The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene

Ilia Voskoboinik, Marie Claude Thia, Annette De Bono, Kylie Browne, Erika Cretney, Jacob T. Jackson, Phillip K. Darcy, Stephen M. Jane, Mark J. Smyth, Joseph A. Trapani

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60 Citations (Scopus)


About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure-function relationships for lymphocyte perforin.

Original languageEnglish
Pages (from-to)811-816
Number of pages6
JournalJournal of Experimental Medicine
Issue number6
Publication statusPublished - 20 Sept 2004
Externally publishedYes


  • CTL
  • Cytotoxic granule
  • HLH
  • Immunodeficiency
  • NK cell

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