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 Ca2+ 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 Ca2+, 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.
- cd45 splicing
McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., & Tchilian, E. Z. (2003). Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing. American Journal of Medical Genetics Part A , 117A(3), 255-260. https://doi.org/10.1002/ajmg.a.10010