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

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
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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  • Cite this

    Orrú, V., Tsai, S. J., Rueda, B., Fiorillo, E., Stanford, S. M., Dasgupta, J., Hartiala, J., Zhao, L., Ortego-Centeno, N., D'Alfonso, S., Arnett, F. C., Wu, H., Gonzalez-Gay, M. A., Tsao, B. P., Pons-Estel, B., Alarcon-Riquelme, M. E., He, Y., Zhang, Z. Y., Allayee, H., ... 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