A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perform mutations associated with familial hemophagocytic lymphohistiocytosis

Abstract

Up to 60% of cases of the autosomal recessive immunodeficiency hemophagocytic lymphohistiocytosis (HLH) are associated with mutations in the perform (PRF1) gene. In this study, we expressed wild-type and mutated perform in rat basophil leukemia cells to study the effect on lytic function of the substitutions A91V and N252S (commonly considered to be neutral polymorphisms) and 22 perform missense substitutions first identified in HLH patients. Surprisingly, we found that A91V perform was expressed at reduced levels compared with wild-type perform, resulting in partial loss of lytic capacity. In contrast, expression and function of N252S-substituted perform were normal. Most HLH-associated mut..