WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4
WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4
复制标题
DOI：
10.1182/blood-2011-12-395608
复制
发表时间：
2012-07-05
期刊：
影响因子：
20.3
通讯作者：
McDermott, David H.
中科院分区：
文献类型：
--
作者：
Liu, Qian;Chen, Haoqian;McDermott, David H.
WHIM综合征是一种罕见的常染色体显性免疫缺陷疾病，之所以如此命名，是因为它的特征是疣、低丙种球蛋白血症、感染和骨髓病（骨髓中中性粒细胞排出缺陷）。将趋化因子受体CXCR 4的C末端截短10-19个氨基酸的功能获得性突变引起WHIM综合征。我们发现了一个常染色体显性遗传的WHIM综合征家系，该家系由CXCR 4基因E343 K（1027 G-> A）的错义突变引起。该突变也位于C-末端结构域，该区域负责受体的负调控。因此，与WHIM综合征中最常见的截短突变CXCR 4（R334 X）一样，CXCR 4（E343 K）在钙通量和趋化性测定中介导的信号传导相对于野生型CXCR 4增加约2倍;然而，CXCR 4（E343 K）对阻断细胞表面正常受体下调的作用降低。因此，除了CXCR 4的C-末端结构域中的截短突变之外，WHIM综合征可能是由该结构域中的单个电荷改变氨基酸取代引起的，E343 K，其导致受体信号传导增加。（血。2012;120（1）：181-189）
WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G -> A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling. (Blood. 2012;120(1):181-189)