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 5 affected members and with an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich-syndrome protein (WASP) (Devriendt, et al 2001). Here, we report and describe a large three-generation family with XLN, with 10 affected males and 8 female carriers. A c.882T>C WAS gene mutation was identified, resulting in an I294T mutation. The infectious course is variable and mild in view of the deep neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced 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 polymerisation 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.

Phosphorylation of WASp is a key regulator of activity and stability in vivo

“…Recently, several human WASp mutations have been identified that result in constitutive activation through disruption of the autoinhibitory conformation, resulting in a phenotype of myeloid cytopenia (30)(31)(32). In all cases, the levels of WASp within peripheral blood cells have been reported to be normal, but they have displayed cytoskeletal abnormalities associated with enhanced and delocalized actin polymerization (26,31).…”

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

“…Three novel mutations (L270P, S272P, and I294T) clustered within the GTPase binding domain of WASP were recently identified in patients with a severe congenital form of X-linked neutropenia (XLN; Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009). The L270P, S272P, and I294T mutations destroy the autoinhibited conformation of WASP and generate an unfolded protein with enhanced actinpolymerizing activity (Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009).…”

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes

“…Contrasting to WAS and XLT wherein inactivating WASP mutations lead to absent or residual protein expression, activating WASP mutations that target the GBD and interfere with autoinhibition cause X-linked neutropenia (XLN, SCN-XL) [37][38][39]. Constitutively active WASP results in intensified and misplaced actin polymerization and results in defective mitosis and cytokinesis as well as apoptosis-prone proliferation, especially in myeloid lineages [40].…”