ISOLATION OF A NOVEL GENE MUTATED IN WISKOTT-ALDRICH SYNDROME

Abstract

Purpose of the Study. Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder associated with severe thrombocytopenia, eczema, bloody diarrhea, B & T cell immunodeficiency and increased risk of malignancies. This study describes the isolation of a novel gene, WAS Protein (WASP) which is mutated in four WAS patients.

Methods. The WAS gene had been localized previously by linkage analyses to a >1 Megabase region in chromosome Xp11.22-p11.23. To isolate the WAS gene, a clone contig was constructed in this interval, followed by isolation of cDNA sequences.

Results. A novel gene, WASP, was isolated, which is believed to be the main genetic locus in WAS. This is supported by the following findings. First, the gene was isolated from the chromosome Xp11.22-p11.23 interval previously identified as containing the WAS gene. Second, lymphoblasts from two unrelated patients clinically diagnosed with WAS failed to express WASP on Northern blots. Two additional WAS patients were also found to have point substitution mutations of an arginine residue. Finally, WASP is expressed in lymphocytic and megakaryocytic cell lineages, indicating a close correlation between tissue-specific gene expression and the disease manifestations of WAS.

Reviewer's Comments. This paper succinctly describes a major breakthrough in the identification of the defective gene in WAS, which is found to be mutated in the four WAS patients studied. This finding brings direction and impetus to research on WAS, provides improved methods for detecting WAS, and brings the possibility of gene replacement therapy for WAS much closer.