanca

AU - Fiorillo, Edoardo

AU - Stanford, Stephanie M.

AU - Dasgupta, Jhimli

AU - Hartiala, Jaana

AU - Zhao, Lei

AU - Ortego-Centeno, Norberto

AU - D'Alfonso, Sandra

AU - Arnett, Frank C.

AU - Wu, Hui

AU - Gonzalez-Gay, Miguel A.

AU - Tsao, Betty P.

AU - Pons-Estel, Bernardo

AU - Alarcon-Riquelme, Marta E.

AU - He, Yantao

AU - Zhang, Zhong-Yin

AU - Allayee, Hooman

AU - Chen, Xiaojiang S.

AU - Martin, Javier

AU - Bottini, Nunzio

AU - Danieli, Giovanna

AU - Galeazzi, Mauro

AU - Grazia, Maria

AU - Migliaresi, Sergio

AU - Domenico, Gian

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=58849120030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58849120030&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddn363

DO - 10.1093/hmg/ddn363

M3 - Article

C2 - 18981062

AN - SCOPUS:58849120030

VL - 18

SP - 569

EP - 579

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 3

ER -