Evaluation of an ALPS-like Patient with a Cytokine Withdrawal Apoptotic Defect

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Abstract

An ALPS-like patient without an identified mutation has been found to have a unique in vitro defect in T cell apoptosis associated with IL-2 withdrawal but normal T cell and B cell apoptosis in response to staurosporine, etoposide, cisplatin and radiation as well as a normal Fas pathway induction of apoptosis. The defect in this patient appears to be particularly associated with the development of lymphoid malignancy as this individual has developed two distinct lymphoid tumors. This suggests the possibility of a distinct defect in the mitochondrial cell death pathway with a number of candidate proteins that were evaluated and expression microarrays were set-up ultimately leading to the identification of a gain of function defect in NRAS. This also defines an that this intrinsic pathway of cell death serves as an alternative pathway for cytokine withdrawl induced lymphocyte apoptosis and suggests that the Fas mediated extrinsic pathway may actually play a more minor role in this. Recently, we have become aware of a second patient with a similar clinical story and a reported mutation in NRAS, this patient will be evaluated by our group to establish the level of the functional apoptotic defect and also will be studied to confirm that a mutation in the gene encoding NRAS is present.