Structure and function of the Wiskott-Aldrich syndrome protein

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.

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.

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.