THE WISKOTT-ALDRICH SYNDROME AND X-LINKED CONGENITAL THROMBOCYTOPENIAARE CAUSED BY MUTATIONS OF THE SAME GENE

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder c haracterized by thrombocytopenia, small platelets, eczema, recurrent i nfections, and immunodeficiency. Besides the classic WAS phenotype, th ere is a group of patients with congenital X-linked thrombocytopenia ( XLT) who have small platelets but only transient eczema, if any, and m inimal immune deficiency. Because the gene responsible for WAS has bee n sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determi ned the approximate location of the mutation in 13 unrelated WAS patie nts with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including ins ertions, deletions, and point mutations resulting in amino acid substi tutions, termination, exon skipping, or splicing defects. Of 4 unrelat ed patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients wi th classic WAS had more complex mutations, resulting in termination co dons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene an d suggest that severe clinical phenotypes are associated with complex mutations. (C) 1995 by The American Society of Hematology.