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.
authors.affiliation: Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Orrú
authors.forename: Sophia J
authors.initials: SJ
authors.lastname: Tsai
authors.forename: Blanca
authors.initials: B
authors.lastname: Rueda
authors.forename: Edoardo
authors.initials: E
authors.lastname: Fiorillo
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.forename: Jhimli
authors.initials: J
authors.lastname: Dasgupta
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Norberto
authors.initials: N
authors.lastname: Ortego-Centeno
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.forename: Bernardo
authors.initials: B
authors.lastname: Pons-Estel
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcon-Riquelme
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: Xiaojiang S
authors.initials: XS
authors.lastname: Chen
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D015331:Cohort Studies; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors; D016415:Sequence Alignment; D044465:White People / Q000235:genetics
chemical_list: C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22