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

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

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

 

 

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

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

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.

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.

 

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).

 

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.

Treatment

• Intravenous immunoglobulin substitution
• Specialized antibiotics
• Splenectomy
• Hematopoietic stem cell transplantation

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.

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.