Transcript The Wiskott-Aldrich Syndrome: An X

The Wiskott-Aldrich
Syndrome:
An X-linked Primary
Immunodeficiency
Kristin Goff
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 Xchromosome
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
Normal platelets
Small Platelets
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 antigenpresenting 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.