Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing

Hemophagocytic lymphohistiocytosis (HLH) composes a group of rare heterogenous disorders characterized by uncontrolled accumulation and infiltration of activated T lymphocytes and macrophages. Cytotoxic T and natural killer cell activity is significantly reduced or absent in these patients. Mutations in the important mediator of lymphocyte cytotoxicity perforin were identified in a number of HLH individuals. Here we report a novel missense mutation thr435met in the conserved Ca 2+ binding domain of perforin in a patient with HLH. Prediction of the 3‐dimensional structure of the thr435met perforin mutant using comparative molecular modeling indicates that the protein's ability to bind Ca 2+ , and therefore its cytolytic function, would be strongly compromised. In addition, this patient exhibited abnormal CD45 splicing caused by a C77G mutation in the gene encoding CD45 ( PTPRC). Our findings suggest a combined role for perforin mutation and abnormal CD45 splicing as significant contributory factors in the pathogenesis of HLH. © 2003 Wiley‐Liss, Inc.