Blood Journal
Leading the way in experimental and clinical research in hematology

High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome

  1. GS Wengler,
  2. LD Notarangelo,
  3. S Berardelli,
  4. G Pollonni,
  5. P Mella,
  6. A Fasth,
  7. AG Ugazio, and
  8. O Parolini
  1. Department of Pediatrics, University of Brescia, Italy.

Abstract

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X- chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.