A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans
A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans
复制标题
DOI：
10.1038/nm.1917
复制
发表时间：
2009-03-01
期刊：
影响因子：
82.9
通讯作者：
Byzova, Tatiana V.
中科院分区：
文献类型：
--
作者：
Malinin, Nikolay L.;Zhang, Li;Byzova, Tatiana V.
单基因缺乏性疾病提供了独特的机会来定义单个分子对人类生理的贡献，并确定由其功能障碍引起的病理。在这里，我们描述了一个缺乏性疾病在两个人类兄弟姐妹，表现为严重出血，频繁感染和骨质疏松症在早期。这些症状与白细胞粘附缺乏症III （LAD-III）患者的症状一致，但比这些症状更严重。从机制上讲，这些症状是由于无法激活造血细胞（包括血小板和白细胞）上表达的整合素而引起的。从两个个体分离的永生化淋巴细胞系显示整合素激活缺陷。先前涉及整合素激活的几种蛋白质，包括ras相关蛋白-1 (RAP1)(1)和钙和二酰基甘油调节的鸟嘌呤核苷酸交换因子-1 (CALDAG-GEF1)(2)，在这些细胞系中存在并起作用。该病的遗传基础可追溯到KINDLIN3（官方基因符号FERMT3）基因编码区的一个点突变(3)。当野生型KINDLIN-3在永活淋巴细胞中表达时，它们的整合素对激活信号产生反应。这些结果确定了一种严重损害受影响个体健康的遗传疾病，并确定了KINDLIN-3在人类整合素激活中的重要作用。此外，同种异体骨髓移植被证明可以减轻疾病的症状。
Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1)(1) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1)(2), were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene(3). When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease.