R. Rengan et al., Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells, BLOOD, 95(4), 2000, pp. 1283-1292
Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothes
ized to cause defective actin cytoskeletal function. This resultant dysfunc
tion of the actin cytoskeleton has been implicated in the pathogenesis of W
iskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated ac
tin polymerization is kinetically normal in the hematopoietic lineages affe
cted in WAS. It was also found that the actin cytoskeleton in WAS platelets
is capable of producing the hallmark cytoarchitectural features associated
with activation, Further analysis revealed accelerated cell death in WAS l
ymphocytes as evidenced by increased caspase-3 activity. This increased act
ivity resulted in accelerated apoptosis of these cells. CD95 expression was
also increased in these cells, suggesting an up-regulation in the FAS path
way in WAS lymphocytes, Additionally, inhibition of actin polymerization in
lymphocytes using cytochalasin B did not accelerate apoptosis in these cel
ls, This suggests that the accelerated apoptosis observed in WAS lymphocyte
s was not secondary to an underlying defect in actin polymerization caused
by mutation of the WAS gene. These data indicate that WASP does not play a
universal role in signaling actin polymerization, but does play a role in d
elaying cell death. Therefore, the principal consequence of mutations in th
e WAS gene is to accelerate lymphocyte apoptosis, potentially through upreg
ulation of the FAS-mediated cell death pathway. This accelerated apoptosis
may ultimately give rise to the clinical manifestations observed in WAS. (C
) 2000 by The American Society of Hematology.