The Role of PRF1 Gene in Immune-Mediated Disorders, Hemophagocytic Lymphohistiocytosis, and Malignancies

By Nucleati Team
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This blog post presents evidence collected from the Nucleotide Germline Cancer Evidence Base, highlighting the association between PRF1 gene mutations and various immune-mediated disorders and malignancies. PRF1 mutations have been strongly linked to familial hemophagocytic lymphohistiocytosis (FHL), an aggressive immune-mediated disorder. In addition, PRF1 gene mutations have been implicated in autoimmune lymphoproliferative syndrome (ALPS), leukemias, and lymphomas.

Case reports of individual or one family

Patient/Family Gene/Variation Clinical Characteristics Mutation(s) PubMed ID
Patient died at 18, 10 years after Chronic active Epstein-Barr virus (CAEBV) infection onset. Novel mutations in both alleles of perforin gene. Patient had CAEBV and hemophagocytic lymphohistiocytosis. Reduced perforin-mediated cytotoxicity observed. NM_005041.6(PRF1):c.1228C>T (p.Arg410Trp) 14576041
4 patients with lymphoma, 1 with T-cell lymphoma and a brother with HLH Biallelic mutations in perforin gene, one patient with additional Fas gene mutation. Perforin deficiency implicated in lymphoma NM_005041.5(PRF1):c.1122G>A (p.Trp374Ter)
NM_005041.6(PRF1):c.755A>G (p.Asn252Ser)
NM_005041.6(PRF1):c.272C>T (p.Ala91Val)
NM_005041.6(PRF1):c.1349C>T (p.Thr450Met)
NM_005041.6(PRF1):c.1262T>G (p.Phe421Cys)
15728124
4-month-old girl with HLH, family history of infant death. Homozygous 1289G insertion in perforin gene (Asp430 frameshift, termination at residue 457). Girl treated with immunochemotherapy, died before hematopoietic stem cell transplantation. PRF1:p.Asp430fs*4 16443553
Female patient with FHL, developed HLH at 3 Homozygous 1090-1091delCT perforin gene mutation. Severe sensorineural hearing loss diagnosed at 3.5 years. Exact causes of hearing loss unclear. NM_005041.6(PRF1):c.1090_1091delCT 16358309
8 primary neonatal-onset HLH patients, with 7 undergoing mutational analysis Mutations in UNC13D gene found in 3 patients and 2 patients had perforin gene mutation. Patients presented varying severity of symptoms and clinical courses; high serum ferritin levels were observed in some patients. NM_005041.6(PRF1):c.445G>A (p.Gly149Ser)
NM_005041.6(PRF1):c.1122G>A (p.Trp374Ter)
19131769
Patient/Family: Two siblings with FHLH, both died, non-consanguineous parents were heterozygous for the mutation. Homozygous c.666C>A (p.His222Gln) mutation in the PRF1 gene in both siblings. First child died in utero with hydrops fetalis, second presented with fatal multiple organ failure soon after birth. NM_005041.6(PRF1):c.666C>A (p.His222Gln) 19595804
Child who died from HLH at 6 months of age, father had severe community-acquired pneumonia. Q481P mutation in the perforin gene. Impaired NK cell activity in the heterozygous father resulted in poor initial control of infections with severe clinical expression. NM_005041.6(PRF1):c.1442A>C (p.Gln481Pro) 19639728
