The Wiskott-Aldrich Syndrome: An X-linked Primary Immunodeficiency

1. The Wiskott-Aldrich Syndrome:An X-linked Primary Immunodeficiency Kristin Goff

2. WAS • Primary immune deficiency disorder • Entails part of the bodies immune system is missing or does not function properly • Caused by genetic defects in the immune system • X-linked recessive trait • Genetic defect causing deficiency is on the X-chromosome • Only affects males and is passed to child from the mother, a healthy carrier of the disorder

5. Symptoms • Thrombocytopenia (low platelet count and disturbed platelet function) • Recurrent infections • Eczema • Malignancies in the form of leukemia and lymphoma occur in more severe cases

6. Normal platelets

7. Small Platelets

8. History • First described by German physician Alfred Wiskott in 1937 • Robert Anderson Aldrich described the disease as an X-linked recessive trait in 1954 • Joined the list of Primary Immune Deficiency Diseases in the 1960’s

9. Mutations • WAS is associated with the absence of the Wiskott-Aldrich Syndrome protein (WASP) which is caused by simple mutations in the WASP gene • Missense and frameshift mutations are two known to cause WAS

10. A missense mutation has the ability to change one amino acid into a different amino acid, altering the protein and possibly causing it to be nonfunctional. A frameshift mutation deletes a DNA base, shifting the entire sequence and changing the amino acids from that point on. In this case, the Mutation turns an amino acid in the protein sequence into a stop codon and translation of the protein is prematurely ended.

11. Actin Reorganization • WASP is involved in the reorganization of the actin skeleton. When the WAS protein is altered, it does not properly bind and actin reorganization is prohibited.

12. Affect on T Lymphocytes • Cytoskeleton reorganization is involved in the binding of T lymphocytes to antigen-presenting cells through CD3 crosslinking. • Without actin reorganization, CD3 is not properly presented at the cells surface and the T cell is not activated. • Causes recurrent viral and fungal infections (as noted in symptoms).

14. Affect on B Lymphocytes • Thymus dependent B lymphocytes need T cells for activation and differentiation. • B cells only able to produce IgM through thymus independent B lymphocytes. • Causes recurrent bacterial infections because proper antibodies are not produced against certain bacteria.

17. Treatment • Intravenous immunoglobulin substitution • Specialized antibiotics • Splenectomy • Hematopoietic stem cell transplantation

18. WAS Discovered in Females • Skewed X-chromosome inactivation in a female carrier can cause the typically healthy female to exhibit clinical signs of the disorder. • Causes the X-chromosome carrying the normal WASP gene to become inactivated so only the X-chromosome with the mutant WASP gene is left active.

19. Summary • WAS is caused by a mutation in the WASP gene. • A mutation in the WASP gene inhibits actin reorganization. • Without actin reorganization, CD3 cannot be presented and T cells are not activated. • Thymus dependent B cells are not activated without production of T cells. • B cell differentiation does not occur and only IgM antibodies are produced.