Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro
Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro
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DOI：
10.1182/blood-2009-08-238709
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发表时间：
2010-06-10
期刊：
影响因子：
20.3
通讯作者：
Hogg, Nancy
中科院分区：
文献类型：
--
作者：
McDowall, Alison;Svensson, Lena;Hogg, Nancy
在白细胞粘附缺陷 III (LAD-III) 疾病中，血小板和白细胞上的整合素会表达，但无法发挥作用，这会导致早期严重出血和感染。 KINDLIN3 (FERMT3) 基因突变是中东、马耳他和土耳其患者患 LAD-III 的原因。我们描述了一位新非裔美国患者的 KINDLIN3 基因中的 2 个新的纯合突变，这些突变破坏了 KINDLIN3 mRNA 的稳定性，导致 kindlin-3 蛋白丢失。野生型 (WT) KINDLIN3 cDNA 的转染恢复了 LAD-III 患者 T 和 B 淋巴细胞中整合素相关的粘附和迁移。我们在体外分别分析了各个突变，以了解有关 kindlin-3 蛋白功能的更多信息。第一个 G>A 突变导致 FERM（蛋白 4.1、ezrin、radixin、moesin）子结构域 2 末端发生 Gly308Arg 变化，第二个突变是碱基缺失，导致 pleckstrin 同源 (PH) 结构域内提前终止。第二个突变阻止 kindlin-3 的膜结合，并且不恢复粘附或迁移，而 FERM 子域 2 突变仅影响迁移。因此，这些 LAD-III 患者突变突出显示了 kindlin-3 的重要功能区域，这些区域以两种不同的方式改变白细胞整合素依赖性功能。 （血。2010；115(23):4834-4842）
In the disorder leukocyte adhesion deficiency III (LAD-III), integrins on platelets and leukocytes are expressed but fail to function and this leads to severe bleeding and infections at an early age. Mutation in the KINDLIN3 (FERMT3) gene is the cause of LAD-III in patients from the Middle East, Malta, and Turkey. We describe 2 novel homozygous mutations in the KINDLIN3 gene of a new African-American patient that destabilize KINDLIN3 mRNA leading to loss of kindlin-3 protein. Transfection of wild-type (WT) KINDLIN3 cDNA restored integrin-related adhesion and migration in the LAD-III patient's T and B lymphocytes. We analyzed the individual mutations separately in vitro to learn more about the function of the kindlin-3 protein. The first G>A mutation gives rise to a Gly308Arg change at the end of FERM (protein 4.1, ezrin, radixin, moesin) subdomain 2, and the second mutation is a base deletion causing early termination within the pleckstrin homology (PH) domain. This second mutation prevented membrane association of kindlin-3 and did not restore either adhesion or migration, whereas the FERM subdomain 2 mutation affected only migration. Thus, these LAD-III patient mutations have highlighted functionally important regions of kindlin-3 that alter leukocyte integrin-dependent function in 2 distinct ways. (Blood. 2010;115(23):4834-4842)