Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
Immunogenetics. 2012 Dec;64(12):869-77. doi: 10.1007/s00251-012-0646-9. Epub 2012 Aug 18.
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.
Fcγ 受体 IIa（FcγRIIa）在抗体依赖的细胞毒性和炎症中发挥重要作用。FCGR2A 基因（编码 FcγRIIa）的遗传多态性导致 FcγRIIa 表达水平或活性的变化，可能导致个体间疾病进展和抗体治疗效果的差异。在这项研究中，我们对 111 名日本受试者的 FCGR2A 的 5'-侧翼区域以及所有外显子及其侧翼区域进行了测序。共发现 48 种遗传变异，包括 12 种新的变异。除了众所周知的功能 497A>G（H166R）多态性外，我们还在 0.005 的频率下检测到 818T>C（L273P）。由于该多态性的功能意义尚未揭示，我们接下来通过在人 Jurkat 细胞中表达野生型和变异蛋白来评估 L273P 取代的功能。L273P 变异蛋白表现出与野生型相似的细胞表面表达和 IgG 结合特性，但由于 FcγRIIa 自身酪氨酸磷酸化增强了约 2 倍，因此显示出更强的信号转导活性。目前的结果表明，L273P 可能通过 FcγRIIa 在抗体依赖的临床反应中具有功能意义。
