Structure and function of the Wiskott-Aldrich syndrome protein.

PURPOSE OF REVIEW: Mutations of the Wiskott-Aldrich syndrome protein can result in highly variable clinical symptoms that affect the hematopoietic/immunologic system. The responsible gene, WASP, has multiple domains, each with unique functions that were only recently fully recognized.

RECENT FINDINGS: Two new comprehensive studies of patients with mutations of the Wiskott-Aldrich syndrome protein unequivocally demonstrated a strong phenotype-genotype correlation; the most predictive variable was the presence or absence of the Wiskott-Aldrich syndrome protein in the lymphoid cells from patients with X-linked thrombocytopenia or Wiskott-Aldrich syndrome, respectively. A third clinical study revealed a high rate (>70%) of autoimmune disorders in patients with classic Wiskott-Aldrich syndrome, possibly caused by immune dysregulation involving both T and B cell defects. In addition, the Wiskott-Aldrich syndrome protein is required for natural killer cell function by participating in the formation of immunologic synapses and facilitating the nuclear translocation of nuclear factor for activated T cell and nuclear factor-kappaB. Finally, the Wiskott-Aldrich syndrome protein was shown to play an important role in lymphoid development and in the maturation and function of myelomonocytic cells.

SUMMARY: The progress made in dissecting the functions of the Wiskott-Aldrich syndrome protein has direct implications for our understanding of the distinct clinical phenotypes (Wiskott-Aldrich syndrome/X-linked thrombocytopenia; intermittent thrombocytopenia; congenital neutropenia), for making diagnostic and prognostic decisions, and for the selection of therapeutic strategies--from conservative symptomatic treatment to curative hematopoietic stem cell transplantation, or, in the future, gene therapy.