WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia

The WASP gene has been recently cloned from Xp11.23 and shownto be mutated in three patients with the Wiskott-Aldrich syndrome(WAS). We have developed a screening protocol for identifyingWASP gene alterations in genomic DNA and have identified a spectrumof novel mutations In 12 additional unrelated families. Thesemissense, nonsense and frameshift mutations involve eight ofthe 12 exons of the gene. Two mutations creating premature terminationcodons were associated with lack of detectable mRNA on Northernblots. Four amino acid substitutions, Leu27Phe, Thr48lle, Val75Metand Arg477Lys, were found In patients with congenital thrombocytopeniaand no clinically evident immune defect indicating that theWASP gene is the site for mutations in X-linked thrombocytopeniaas well as in WAS. A T-cell line from a WAS patient containedtwo independent DNA alterations, a constitutional frameshiftmutation, also present in peripheral blood leukocytes from thepatient, and a compensatory splice site mutation unique to thecell line. The distribution of eight missense mutations providesvaluable information on amino acids which are essential fornormal protein function, and suggests that sites in the firsttwo exons are hot-spots for mutation.