Female infant with type 2 FHL (FHL2), born with biallelic PRF1 mutations. Novel substitution D49N and previously identified in-frame deletion K285del in the PRF1 gene. Mutations were detrimental for NK cell function, leading to a clinically severe presentation and rapidly fatal outcome. NM_005041.6(PRF1):c.147C>A (p.Asp49Glu)
p.Lys285del
22186995
25-year-old male patient with PCNSL, had two older brothers, one of whom died from genetically confirmed (perforin mutation/PRF1) HLH. Patient and father were heterozygous carriers of perforin mutation. PCNSL and HLH in brothers; patient with PCNSL had a longer survival time than median survival for PCNSL. NM_005041.6(PRF1):c.1310C>T (p.Ala437Val) 25845254
FHL2 patient and her asymptomatic brother with compound PRF1
mutations and EBV infection
Heterozygous missense (c.916G>A) and frameshift (c.65delC) in PRF1; homozygous missense mutation (S1006L) in PCDH18 in the patient only. Patient diagnosed with FHL2 and positive EBV infection. Asymptomatic brother with same mutations and EBV infection status. NM_005041.6(PRF1):c.916G>A (p.Gly306Ser)NM_005041.6(PRF1):c.916G>A (p.Gly306Ser)
NM_005041.6(PRF1):c.65delC (p.Pro22ArgfsTer29)
26739415
8-year-old boy with hepatosplenomegaly, hepatitis, epilepsy, and pancytopenia; consanguineous parents. Novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120T>G, p.W374G). Patient suffered from HLH disease. First report of PRF1 mutation in Iranian patients with HLH. NM_005041.6(PRF1):c.1120T>G (p.Trp374Gly) 28468610
Half-brothers diagnosed with type 2 FHL; mother and grandfather confirmed carriers. Both half-brothers had heterozygous mutations c.282C>A/p.N94K and c.1349C>T/p.T450M in PRF1 gene Both half-brothers improved after treatment with HLH-04 schedule. Early HSCT recommended for FHL diagnosis. NM_005041.6(PRF1):c.282C>A (p.Asn94Lys)
NM_005041.6(PRF1):c.1349C>T (p.Thr450Met)
30045285
Patient with metastatic breast cancer treated with
pembrolizumab.
Germline polymorphism in perforin-1 (PRF1), PRFA91V. Developed pembrolizumab-associated HLH, leading to multiorgan system failure. No evidence of malignancy after 2 years. NM_005041.6(PRF1):c.272C>T (p.Ala91Val) 30287596
Two siblings with FHL; parents are carriers. Both probands have compound heterozygous mutations c.1349C>T and c.853_855del in PRF1 gene Proband 1 had fever, hepatosplenomegaly, decreased peripheral blood cell count; Proband 2 had convulsions and disturbance of consciousness with fever. NM_005041.6(PRF1):c.1349C>T (p.Thr450Met)
NM_005041.6(PRF1):c.853_855del (p.Lys285del)
34938098
Female Chinese neonate with FHL2, family not mentioned. Gene/Variation: Compound heterozygous PRF1 mutation (c.658G>C, c.1066C>T). Compound heterozygous PRF1 mutation (c.658G>C, c.1066C>T). Neonate had fever, thrombocytopenia, and petechiae. Early symptom onset before 1 month old is atypical. NM_005041.6(PRF1):c.658G>C (p.Gly220Arg)
NM_005041.6(PRF1):c.1066C>T (p.Arg356Trp)
34368327
Summary of case reports

