Genetic polymorphisms of FCGR2A encoding Fcγ receptor IIa in a Japanese population and functional analysis of the L273P variant.
Fcγ receptor IIa (FcγRIIa) plays an important role in antibody-dependent cellular cytotoxicity and inflammation. Changes in FcγRIIa expression levels or activity caused by genetic polymorphisms in FCGR2A, the gene encoding FcγRIIa, may lead to differences in disease progression as well as efficacy of antibody therapeutics between individuals. In this study, we sequenced the 5'-flanking region along with all exons and their flanking regions of FCGR2A from 111 Japanese subjects. Forty-eight genetic variations were found including 12 novel ones. Beside the well-known functional 497A > G (H166R) polymorphism, we detected 818T > C (L273P) at 0.005 frequency. Since the functional significance of this polymorphism has not been revealed, we next assessed the functions of the L273P substitution by expressing wild-type and the variant proteins in human Jurkat cells. The L273P variant protein showed similar cell surface expression and IgG-binding properties as the wild-type, but it exhibited a stronger signal transduction activity based on the approximately 2-fold enhancement of tyrosine phosphorylation of FcγRIIa itself. The current results suggest that L273P could have functional significance in the antibody-dependent clinical responses through FcγRIIa.
Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
Minoru
M
Tada
Akiko
A
Ishii-Watabe
Keiko
K
Maekawa
Hiromi
H
Fukushima-Uesaka
Kouichi
K
Kurose
Takuo
T
Suzuki
Nahoko
N
Kaniwa
Jun-Ichi
J
Sawada
Nana
N
Kawasaki
Takako Eguchi
TE
Nakajima
Ken
K
Kato
Yasuhide
Y
Yamada
Yasuhiro
Y
Shimada
Teruhiko
T
Yoshida
Takashi
T
Ura
Miyuki
M
Saito
Kei
K
Muro
Toshihiko
T
Doi
Nozomu
N
Fuse
Takayuki
T
Yoshino
Atsushi
A
Ohtsu
Nagahiro
N
Saijo
Haruhiro
H
Okuda
Tetsuya
T
Hamaguchi
Yoshiro
Y
Saito
Yasuhiro
Y
Matsumura
D044466:Asian People / Q000235:genetics*; D002460:Cell Line; D005091:Exons; D006801:Humans; D019169:Jurkat Cells; D007930:Leucine / Q000235:genetics; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
C445323:FCGR2A protein, human; D017452:Receptors, IgG; D014443:Tyrosine; D011392:Proline; D007930:Leucine