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.

Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation

“…47,48 Patients with FHL usually present in infancy or very early in childhood and in the absence of bone marrow transplantation most patients die within 1 year after diagnosis. 23,27,49 Patients with FHL and nonsense mutations tend to present within the first few months of life, whereas those with missense mutations usually present by 2 years of age. 23 Although our patient showed many of the features of FHL early in the course of his disease, 22 he presented at an older age (7 years) than most patients with FHL, survived for 10 years after diagnosis, and did not have a family history of hemophagocytic lymphohistiocytosis.…”

A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype

“…Since the identification of this gene, which is responsible for the disease in a subgroup of patients, 2 several groups have reported on the identification of novel mutations. [3][4][5][6] Small deletions and nonsense and missense mutations were described and scattered both coding exons of the gene. In this family, the homozygous A91V and the heterozygous R231H exchange was detectable in both twins, one of them presenting typical signs of hemophagocytic lymphohistiocytosis (HLH) at the age of 11 years with a rapidly fatal course of the disease.…”

Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations

“…[1][2][3][4][5][6] Flow cytometric detection of perforin in peripheral blood natural killer (NK) cells and cytotoxic T lymphocytes was previously studied in a small number of patients by our group and suggested that flow cytometry offered a rapid and sensitive approach for detection of perforin deficiency. 7 To more accurately determine the clinical diagnostic accuracy of flow cytometric screening for the detection of PRF1 mutations, we reviewed the reported results of 750 clinical samples submitted to the Diagnostic Immunology Laboratory at Cincinnati Children's Hospital by the ordering physician for perforin testing between August 2009 and December 2014; genetic sequencing was also performed as directed by the ordering physician.…”