title: A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.
abstract: 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.
authors.affiliation: Centre for Human Genetics/Department of Haematology, University Hospital Leuven and University of Leuven, Leuven, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Beel
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Cotter
authors.forename: Jan
authors.initials: J
authors.lastname: Blatny
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bond
authors.forename: Geoff
authors.initials: G
authors.lastname: Lucas
authors.forename: Frances
authors.initials: F
authors.lastname: Green
authors.forename: Vik
authors.initials: V
authors.lastname: Vanduppen
authors.forename: Daisy W
authors.initials: DW
authors.lastname: Leung
authors.forename: Sean
authors.initials: S
authors.lastname: Rooney
authors.forename: Owen P
authors.initials: OP
authors.lastname: Smith
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rosen
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009503:Neutropenia / Q000235:genetics*; D010375:Pedigree; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein