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

Hum Mol Genet. 2009 Feb 1;18(3):569-79. doi: 10.1093/hmg/ddn363. Epub 2008 Nov 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cohort Studies
  • Humans
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / metabolism*
  • Risk Factors
  • Sequence Alignment
  • White People / genetics

Substances

  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22