Identification and functional analysis of CBLB mutations in type 1 diabetes.
Casitas B-lineage lymphoma b (Cblb) is a negative regulator of T-cell activation and dysfunction of Cblb in rats and mice results in autoimmunity. In particular, a nonsense mutation in Cblb has been identified in a rat model of autoimmune type 1 diabetes. To clarify the possible involvement of CBLB mutation in type 1 diabetes in humans, we performed mutation screening of CBLB and characterized functional properties of the mutations in Japanese subjects. Six missense mutations (A155V, F328L, N466D, K837R, T882A, and R968L) were identified in one diabetic subject each, excepting N466D. Of these mutations, F328L showed impaired suppression of T-cell activation and was a loss-of-function mutation. These data suggest that the F328L mutation is involved in the development of autoimmune diseases including type 1 diabetes, and also provide insight into the structure-function relationship of CBLB protein.
Yokoi
Norihide
N
Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Fujiwara
Yuuka
Y
Wang
He-Yao
HY
Kitao
Mai
M
Hayashi
Chihiro
C
Someya
Tomohiro
T
Kanamori
Masao
M
Oiso
Yutaka
Y
Tajima
Naoko
N
Yamada
Yuichiro
Y
Seino
Yutaka
Y
Ikegami
Hiroshi
H
Seino
Susumu
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D009154:Mutation / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl