A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.
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.
Orrú
Valeria
V
Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Tsai
Sophia J
SJ
Rueda
Blanca
B
Fiorillo
Edoardo
E
Stanford
Stephanie M
SM
Dasgupta
Jhimli
J
Hartiala
Jaana
J
Zhao
Lei
L
Ortego-Centeno
Norberto
N
D'Alfonso
Sandra
S
Arnett
Frank C
FC
Wu
Hui
H
Gonzalez-Gay
Miguel A
MA
Tsao
Betty P
BP
Pons-Estel
Bernardo
B
Alarcon-Riquelme
Marta E
ME
He
Yantao
Y
Zhang
Zhong-Yin
ZY
Allayee
Hooman
H
Chen
Xiaojiang S
XS
Martin
Javier
J
Bottini
Nunzio
N
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
C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22