Mutations of the WASP gene in 10 Japanese patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characteri zed by thrombocytopenia, immunodeficiency, and eczema. X-linked thrombocyto penia (XLT) is a mild form of WAS with isolated thrombocytopenia. Both phen otypes are caused by mutation of the Wiskott-Aldrich syndrome protein (WASP ) gene. In this study, we identified mutations of the WASP gene in 10 Japan ese patients from 9 unrelated families with WAS/XLT. All XLT patients (n = 3) and one WAS patient had a missense mutation at the PH domain of WASP. Tw o WAS patients had nonsense mutations. One WAS patient had exon 8 skipping caused by one nucleotide deletion at the acceptor site of intron 7. Three W AS patients had genomic deletions; one of the three had a large genomic del etion involving exons 3 to 7. Codons 45 and 86 seem to be the hot spots of the WASP mutation, because missense mutations in these codons have been rep orted previously in several WAS/XLT patients in addition to the patients in this report, and patients with the same mutation show a similar clinical p henotype. All other mutations are novel, indicating that the mutations of W ASP are heterogeneous. EB virus-transformed cell lines from XLT patients ex pressed nearly normal amounts of WASP, whereas those from typical WAS patie nts expressed almost undetectable amounts of WASP. We conclude that the ana lysis of gene mutation and protein expression of WASP are useful together i n assessing the severity of WAS. (C) 2000 The Japanese Society of Hematolog y.