Mutations in the perform gene have been found in patients with hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disease. We describe a patient expressing perform with amino acid changes A91V and W374X. The ability of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to lyse target cells is greatly reduced. Here we demonstrate that perform from this patient is not recognized using an antibody raised against native perform (δG9), but is readily detected using an antibody raised against a peptide epitope (2d4), suggesting that the epitope recognized by δG9 is destroyed by the change at A91V. Immunoblotting reveals no protein corresponding to the truncated transcript encoded by W374X, revealing that only perform with the A91V change Is expressed in CTLs from the patient. Patient CTLs show bands corresponding to the immature and intermediate forms of perform, but the mature active form of perform is absent or barely detectable. The conformational changes and impaired cleavage of A91V perform are likely to explain the reduced cytotoxicity in CTLs and NK cells from this patient and are likely to contribute to the pathogenesis of HLH.
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