Human Molecular Genetics Advance Access published online on November 3, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn363
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"A LOSS-OF-FUNCTION VARIANT OF PTPN22 IS ASSOCIATED WITH REDUCED RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS"
1 Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 2 Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA 3 Instituto de Parasitologia y Biomedicina "Lopez-Neyra", CSIC, Granada, Spain 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 5 Department of Internal Medicine, Hospital Clinico San Cecilio, Granada, Spain 6 Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy 7 Department of Rheumatology, University of Texas Medical School, Houston, TX, USA 8 David Geffen School of Medicine, University of California, Los Angeles, CA, USA 9 Rheumatology Unit, Hospital Xeral-Calde, Lugo, Spain 10 Sanatorio Parque, Rosario, Argentina 11 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden 12 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
* Address correspondence to: Nunzio Bottini, M.D., Ph.D., USC Institute for Genetic Medicine, 2250 Alcazar Street, CSC 204, Los Angeles, CA 90033. Phone: (323)-442-2634. Fax: (323)-442-2764. Email: nunzio{at}usc.edu
Received July 5, 2008; Revised October 30, 2008; Accepted October 30, 2008
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.
# These authors contributed equally to this work.
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