WISKOTT-ALDRICH SYNDROME - NO STRICT GENOTYPE-PHENOTYPE CORRELATIONS BUT CLUSTERING OF MISSENSE MUTATIONS IN THE AMINO-TERMINAL PART OF THEWASP GENE-PRODUCT

The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutat ed in patients presenting with WAS and in patients showing X-linked th rombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequenc ing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons con trasted with a random distribution of nonsense mutations. More than 85 % of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical p icture for a classical WAS phenotype. A substitution at codon 86 resul ted in an extremely variable expression of the disease in a large Swis s family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), w hich is involved in the maintenance of cytoarchitecture by interacting with actin-like filaments.