Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is caused by mutations of the Wiskott-Aldrich syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review will focus on recent progress in understanding the molecular basis of Wiskott-Aldrich syndrome and its ramifications for the cure of this lethal disease.

The discovery of the causative gene has revealed a spectrum of clinical phenotypes demonstrating a strong genotype/phenotype correlation. The discovery of unique functional domains of Wiskott-Aldrich syndrome protein has been instrumental in defining mechanisms that control activation of Wiskott-Aldrich syndrome protein. Long-term follow up of patients undergoing hematopoietic stem cell transplantation has led to important modifications of the procedure. Studies of Wiskott-Aldrich syndrome protein-deficient cell lines and wasp-knockout mice have paved the way for possible gene therapy.

Wiskott-Aldrich syndrome protein gene mutations result in four clinical phenotypes: classic Wiskott-Aldrich syndrome and X-linked thrombocytopenia, intermittent thrombocytopenia and neutropenia. Wiskott-Aldrich syndrome protein is a signaling molecule and instrumental for cognate and innate immunity, cell motility and protection against autoimmune disease. The success of hematopoietic stem cell transplantation is related to the recipient's age, donor selection, the conditioning regimen and the extent of reconstitution. Since Wiskott-Aldrich syndrome protein is expressed exclusively in hematopoietic stem cells, and because Wiskott-Aldrich syndrome protein exerts a strong selective pressure, gene therapy is expected to cure the disease.