Alternative titles; symbols
HGNC Approved Gene Symbol: PRF1
SNOMEDCT: 304132006, 306058006; ICD10CM: D61.9; ICD9CM: 284.9;
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38) : 10:70,597,348-70,602,741 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Aplastic anemia | 609135 | 3 | |
| Hemophagocytic lymphohistiocytosis, familial, 2 | 603553 | Autosomal recessive | 3 | |
| Lymphoma, non-Hodgkin | 605027 | 3 |
Perforin-1 (PRF1) is one of the major cytolytic proteins of cytolytic granules. One of the main pathways of lymphocyte-mediated cytolysis entails the secretion onto target membranes of cytolytic granules contained in cytolytic effector lymphocytes of T-cell or NK-cell type. Perforin has a molecular mass of 70 to 75 kD and shows extensive similarity in structure to complement component C9 (120940). PRF1 is a pore-forming protein with a mechanism of transmembrane channel formation similar to C9. Podack et al. (1988) reviewed information on the structure and expression of PRF1 obtained through the analysis of cDNA clones. Shinkai et al. (1988) demonstrated homology of perforin with C9 at their respective functionally conserved regions. They also found that perforin is expressed only in killer cell lines and not in helper T lymphocytes or other tumor cells tested. Lichtenheld et al. (1988) determined the primary structure of human perforin. In the mouse, Trapani et al. (1990) found that the perforin gene has a simplified structure compared to C9.
Using a panel of somatic cell hybrid cell lines, Trapani et al. (1990) mapped the Pfp gene to mouse chromosome 10. By in situ hybridization with a human perforin cDNA probe, Shinkai et al. (1989) assigned the PFP gene to 17q11-q21. Fink et al. (1992) was prompted to reexamine the mapping of PRF1 in the human because the gene was undetectable in a human chromosome 17 reference library in which clones for vitronectin, which maps to the region where PRF1 was supposed to lie, and because of the lack of any known homology between human chromosome 17 and mouse chromosome 10. Using the cosmid DNA containing the PRF1 gene as a probe for fluorescence in situ hybridization, they mapped the gene to human 10q22, a region that is syntenic with mouse chromosome 10. Thus, the perforin locus is not linked to that of any of the genes of the terminal complement system with which it shows partial homology of sequence. Lymphocyte-mediated cytotoxicity is thought to consist of the polarized secretion of granule-stored perforin leading to target-cell lysis. Nevertheless, perforin-independent pathways were postulated to explain the cytolytic activity of lymphocytes that apparently lacked perforin and the DNA degradation found in dying target cells.
Crystal Structure
Law et al. (2010) elucidated the mechanism of perforin pore formation by determining the x-ray crystal structure of monomeric murine perforin, together with a cryoelectron microscopy reconstruction of the entire perforin pore. Perforin is a thin key-shaped molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol-dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, calcium ion-dependent membrane binding. Most unexpectedly, however, electron microscopy revealed that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. Law et al. (2010) concluded that their data revealed remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provided new insights into how related immune defense molecules such as complement proteins assemble into pores.
Familial Hemophagocytic Lymphohistiocytosis
Stepp et al. (1999) identified mutations in homozygosity and compound heterozygosity in patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553). Four patients had missense mutations and 4 patients had homozygous nonsense mutations. Stepp et al. (1999) generated cytotoxic cells by culturing previously frozen cells from 4 FHL patients and controls in phytohemagglutinin and interleukin-2 (147680). CD3 (see 186740)-dependent cytolytic activity was measured in a 4-hour assay. Cells from all patients had greatly reduced cytolytic activity compared with cells from normal controls. Cells from a patient with a premature stop codon displayed no cytotoxicity, and cells from 3 patients with missense mutations showed greatly reduced lysis of the target cells. Stepp et al. (1999) concluded that perforin-mediated cytotoxic activity of CD8+ T cells is defective in FHL patients. No perforin protein was detectable in patient cells using immunostaining. Two patients with low-level cytotoxic activity had a small amount of detectable perforin staining.
