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© 1995 Oxford University Press

RESEARCH-ARTICLE

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

Jonathan M.J. Derry1, Julie A. Kerns1, Kenneth I. Weinberg3, Hans D. Ochs4, Victor Volpini5, Xavier Estivill5, Ann P. Walker6 and Uta Francke1,2,*

1Howard Hughes Medical Institute Stanford, CA 94305 2Departments of Genetics and Pediatrics, Stanford University Medical Center Stanford, CA 94305 3Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital of Los Angeles Los Angeles, CA 90027 4Department of Pediatrics, University of Washington School of Medicine Seattle, WA 98195, USA 5Molecular Genetics Department, IRO Autovia de Castelldefels, 08907 Hospitalet, Barcelona, Spain 6Deparment of Pediatrics, University of California Irvine Medical Center Orange, CA 92613, USA

*To Whom correspondence should be addresed

Received February 28, 1995; Revised April 17, 1995; Accepted April 17, 1995

The WASP gene has been recently cloned from Xp11.23 and shown to be mutated in three patients with the Wiskott-Aldrich syndrome (WAS). We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations In 12 additional unrelated families. These missense, nonsense and frameshift mutations involve eight of the 12 exons of the gene. Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots. Four amino acid substitutions, Leu27Phe, Thr48lle, Val75Met and Arg477Lys, were found In patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X-linked thrombocytopenia as well as in WAS. A T-cell line from a WAS patient contained two independent DNA alterations, a constitutional frameshift mutation, also present in peripheral blood leukocytes from the patient, and a compensatory splice site mutation unique to the cell line. The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation.


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