Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus.

Mutation in the gene encoding the recently isolated WASP protein has now been identified as the genetic defect responsible for the X-linked Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disease associated with extensive phenotypic variability. To elucidate the range of WASP mutations responsible for WAS, we used PCR-SSCP analysis to screen for WASP gene mutation in 19 unrelated boys with the diagnosis of classical or attenuated WAS or isolated thrombocytopenia. All 19 patients had WASP mutations, each of which localized to the initial three or terminal three exons of the gene, and the majority of which were unique in each case. However, a missense mutation which results in substitution of the arginine at WAS codon 86 was identified in three boys with severe WAS as well as in one boy presenting with thrombocytopenia alone. While the three mutations found in the isolated thrombocytopenia patients leave the reading frame intact, about one-half of the gene alterations detected in both severe and attenuated WAS patients result in frameshifted transcript and premature translation termination. These findings therefore confirm the association of WAS with WASP mutation and identify WASP mutation as a cause for isolated congenital thrombocytopenia in males. While the WASP gene defects responsible for isolated thrombocytopenia and other mild presentations of WAS do not appear distinct from those resulting in severe WAS, these data indicate that analysis of WASP gene mutation provides a valuable tool for distinguishing the spectrum of WAS patients and the subset of males with isolated thrombocytopenia who represent mild cases of WAS.