Perforin gene defects in familial hemophagocytic lymphohistiocytosis

Susan E. Stepp, Rémi Dufourcq-Lagelouse, Françoise Le Deist, Sadhna Bhawan, Stéphanie Certain, Porunelloor A. Mathew, Jan Inge Henter, Michael Bennett, Alain Fischer, Geneviève De Saint Basile, Vinay Kumar

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Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.

Original languageEnglish
Pages (from-to)1957-1959
Number of pages3
JournalScience
Volume286
Issue number5446
DOIs
StatePublished - 3 Dec 1999

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    Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J. I., Bennett, M., Fischer, A., De Saint Basile, G., & Kumar, V. (1999). Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science, 286(5446), 1957-1959. https://doi.org/10.1126/science.286.5446.1957