title: The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle 98195, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: R M
authors.initials: RM
authors.lastname: Blaese
authors.forename: J M
authors.initials: JM
authors.lastname: Derry
authors.forename: A
authors.initials: A
authors.lastname: Junker
authors.forename: U
authors.initials: U
authors.lastname: Francke
authors.forename: S H
authors.initials: SH
authors.lastname: Chen
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
mesh_terms: D001483:Base Sequence; D001792:Blood Platelets / Q000648:ultrastructure; D002460:Cell Line; D048429:Cell Size; D016172:DNA Fingerprinting; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D013921:Thrombocytopenia / Q000151:congenital / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics*; D051316:Wiskott-Aldrich Syndrome Protein; D014960:X Chromosome
chemical_list: D018076:DNA, Complementary; D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein