Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis

TLDR

Familial hemophagocytic lymphohistiocytosis is a rare, autosomal recessive disorder marked by uncontrolled T‑cell and macrophage activation, excessive cytokine production, and genetic heterogeneity involving loci such as 9q21.3‑22 and 10q21‑22. Sequencing of the perforin gene in eight 10q21‑22‑linked FHL patients uncovered homozygous nonsense and missense mutations, and functional studies showed defective cytotoxicity and absent perforin, establishing perforin defects as the cause of this FHL subtype and highlighting perforin’s role in cell lysis and immune regulation.

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.