Perforin gene defects in familial hemophagocytic lymphohistiocytosis

SE Stepp, R Dufourcq-Lagelouse, FL Deist, S Bhawan… - Science, 1999 - science.org
SE Stepp, R Dufourcq-Lagelouse, FL Deist, S Bhawan, S Certain, PA Mathew, JI Henter…
Science, 1999science.org
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 …
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.
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