Goransdotter Ericson et al. (2001) reported a comprehensive survey of 34 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 mutation, and 1 patient was a compound heterozygote. In 4 families, a previously reported mutation in codon 374 (W374X; 170280.0002), causing a premature stop codon, was identified, making this the most common perforin mutation identified in FHL patients. They found perforin mutations in 20% (7 of 34) of all FHL patients investigated, with a somewhat higher prevalence, approximately 30% (6 of 20), in children whose parents originated from Turkey. They concluded that perforin mutations account for 20 to 40% of FHL cases, that the locus on chromosome 9 (FHL1; 267700) accounts for approximately 10%, and that most FHL cases are caused by mutations in as yet unidentified genes.
In 25 (58%) of 43 unrelated North American families with children diagnosed with primary hemophagocytic lymphohistiocytosis, Molleran Lee et al. (2004) identified mutations in the PRF1 gene. There was no significant difference in median age at diagnosis when comparing patients with or without perforin mutations (6 months vs 7 months, respectively); however, comparing patients with PRF1 mutations who expressed low levels of perforin to those with no detectable perforin, the median age at onset was 54 months versus 3 months, respectively (p less than 0.001).
Role in Lymphoma
Clementi et al. (2002) reported 2 sibs with adult-onset FHL in whom they identified compound heterozygosity for a W374X mutation and an A91V (170280.0011) substitution. At age 21 years, the sister presented with fever, weight loss, weakness, hepatosplenomegaly, and pancytopenia. Repeat bone marrow biopsies showed a T-cell infiltration with no evidence for clonal proliferation. She was diagnosed with a T-cell lymphoblastic lymphoma (605027) and underwent autologous bone marrow transplantation. Her brother presented 2 years later at age 22 years with decreased liver function, fever, lymphadenopathy, pancytopenia, and neurologic symptoms consistent with FHL. Both patients had complete absence of NK cell activity and perforin expression.
Clementi et al. (2004) reported a 27-year-old man with autoimmune lymphoproliferative syndrome (ALPS; 601859) who later developed a large B-cell lymphoma. Genetic analysis identified heterozygous mutations in the FAS gene (134637), which has been known to be associated with ALPS, and the perforin gene (N252S; 170280.0009). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. The authors concluded that the combined effect of the 2 mutant genes contributed to the development of APLS and lymphoma in this patient.
Clementi et al. (2005) reported 3 additional patients with lymphoma who were compound heterozygous for mutations in the PRF1 gene. A 7-year-old boy had Epstein-Barr virus-positive Hodgkin lymphoma, which was successfully treated, and developed a large B-cell non-Hodgkin lymphoma 3 years later. During treatment for the second disease, he developed severe hemophagocytosis. Hematopoietic stem cell transplantation was successful. An unrelated 7-year-old girl developed a subcutaneous T-cell lymphoma associated with hemophagocytosis on bone marrow biopsy. An 18-year-old girl developed peripheral T-cell lymphoma with marrow infiltration and evidence of hemophagocytosis, and underwent successful bone marrow transplantation. Clementi et al. (2005) reported another 3 patients, with lymphoma, B-cell, T-cell and Hodgkin disease, respectively, who all had the same heterozygous A91V substitution (170280.0011) in the PRF1 gene. Clementi et al. (2005) noted that all of the patients they reported with lymphoma and mutations in the PRF1 gene were young, between the ages of 7 and 29 years. The findings suggested a more complex dysregulation of the immune system in the absence of perforin, with some patients developing FHL and some developing other lymphoproliferative disorders, including various forms of lymphoma. The authors postulated that heterozygous mutations in the PRF1 gene may increase susceptibility to the development of lymphoma, perhaps acting as a synergistic factor with other genetic mutations.
Aplastic Anemia
Solomou et al. (2007) identified mutations in the PRF1 gene (170280.0011-170280.0013) in 5 unrelated patients with adult-onset aplastic anemia (609135). Four of the 5 patients showed hemophagocytosis on bone marrow biopsy, but none had clinical manifestations of the hemophagocytosis syndrome. Perforin protein levels in these patients were very low or absent, perforin granules were absent, and natural killer cell cytotoxicity was significantly decreased. Solomou et al. (2007) concluded that PRF1 gene alterations may explain aberrant proliferation and activation of cytotoxic T cells in aplastic anemia.
Risma et al. (2006) classified 21 human PRF1 disease-associated missense mutations into 3 broad classes based on expression in rat basophilic leukemia (RBL-1) cells. Class 1 mutations (see, e.g., A91V, 170280.0011, G429E, 170280.0005) resulted in partial maturation of perforin; class 2 mutations (see, e.g., R225W, 170280.0004) resulted in no apparent proteolytic maturation of the perforin protein; and class 3 mutations resulted in no recognizable forms of perforin due to protein misfolding and protein degradation. Class 1 mutations exhibited lytic function and were associated with residual protein detection and variable cytotoxic function. Patients with class 1 mutations had later disease onset compared to those with class 2 or 3 mutations. By contrast, class 3 mutations caused severely diminished protein detection and cytotoxicity, and patients with class 3 mutations had disease onset before 1 year of age and absent NK function. Patients with class 2 mutations had an intermediate phenotype. Risma et al. (2006) concluded that the pathogenic mechanism of perforin missense mutations may involve a protein dosage effect of the mature protein.
Trizzino et al. (2008) analyzed data from 124 FHL patients, who had 63 different mutations in the PRF1 gene, including 11 nonsense, 10 frameshift, 38 missense, and 4 in-frame deletions. The W374X mutation was present in 32 patients and was associated with Turkish origin; 50delT (170280.0001) was found in 21 patients and was associated with African American origin; and 1090delCT (170280.0014) was found in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40 patients, reduced in 6, and normal in 4. Later onset and residual cytotoxic function were observed in patients with at least 1 missense mutation.
To evaluate the role of perforin, Lowin et al. (1994) used gene targeting in embryonic stem cells to produce mice lacking perforin. Mice homozygous for the disrupted gene had no perforin mRNA. The mice were healthy, however, and activation and granzyme A secretion of perforin-free cytolytic T cells were unaltered. The killing activity of cytolytic T cells as well as of natural killer (NT) cells was impaired but not abolished. Lowin et al. (1994) concluded that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis; however, alternative perforin-independent lytic mechanisms also exist.
When perforin-deficient mice were infected with lymphocytic choriomeningitis virus, CD8+ T cell-, interferon gamma- (IFNG; 147570), and TNF-alpha (191160)-dependent immunopathology and mortality similar to that in humans with FHL was seen (Matloubian et al., 1999 and Binder et al., 1998).
Badovinac et al. (2000) showed that Prf1 knockout mice eliminated Listeria monocytogenes as well as wildtype mice did but had a higher number of antigen-specific cytotoxic CD8 cells; the ratio of cells responding to immunodominant antigens was the same, as measured by intracellular cytokine or MHC class I tetramer staining. Likewise, the rate of CD8-positive T-cell death after clearance of infection was indistinguishable from wildtype mice. In mice that also had disruption of the Ifng gene, there was a much greater expansion of cytotoxic T cells, an equivalence of cells responding to dominant antigens, and an attenuated rate of T-cell death compared to wildtype. In contrast to Ifng knockout mice, Badovinac et al. (2000) found the Prf1 knockout mice failed to clear lymphocytic choriomeningitis virus and died. The authors proposed that their findings may suggest strategies for enhancing T-cell memory in response to vaccination.
Smyth et al. (2000) found that Pfp1-null mice had a high incidence of spontaneous lymphoma of distinct cell lineages, including T cells, B cells, and natural killer cells, compared to wildtype mice. The susceptibility to lymphoma was accentuated in mice who also lacked the tumor suppressor gene p53 (191170). Pfp1-null mice were at least 1,000-fold more susceptible to these lymphomas when transplanted with the malignant cells, compared to immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. The findings implicated direct cytotoxicity by lymphocytes in regulating lymphomagenesis.
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous union, Stepp et al. (1999) found homozygosity for deletion of a T at nucleotide 50 of the PRF1 gene, resulting in a frameshift and stop in exon 2.
In 2 patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from unrelated consanguineous families, Stepp et al. (1999) identified a homozygous G-to-A transition at nucleotide 1122 of the PRF1 gene, resulting in a trp374-to-ter (W374X) substitution.
In 2 sibs with adult-onset hemophagocytic lymphohistiocytosis, diagnosed at ages 22 and 21 years, respectively, Clementi et al. (2002) identified compound heterozygosity for the W374X mutation and an A91V substitution (170280.0011). The unrelated parents from southern Italy were each heterozygous for 1 of the substitutions. The patients had an atypical presentation and an unusually mild course of the disease. Clementi et al. (2005) later reported that 1 of the sibs had a non-Hodgkin lymphoma (605027).
Zur Stadt et al. (2006) found the W374X mutation in PRF1 in 12 of 32 patients from Turkey and noted that it was associated with very early onset of the disease (below the age of 3 months) in all cases. In contrast, they found the W374X mutation in only 3 of 23 patients from Germany.
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous family, Stepp et al. (1999) found homozygosity for a 190C-T transition in the PRF1 gene, resulting in a glu64-to-ter (Q64X) substitution.
Goransdotter Ericson et al. (2001) found the Q64X mutation in 4 families and pointed out that it was the most common perforin mutation identified in FHL patients.
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified compound heterozygosity for mutations in the PRF1 gene: a 673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a 1286G-A transition, resulting in a gly429-to-glu mutation (G429E; 170280.0005).
Voskoboinik et al. (2004) developed a robust expression system in rat basophil leukemia (RBL) cells in order to define the basis of perforin dysfunction associated with the R225W and G429E mutations inherited by a compound heterozygote FHL patient. RBL cells expressing the 67-kD wildtype perforin efficiently killed human Jurkat T-cell lines. Mutation of the rodent protein at residues comparable to R225W resulted in a truncated 45-kD protein and a complete loss of cytotoxicity. Immunohistochemical analysis showed that wildtype perforin, but not R225W perforin, was packaged in secretory granules. In contrast, the rodent equivalent of the G429E mutation was correctly processed, stored, and released, but it possessed reduced cytotoxic capacity. Voskoboinik et al. (2004) concluded that the cellular basis for perforin mutation dysfunction in FHL patients involving other mutations can be studied using the RBL expression system.
Molleran Lee et al. (2004) identified a homozygous R225W mutation in 2 unrelated patients with FHL2. One was a 2-year-old Filipino boy and the other was a 5-year-old Caucasian girl. The patients were ascertained from a large cohort of 50 unrelated patients with a clinical diagnosis of FHL. No specific clinical details were available, but laboratory studies showed decreased NK function with variably decreased perforin-expressing NK cells (91% and 53%, respectively). These changes were not as severe as seen in patients with other PRF1 mutations. Molleran Lee et al. (2004) noted the relatively later age at onset of these patients.
Chiapparini et al. (2011) reported a 13-year-old girl with FHL2 who presented with ataxia, headache, double vision, vomiting, and a progressive increase in intracranial pressure. She had papilledema and brain MRI showed a swollen cerebellum with tonsillar herniation and signal abnormalities; some T2 hyperintensities were also present in supratentorial areas. CSF showed protein, IgG, and IgM levels consistent with blood-brain barrier damage. She was treated with steroids, but developed fever, worsening ataxia, and decreased sensation in the lower limbs after interruption of steroids. She also had organomegaly. Laboratory studies showed increased triglycerides and ferritin, anemia, elevated liver enzymes, and decreased NK activity. Bone marrow biopsy showed hypoplasia of the myeloid line with adequate erythropoiesis and an infiltration of lymphocytes and histiomonocytoid cells; hemophagocytosis was rare. She underwent bone marrow biopsy and was in good condition after 18 months. Genetic analysis identified a homozygous R225W mutation. Chiapparini et al. (2011) noted the unusual but prominent neurologic presentation in this patient.
