Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.
The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted 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 picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments.
Schindelhauer
D
D
Abteilung für Pädiatrische Genetik der Kinderpoliklinik, München, Germany.
Weiss
M
M
Hellebrand
H
H
Golla
A
A
Hergersberg
M
M
Seger
R
R
Belohradsky
B H
BH
Meindl
A
A
D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics*; D051316:Wiskott-Aldrich Syndrome Protein
D018389:Codon, Nonsense; D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein