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The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are
caused by mutations of the same gene
Q Zhu, M Zhang, RM Blaese, JM Derry, A Junker, U Francke, SH Chen and HD Ochs
Department of Pediatrics, University of Washington School of Medicine,
Seattle 98195, USA.
The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder
characterized by thrombocytopenia, small platelets, eczema, recurrent
infections, and immunodeficiency. Besides the classic WAS phenotype, there
is a group of patients with congenital X-linked thrombocytopenia (XLT) who
have small platelets but only transient eczema, if any, and minimal immune
deficiency. Because the gene responsible for WAS has been sequenced, it was
possible to correlate the WAS phenotypes with WAS gene mutations. Using a
fingerprinting screening technique, we determined the approximate location
of the mutation in 13 unrelated WAS patients 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 insertions, deletions, and point
mutations resulting in amino acid substitutions, termination, exon
skipping, or splicing defects. Of 4 unrelated patients with the XLT
phenotype, 3 had missense mutations affecting exon 2 and 1 had a
splice-site mutation affecting exon 9. Patients with classic WAS had more
complex mutations, resulting in termination codons, frameshift, and early
termination. These findings provide direct evidence that XLT and WAS are
caused by mutations of the same gene and suggest that severe clinical
phenotypes are associated with complex mutations.
Volume 86,
Issue 10,
pp. 3797-3804,
11/15/1995
Copyright © 1995 by The American Society of Hematology
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