Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macr ophages). Cytotoxic T and natural killer (NK) cell activity is markedly red uced or absent in these patients, and mutations in a lytic granule constitu ent, perforin, were recently identified in a number of FHL individuals. Her e, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative freque ncy of perforin mutations in FHL. Perforin mutations were identified in 7 o f the 34 families investigated. Six children were homozygous for the mutati ons, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a pr emature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mut ations in 20% of all FHL patients investigated (7/34), with a somewhat high er prevalence, similar to 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phen otype of the patients was evident from the present study. Our combined resu lts from mutational analysis of 34 families and linkage analysis of a subse t of consanguineous families indicate that perforin mutations account for 2 0%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for similar to 10%, whereas the major part of the FHL cases are caused by mutations in not -yet-identified genes.