Dias et al. (2013) reported 2 sisters, born of consanguineous Lebanese parents, who were found by exome sequencing to carry a heterozygous R225W mutation. The phenotype was not entirely consistent with FHL2, but there were some similar features. One child presented with ataxia, abnormal eye movements, dysarthria, and white matter changes on brain MRI after an episode of gastroenteritis. She had partial resolution, but then showed further white matter changes on MRI and developed splenomegaly, lymphadenopathy, mild pancytopenia, elevated liver enzymes, and hypertrophic cardiomyopathy. Bone marrow biopsy was normal except for iron depletion. Immunologic studies showed normal numbers of T, B, and NK cells. She then developed seizures and loss of vision and cognitive and motor skills. There was intermittent fever and neck rigidity during this time; she died at age 61 months. Laboratory studies showed decreased production of IL1B (147720) and a broad decrease in inflammatory cytokines. The older sister had mild developmental delay and hearing loss. At age 75.5 months, she developed seizures, fever, and deterioration of mental status associated with varicella meningitis. She recovered transiently, but then developed ataxia and diffuse white matter changes on brain MRI. She died at age 91 months. The brain imaging in these patients showed cerebellar atrophy with T2-weighted hyperintense lesions in the cerebellum and cerebral white matter with later involvement of the gray matter. One girl also had signal changes in the periventricular and deep white matter.
For discussion of the gly429-to-glu (G429E) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Stepp et al. (1999), see 170280.0004.
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) from a consanguineous family, Stepp et al. (1999) identified a homozygous 1034C-T transition in the PRF1 gene, resulting in a pro345-to-leu (P345L) substitution.
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified compound heterozygosity for mutations in the PRF1 gene: an 836C-A transversion, resulting in a cys279-to-tyr (C279Y) substitution, and a 548T-G transversion, resulting in a val183-to-gly (V183G; 170280.0008) substitution.
For discussion of the val183-to-gly (V183G) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Stepp et al. (1999), see 170280.0007.
This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, with the 'included' title of LYMPHOMA, NON-HODGKIN, has been reclassified based on the report by Clementi et al. (2005).
In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified a 755A-G transition in the PRF1 gene, resulting in an asn252-to-ser (N252S) substitution.
In a 27-year-old man with autoimmune lymphoproliferative syndrome (601859) who later developed a T-cell-rich, histiocyte-rich, diffuse large B-cell lymphoma (605027), Clementi et al. (2004) identified a heterozygous N252S mutation in the PRF1 gene and a heterozygous mutation in the FAS gene (134637). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. Clementi et al. (2004) noted that the N252S substitution occurs within the membrane attack complex of the perforin protein, a region involved in the pore-forming activity of the molecule. However, both the patient and his mother had normal levels of perforin and normal NK cell activity. The authors suggested that the combined effect of the 2 mutant genes contributed to the development of ALPS and lymphoma in this patient. Rieux-Laucat et al. (2005) cast doubt on the pathogenicity of the N252S mutation, and the primary authors provided a rebuttal (Clementi et al., 2005).
Clementi et al. (2005) identified the N252S mutation in 1 of 660 (0.02%) control alleles, suggesting that it is a benign polymorphism.
Wagner et al. (1995) described a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) with a defect in splicing of CD45 (151460). McCormick et al. (2003) analyzed the perforin status in this patient and identified a novel 1304C-T transition in exon 3 of the PRF1 gene, resulting in a thr435-to-met (T435M) mutation. Threonine-435 is conserved between human, mouse, and rat, and is located in the highly conserved Ca(2+)-binding domain of perforin. Molecular modeling predicted that the T435M mutation would affect the calcium binding of the molecule and therefore impair perforin function. The abnormal CD45 splicing was caused by a 77C-G polymorphism in exon A of the CD45 gene, which cosegregated with the T435M mutation in the family. McCormick et al. (2003) postulated that both mutations were involved in the disorder.
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.
In a 33-year-old Hispanic patient with aplastic anemia (609135), Solomou et al. (2007) identified a heterozygous G-to-T transversion in exon 3 of the PRF1 gene, resulting in a ser388-to-ile (S388I) substitution. The patient was also heterozygous for a synonymous ala274-to-ala (A274A) polymorphism in the PRF1 gene. Bone marrow biopsy showed hemophagocytosis, but the patient had no other clinical features of hemophagocytic syndrome. Perforin granules were absent in CD8(+) T cells. There was no clinical response to immunosuppression.
