This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, SUSCEPTIBILITY TO, with 2 'included' designations, LYMPHOMA, NON-HODGKIN, SUSCEPTIBILITY TO and APLASTIC ANEMIA, SUSCEPTIBILITY TO, has been reclassified based on the reports by Molleran Lee et al. (2004), zur Stadt et al. (2004), and Lek et al. (2016).
In 2 sibs with adult onset and atypical presentation of hemophagocytic lymphohistiocytosis (FHL2; 603553), Clementi et al. (2002) identified compound heterozygosity of a 272C-T transition in exon 2 of the PRF1 gene, resulting in an ala91-to-val (A91V) substitution, and a trp374-to-ter (W374X; 170280.0002) mutation in the PRF1 gene. Clementi et al. (2005) reported that 1 of the sibs had a non-Hodgkin lymphoma (605027).
Busiello et al. (2004) reported a family in which fraternal twins were both homozygous for the A91V substitution but showed markedly different phenotypic expression. The proband presented at age 13 years with persistent fever, hepatosplenomegaly, cytopenia, and lymph node enlargement. Signs of hemophagocytosis in a liver biopsy specimen led to the diagnosis of FHL. The patient died after a rapidly progressive disease course. All the remaining family members, including the homozygous twin, were considered normal. Natural killer activity was severely impaired in the patient but normal in the asymptomatic twin. Both twins and the father carried a second PRF1 mutation in heterozygous state: 695G-A transition resulting in an R231H amino acid change. The report highlighted the long disease-free interval during which biochemical or immunologic alterations may not be evident and the suggestion that factors other than mutation in the perforin gene may be involved.
Clementi et al. (2006) identified the A91V substitution of PRF1 in 6 of 28 patients with Dianzani autoimmune lymphoproliferative disease (DALD; 605233), a disorder that resembles autoimmune lymphoproliferative syndrome (ALPS; 601859) but lacks expansion of double-negative T cells. Presence of A91V conferred an odds ratio of 3 for DALD, and the odds ratio increased to 17 if variations in the osteopontin (SPP1; 166490) gene associated with increased osteopontin production were also present. However, A91V was relatively frequent (4.6%) in controls. Clementi et al. (2006) suggested that A91V may be a susceptibility factor for DALD in patients with defective FAS (TNFRSF6; 134637) function.
Solomou et al. (2007) identified a heterozygous A91V substitution in 3 unrelated adults who developed aplastic anemia (609135) at ages 31, 77, and 78, respectively. Two of these patients had evidence of hemophagocytosis on bone marrow biopsy with no other clinical features of hemophagocytic syndrome. One patient had no response to immunosuppression, and 2 had only partial responses. Perforin protein levels and perforin granules were markedly decreased or absent in CD8(+) T cells. All 3 patients also carried a heterozygous synonymous his300-to-his (H300H) polymorphism in exon 3 of the PRF1 gene. The A91V substitution was identified in 24 (1.0%) of 2,312 control chromosomes.
Molleran Lee et al. (2004) and zur Stadt et al. (2004) identified the A91V substitution with an allelic frequency of 3% and 9%, respectively, suggesting that it is a polymorphism.
Lek et al. (2016) noted that the A211V (A91V) variant has a high allele frequency (0.0174) in the South Asian population in the ExAC database, suggesting that it is not pathogenic.
Variant Function
In rat basophil leukemia cells, Voskoboinik et al. (2005) found that the A91V PRF1 protein showed decreased expression, resulting in partial loss of lytic capacity.
In studies of rat basophil leukemia cells and perforin-deficient mouse cytotoxic T cells, Voskoboinik et al. (2007) found that human A91V mutant protein had a 10-fold decrease in target cell lysis activity compared to wildtype protein. The mutant protein was also present at lower levels. Further studies suggested that the mutant protein undergoes abnormal folding. Voskoboinik et al. (2007) suggested that the diminished lytic activity of the A91V protein may be partly rescued by other granule toxins, thus resulting in a less dramatic clinical effect.
