Devriendt K, Kim A S, Mathijs G, Frints S G, Schwartz M, Van Den Oord J J, Verhoef G E, Boogaerts M A, Fryns J P, You D, Rosen M K, Vandenberghe P
Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium.
Nat Genet. 2001 Mar;27(3):313-7. doi: 10.1038/85886.
The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex. Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene. Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro, the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.
威斯科特-奥尔德里奇综合征蛋白（WASP；由WAS基因编码）及其同源物是肌动蛋白细胞骨架的重要调节因子，介导Rho家族小GTP酶与肌动蛋白成核/交联因子Arp2/3复合体之间的信号传导。许多WAS突变会损害造血组织中的细胞骨架控制，导致功能性和发育性缺陷，从而定义了X连锁的威斯科特-奥尔德里奇综合征（WAS）和相关的X连锁血小板减少症（XLT）。这些疾病似乎是由于WASP信号传导减少所致，通常是由于该基因的转录或翻译减少。在这里，我们描述了一种新的疾病，X连锁严重先天性中性粒细胞减少症（XLN），它是由WAS基因中编码保守GTP酶结合域（GBD）区域的一个新的L270P突变引起的。在体外，突变蛋白通过破坏野生型蛋白中的一个自抑制域而持续激活，这表明WASP自抑制的丧失是XLN中的一个关键事件。我们的研究结果突出了精确调节WASP在造血发育和功能中的重要性，因为其活性的受损与增强会导致不同的细胞缺陷谱和临床表型。