In a 21-year-old African American patient with aplastic anemia (609135), Solomou et al. (2007) identified a heterozygous G-to-A transition in exon 2 of the PRF1 gene, resulting in an arg4-to-his (R4H) substitution. Bone marrow biopsy showed features of hemophagocytosis, but the patient had no other clinical manifestations of the hemophagocytosis syndrome. There was no clinical response to immunosuppression.
In a Japanese patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Ueda et al. (2003) identified homozygosity for a 2-bp deletion (1090delCT) in exon 3 of the PRF1 gene, resulting in a frameshift and premature termination after 456 amino acids. Two additional Japanese FHL2 patients were found to be compound heterozygous 1090delCT and a 1-bp deletion (207delC; 170280.0015) in exon 2, resulting in frameshift and premature termination after 106 amino acids. A fourth Japanese patient was compound heterozygous for 1090delCT and a 1246C-T transition in exon 3 of the PRF1 gene, resulting in a gln416-to-ter (Q416X; 170280.0016) substitution. Ueda et al. (2003) noted that although none of these patients were directly related, they all had ancestors who originated from the southwestern part of Japan.
For discussion of the 1-bp deletion in the PRF1 gene (207delC) that was found in compound heterozygous state in patients with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Ueda et al. (2003), see 170280.0014.
For discussion of the gln416-to-ter (Q416X) mutation in the PRF1 gene that was found in compound heterozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553) by Ueda et al. (2003), see 170280.0014.
Badovinac, V. P., Tvinnereim, A. R., Harty, J. T. Regulation of antigen-specific CD8(+) T cell homeostasis by perforin and interferon-gamma. Science 290: 1354-1357, 2000. [PubMed: 11082062] [Full Text: https://doi.org/10.1126/science.290.5495.1354]
Binder, D., van den Broek, M. F., Kagi, D., Bluethmann, H., Fehr, J., Hengartner, H., Zinkernagel, R. M. Aplastic anemia rescued by exhaustion of cytokine-secreting CD8+ T cells in persistent infection with lymphocytic choriomeningitis virus. J. Exp. Med. 187: 1903-1920, 1998. [PubMed: 9607930] [Full Text: https://doi.org/10.1084/jem.187.11.1903]
Busiello, R., Adriani, M., Locatelli, F., Galgani, M., Fimiani, G., Clementi, R., Ursini, M. V., Racioppi, L., Pignata, C. Atypical features of familial hemophagocytic lymphohistiocytosis. (Letter) Blood 103: 4610-4612, 2004. [PubMed: 14739222] [Full Text: https://doi.org/10.1182/blood-2003-10-3551]
Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M. Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis. Neurol. Sci. 32: 473-477, 2011. [PubMed: 21234777] [Full Text: https://doi.org/10.1007/s10072-010-0467-2]
Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U. Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function. Blood 108: 3079-3084, 2006. [PubMed: 16720836] [Full Text: https://doi.org/10.1182/blood-2006-02-001412]
Clementi, R., Dagna, L., Dianzani, U., Dupre, L., Dianzani, I., Ponzoni, M., Cometa, A., Chiocchetti, A., Sabbadini, M. G., Rugarli, C., Ciceri, F., Maccario, R., Locatelli, F., Danesino, C., Ferrarini, M., Bregni, M. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. New Eng. J. Med. 351: 1419-1424, 2004. [PubMed: 15459303] [Full Text: https://doi.org/10.1056/NEJMoa041432]
Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter) Blood 100: 2266-2267, 2002. [PubMed: 12229880] [Full Text: https://doi.org/10.1182/blood-2002-04-1030]
Clementi, R., Ferrarini, M., Bregni, M. Autoimmune lymphoproliferative syndrome and perforin. (Letter) New Eng. J. Med. 352: 306-307, 2005.
Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M., Roncarolo, M. G. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood 105: 4424-4428, 2005. [PubMed: 15728124] [Full Text: https://doi.org/10.1182/blood-2004-04-1477]
Dias, C., McDonald, A., Sincan, M., Rupps, R., Markello, T., Salvarinova, R., Santos, R. F., Menghrajani, K., Ahaghotu, C., Sutherland, D. P., Fortuno, E. S., III, Kollmann, T. R., Demos, M., Friedman, J. M., Speert, D. P., Gahl, W. A., Boerkoel, C. F. Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation. Europ. J. Hum. Genet. 21: 1232-1239, 2013. [PubMed: 23443029] [Full Text: https://doi.org/10.1038/ejhg.2013.20]
Fink, T. M., Zimmer, M., Weitz, S., Tschopp, J., Jenne, D. E., Lichter, P. Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10. Genomics 13: 1300-1302, 1992. [PubMed: 1505959] [Full Text: https://doi.org/10.1016/0888-7543(92)90050-3]
Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am. J. Hum. Genet. 68: 590-597, 2001. [PubMed: 11179007] [Full Text: https://doi.org/10.1086/318796]
Law, R. H. P., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., D'Angelo, M. E., Orlova, E. V., Coulibaly, F., Verschoor, S., Browne, K. A., Ciccone, A., Kuiper, M. J., Bird, P. I., Trapani, J. A., Saibil, H. R., Whisstock, J. C. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468: 447-451, 2010. [PubMed: 21037563] [Full Text: https://doi.org/10.1038/nature09518]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
Lichtenheld, M. G., Olsen, K. J., Lu, P., Lowrey, D. M., Hameed, A., Hengartner, H., Podack, E. R. Structure and function of human perforin. Nature 335: 448-451, 1988. [PubMed: 3419519] [Full Text: https://doi.org/10.1038/335448a0]
Lowin, B., Beermann, F., Schmidt, A., Tschopp, J. A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity. Proc. Nat. Acad. Sci. 91: 11571-11575, 1994. [PubMed: 7972104] [Full Text: https://doi.org/10.1073/pnas.91.24.11571]
Matloubian, M., Suresh, M., Glass, A., Galvan, M., Chow, K., Whitmire, J. K., Walsh, C. M., Clark, W. R., Ahmed, R. A role for perforin in downregulating T-cell responses during chronic viral infection. J. Virol. 73: 2527-2536, 1999. [PubMed: 9971838] [Full Text: https://doi.org/10.1128/JVI.73.3.2527-2536.1999]
McCormick, J., Flower, D. R., Strobel, S., Wallace, D. L., Beverley, P. C. L., Tchilian, E. Z. Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing. Am. J. Med. Genet. 117A: 255-260, 2003. [PubMed: 12599189] [Full Text: https://doi.org/10.1002/ajmg.a.10010]
Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J. Med. Genet. 41: 137-144, 2004. [PubMed: 14757862] [Full Text: https://doi.org/10.1136/jmg.2003.011528]
Podack, E. R., Lowrey, D. M., Lichtenheld, M., Olsen, K. J., Aebischer, T., Binder, D., Rupp, F., Hengartner, H. Structure, function and expression of murine and human perforin 1 (P1). Immun. Rev. 103: 203-211, 1988. [PubMed: 3292394] [Full Text: https://doi.org/10.1111/j.1600-065x.1988.tb00756.x]
Rieux-Laucat, F., Le Deist, F., De Saint Basile, G. Autoimmune lymphoproliferative syndrome and perforin. (Letter) New Eng. J. Med. 352: 306 only, 2005. [PubMed: 15659737] [Full Text: https://doi.org/10.1056/NEJM200501203520319]
Risma, K. A., Frayer, R. W., Filipovich, A. H., Sumegi, J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J. Clin. Invest. 116: 182-192, 2006. [PubMed: 16374518] [Full Text: https://doi.org/10.1172/JCI26217]
Shinkai, Y., Takio, K., Okumura, K. Homology of perforin to the ninth component of complement (C9). Nature 334: 525-527, 1988. [PubMed: 3261391] [Full Text: https://doi.org/10.1038/334525a0]
