Perforin gene defects in familiar hemophagocytic lymphohistiocytosis

Familiar hemophagocytic Lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activati on 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 t he coding regions of the perforin gene of eight unrelated 10q21-22-linked F HL patients revealed homozygous nonsense mutations in four patients and mis sense mutations in the other four patients. Cultured Lymphocytes from patie nts 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, invol ved not only in the Lysis of abnormal cells but also in the downregulation of cellular immune activation.