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

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Human molecular genetics, ISSN: 1460-2083, Vol: 18, Issue: 3, Page: 569-79

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PMC2722189; 2722189
Valeria OrrĂº; Edoardo Fiorillo; Stephanie M. Stanford; Jaana Hartiala; Lei Zhao; Hooman Allayee; Nunzio Bottini; Sophia J. Tsai; Jhimli Dasgupta; Xiaojiang S. Chen; Blanca Rueda; Javier Martin; Norberto Ortego-Centeno; Sandra D'Alfonso; Frank C. Arnett; Hui Wu; Betty P. Tsao; Miguel A. Gonzalez-Gay; Bernardo Pons-Estel; Marta E. Alarcon-Riquelme; Yantao He; Zhong Yin Zhang; Giovanna Danieli; Mauro Galeazzi; Maria Grazia Sabbadini; Sergio Migliaresi; Gian Domenico Show More Hide
Oxford University Press (OUP); IRL Press at Oxford University Press
Biochemistry, Genetics and Molecular Biology; Medicine; Amino Acid Sequence; Cell Line; Cohort Studies; European Continental Ancestry Group; Humans; Lupus Erythematosus; Systemic; Models; Molecular; Molecular Sequence Data; Mutation; Missense; Polymorphism; Genetic; Protein Structure; Tertiary; Protein Tyrosine Phosphatase; Non-Receptor Type 22; Risk Factors; Sequence Alignment; Medicine and Health Sciences
article description
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.