Beel Karolien, Cotter Melanie M, Blatny Jan, Bond Jonathan, Lucas Geoff, Green Frances, Vanduppen Vik, Leung Daisy W, Rooney Sean, Smith Owen P, Rosen Michael K, Vandenberghe Peter
Centre for Human Genetics/Department of Haematology, University Hospital Leuven and University of Leuven, Leuven, Belgium.
Br J Haematol. 2009 Jan;144(1):120-6. doi: 10.1111/j.1365-2141.2008.07416.x. Epub 2008 Nov 1.
X-linked neutropenia (XLN, OMIM #300299) is a rare form of severe congenital neutropenia. It was originally described in a three-generation family with five affected members that had an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich syndrome protein (WASP) [Devriendt et al (2001) Nature Genetics, Vol. 27, 313-317]. Here, we report and describe a large three-generation family with XLN, with 10 affected males and eight female carriers. A c.882T>C mutation was identified in the WAS gene, resulting in an I294T mutation. The infectious course is variable and mild in view of the profound neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced natural killer (NK)-cell counts also appear as consistent XLN features. However, inverted CD4/CD8 ratios were not found in this family, nor were cases identified with myelodysplastic syndrome or acute myeloid leukaemia. Female carriers exhibited a variable attenuated phenotype. Like L270P WASP, I294T WASP is constitutively active towards actin polymerization. In conclusion, this largest XLN kindred identified to date provides new independent genetic evidence that mutations disrupting the auto-inhibitory GBD of WASP are the cause of XLN. Reduced NK cells, low to low normal platelet counts and low to low-normal IgA levels are also features of XLN.
X连锁中性粒细胞减少症（XLN，OMIM #300299）是一种罕见的严重先天性中性粒细胞减少症。它最初在一个三代家族中被描述，该家族有五名受影响成员，其威斯科特-奥尔德里奇综合征蛋白（WASP）的GTP酶结合域（GBD）存在L270P突变[Devriendt等人（2001年）《自然遗传学》，第27卷，313 - 317页]。在此，我们报告并描述了一个患有XLN的大型三代家族，其中有10名受影响男性和8名女性携带者。在WAS基因中鉴定出一个c.882T>C突变，导致I294T突变。鉴于严重的中性粒细胞减少症，感染病程多变且较轻。除了最初的描述外，低正常的IgA水平、低至低正常的血小板计数以及自然杀伤（NK）细胞计数减少也表现为XLN的一致特征。然而，在这个家族中未发现CD4/CD8比值倒置，也未发现骨髓增生异常综合征或急性髓系白血病病例。女性携带者表现出可变的减轻型表型。与L270P WASP一样，I294T WASP对肌动蛋白聚合具有组成型活性。总之，这个迄今为止鉴定出的最大的XLN家族提供了新的独立遗传证据，表明破坏WASP自身抑制性GBD的突变是XLN的病因。NK细胞减少、血小板计数低至低正常以及IgA水平低至低正常也是XLN的特征。