Cohort studies

Cohort Setup Outcomes Mutation(s) PubMed Id
265 Chinese patients with HLH Analyzed PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP genes 32.83% had mutations, mostly in UNC13D; unique variant profile in Chinese patients NM_005041.6(PRF1):c.674G>A (p.Arg225Gln)
NM_005041.6(PRF1):c.148G>A (p.Val50Met)
NM_005041.6(PRF1):c.98G>A (p.Arg33His)
29665027
86 AML and MDS families. Whole exome sequencing in 37 uncharacterized families. Germline variants in 16 loci; 65 new candidate loci identified. p.Glu275Lys
p.Asn252Ser
32098966
1892 patients submitted for HLH genetic analysis. Targeted next-generation sequencing panel approach for 15 HLH-associated genes. 10.4% of patients had a definite genetic diagnosis; 10 HLH-associated genes identified. NM_005041.6(PRF1):c.1304C>T (p.Thr435Met)
NM_005041.6(PRF1):c.1081A>T (p.Arg361Trp)
NM_005041.6(PRF1):c.112G>A (p.Val38Met)
NM_005041.6(PRF1):c.659G>A (p.Gly220Asp)
NM_005041.6(PRF1):c.886T>C (p.Tyr296His)
NM_005041.6(PRF1):c.563C>T (p.Pro188Leu)
NM_005041.6(PRF1):c.614A>G (p.Asn205Ser)
NM_005041.6(PRF1):c.1314T>A (p.Tyr438Ter)
32542393
101 molecularly characterized FHL patients from 20 referral centers in India. Retrospective analysis of PRF1, UNC13D, STX11, and STXBP2 gene mutations. 76 different disease-causing mutations; poor survival (28%) NM_005041.6(PRF1):c.82C>T (p.Arg28Cys)
NM_005041.6(PRF1):c.781G>A (p.Glu261Lys)
NM_005041.6(PRF1):c.386G>C (p.Trp129Ser)
NM_005041.6(PRF1):c.1349C>T (p.Thr450Met)
NM_005041.6(PRF1):c.528_529delinsAA (p. Cys176Ter)
NM_005041.6(PRF1):c.673C>T (p.Arg225Trp)
33746956
171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors. Targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity. 94 gene variants detected; lower survival in patients with germline mutations. NM_005041.6(PRF1):c.674G>A (p.Arg225Gln) 34170459
Two pregnancy-related malignant PT patients. Whole-exome NGS on tumor samples and paired normal breast tissues. TP53 and PTEN identified as potential drug targets; PRF1 germline mutation found. NM_005041.6(PRF1):c.65del (p.P22Rfs*29) 36471415
9,197 East Asians (1,909 Koreans) from gnomAD. Analyzed exomes for four fHLH genes. Higher carrier frequency and incidence of fHLH in Koreans among East Asians. NM_005041.6(PRF1):c.673C>T (p.Arg225Trp)
NM_005041.6(PRF1):c.1066C>T (p.Arg356Trp)
NM_005041.6(PRF1):c.1090_1091del (p.Leu364GlufsTer93)
NM_005041.6(PRF1):c.1168C>T (p.Arg390Ter)
NM_005041.6(PRF1):c.1244C>G (p.Ala415Gly)
NM_005041.6(PRF1):c.1349C>T (p.Thr450Met)
NM_005041.6(PRF1):c.65del (p.Pro22ArgfsTer29)
36440336

Summary

  • PRF1 gene mutations have been strongly associated with familial hemophagocytic lymphohistiocytosis (FHL), an aggressive immune-mediated disorder. Studies have revealed various PRF1 mutations leading to reduced perforin activity, which is crucial for immune response regulation (PMID: 20301479, 23109706, 32420596).
  • PRF1 mutations have also been linked to some cases of autoimmune lymphoproliferative syndrome (ALPS), a disorder characterized by lymphadenopathy, splenomegaly, and autoimmunity (PMID: 26076843).
  • The PRF1 gene has been implicated in leukemias and lymphomas, suggesting that PRF1 mutations may play a role in the development of these malignancies (PMID: 22008757, 25527562).
  • A study on the carrier frequency and expected incidence of familial HLH in East Asians and Koreans found higher carrier frequency and predicted incidence among Koreans compared to other East Asian populations. The variant spectrum of fHLH genes in East Asian and Korean populations differed greatly from those of other ethnic groups (PMID: 36440336).

Conclusions

In conclusion, the body of evidence supporting the association between PRF1 mutations and hemophagocytic lymphohistiocytosis is robust and well-established. Additionally, there are emerging findings that suggest PRF1 mutations may play a role in the development of certain leukemias and lymphomas. These associations highlight the importance of understanding the role of PRF1 in immune system function and cancer development. Further research is needed to clarify the specific mechanisms through which PRF1 mutations contribute to these diseases and to explore the potential for targeted therapies based on these genetic insights. As our knowledge of the associations between PRF1 mutations and these disorders expands, so too does the potential for improved diagnostic tools and treatment strategies, offering hope for patients and their families.