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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-02-0388.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2763-2768
HEMATOPOIESIS
Wiskott-Aldrich syndrome in a female
Maxim I. Lutskiy,
Yoji Sasahara,
Dianne M. Kenney,
Fred S. Rosen, and
Eileen Remold-O'Donnell
From the Center for Blood Research, and the Division of
Immunology, Children's Hospital, and the Department of Pediatrics,
Harvard Medical School, Boston, MA.
Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized
by thrombocytopenia, eczema, and various degrees of immune deficiency.
Carriers of mutated WASP have nonrandom X
chromosome inactivation in their blood cells and are disease-free. We
report data on a 14-month-old girl with a history of WAS in her family who presented with thrombocytopenia, small platelets, and immunologic dysfunction. Sequencing of the WASP gene showed that the
patient was heterozygous for the splice site mutation previously found in one of her relatives with WAS. Sequencing of all WASP exons revealed
no other mutation. Levels of WASP in blood mononuclear cells
were 60% of normal. Flow cytometry after intracellular staining of
peripheral blood mononuclear cells with WASP monoclonal antibody revealed both WASPbright and WASPdim
populations. X chromosome inactivation in the patient's blood cells
was found to be random, demonstrating that both maternal and paternal
active X chromosomes are present. These findings indicate that the
female patient has a defect in the mechanisms that lead in disease-free
WAS carriers to preferential survival/proliferation of cells bearing
the active wild-type X chromosome. Whereas the patient's lymphocytes
are skewed toward WASPbright cells, about 65% of her
monocytes and the majority of her B cells (CD19+) are
WASPdim. Her naive T cells
(CD3+CD45RA+) include WASPbright
and WASPdim populations, but her memory T cells
(CD3+CD45RA ) are all WASPbright.
After activation in vitro of T cells, all cells exhibited
CD3+CD45RA phenotype and most were
WASPbright with active paternal (wild-type) X chromosome,
suggesting selection against the mutated WASP allele during
terminal T-cell maturation/differentiation.
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