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Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing
Author(s) -
McCormick James,
Flower Darren R.,
Strobel Stephan,
Wallace Diana L.,
Beverley Peter C.L.,
Tchilian Elma Z.
Publication year - 2002
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.10010
Subject(s) - perforin , hemophagocytic lymphohistiocytosis , missense mutation , mutation , mutant , biology , cytolysis , cytotoxic t cell , rna splicing , immunology , cancer research , gene , genetics , cd8 , medicine , immune system , disease , pathology , in vitro , rna
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.