Shinkai, Y., Yoshida, M. C., Maeda, K., Kobata, T., Maruyama, K., Yodoi, J., Yagita, H., Okumura, K. Molecular cloning and chromosomal assignment of a human perforin (PFP) gene. Immunogenetics 30: 452-457, 1989. [PubMed: 2592021] [Full Text: https://doi.org/10.1007/BF02421177]
Smyth, M. J., Thia, K. Y. T., Street, S. E. A., MacGregor, D., Godfrey, D. I., Trapani, J. A. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192: 755-760, 2000. [PubMed: 10974040] [Full Text: https://doi.org/10.1084/jem.192.5.755]
Solomou, E. E., Gibellini, F., Stewart, B., Malide, D., Berg, M., Visconte, V., Green, S., Childs, R., Chanock, S. J., Young, N. S. Perforin gene mutations in patients with acquired aplastic anemia. Blood 109: 5234-5237, 2007. [PubMed: 17311987] [Full Text: https://doi.org/10.1182/blood-2006-12-063495]
Stanley, K., Luzio, P. A family of killer proteins. Nature 334: 475-476, 1988. [PubMed: 3261390] [Full Text: https://doi.org/10.1038/334475a0]
Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286: 1957-1959, 1999. [PubMed: 10583959] [Full Text: https://doi.org/10.1126/science.286.5446.1957]
Trapani, J. A., Kwon, B. S., Kozak, C. A., Chintamaneni, C., Young, J. D.-E., Dupont, B. Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10: similarities to and differences from C9. J. Exp. Med. 171: 545-557, 1990. [PubMed: 2303785] [Full Text: https://doi.org/10.1084/jem.171.2.545]
Trizzino, A., zur Stadt, U., Ueda, I., Risma, K., Janka, G., Ishii, E., Beutel, K., Sumegi, J., Cannella, S., Pende, D., Mian, A., Henter, J.-I., Griffiths, G., Santoro, A., Filipovich, A., Arico, M. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations. J. Med. Genet. 45: 15-21, 2008. [PubMed: 17873118] [Full Text: https://doi.org/10.1136/jmg.2007.052670]
Ueda, I., Morimoto, A., Inaba, T., Yagi, T., Hibi, S., Sugimoto, T., Sako, M., Yanai, F., Fukushima, T., Nakayama, M., Ishii, E., Imashuku, S. Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Brit. J. Haemat. 121: 503-510, 2003. [PubMed: 12716377] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04298.x]
Voskoboinik, I., Sutton, V. R., Ciccone, A., House, C. M., Chia, J., Darcy, P. K., Yagita, H., Trapani, J. A. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood 110: 1184-1190, 2007. [PubMed: 17475905] [Full Text: https://doi.org/10.1182/blood-2007-02-072850]
Voskoboinik, I., Thia, M.-C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., Darcy, P. K., Jane, S. M., Smyth, M. J., Trapani, J. A. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J. Exp. Med. 200: 811-816, 2004. [PubMed: 15365097] [Full Text: https://doi.org/10.1084/jem.20040776]
Voskoboinik, I., Thia, M.-C., Trapani, J. A. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood 105: 4700-4706, 2005. [PubMed: 15755897] [Full Text: https://doi.org/10.1182/blood-2004-12-4935]
Wagner, R., Morgan, G., Strobel, S. A prospective study of CD45 isoform expression in haemophagocytic lymphohistiocytosis; an abnormal inherited immunophenotype in one family. Clin. Exp. Immun. 99: 216-220, 1995. [PubMed: 7851014] [Full Text: https://doi.org/10.1111/j.1365-2249.1995.tb05535.x]
Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum. Mutat. 27: 62-68, 2006. [PubMed: 16278825] [Full Text: https://doi.org/10.1002/humu.20274]
zur Stadt, U., Beutel, K., Weber, B., Kabisch, H., Schneppenheim, R., Janka, G. A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. (Letter) Blood 104: 1909 only, 2004. [PubMed: 15342365] [Full Text: https://doi.org/10.1182/blood-2004-02-0733]