Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis

Abstract

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 (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, 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 premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes.

Figure 1

Schematic representation of the perforin gene, showing the localization of mutations in FHL. The three exons of the perforin gene are represented by boxes, introns by lines. The coding region of the perforin gene comprises exon 2 and 3 and is indicated by coloured boxes. In the upper part of the figure, mutations identified in the present study are indicated. The trp374→stop mutation, initially reported by Stepp et al. (1999), was identified in four families (see table 2). The lower part represents previously described mutations in the perforin gene (Stepp et al. 1999). The mutations have been grouped with regard to whether they are nonsense mutations, missense mutations, or deletions.