Prf1, encoding the pore-forming protein perforin, is crucial for the immune system. It is involved in the cytotoxic T-cell and natural killer cell-mediated immune response, where it forms pores in target cell membranes, enabling the entry of granzymes and subsequent induction of apoptosis [4]. This process is essential for controlling infections and tumor surveillance.

Mutations in Prf1 are strongly associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome. Homozygous, semi-zygous, or complex heterozygous variants can cause familial HLH [2]. For example, a 42-year-old male with a heterozygous mutation of PRF1: c.674G>A (p.R225Q) presented with HLH symptoms [1]. A meta-analysis indicated that the PRF1 Ala91Val polymorphism affects the risk of developing HLH [3]. Also, a 17-year-old male with a pathogenic homozygous missense mutation (c.1081A>T p.(Arg361Trp)) in the PRF1 gene was diagnosed with familial HLH type 2 [5]. A 20-year-old female with two heterozygous missense variants in the PRF1 gene (A91V and R104C) had de novo primary HLH [6].

In conclusion, Prf1 is essential for cytotoxic immune responses. The study of Prf1, especially through genetic mutations in human cases, has significantly contributed to our understanding of HLH. These findings highlight the importance of Prf1 in maintaining immune homeostasis and the potential consequences of its dysfunction in the development of severe hyperinflammatory diseases.

References:

1. Xin, Xiangke, Wang, Na, Zhang, Yicheng. 2023. Hemophagocytic lymphohistiocytosis with a hemizygous PRF1 c.674G>A mutation. In The American journal of the medical sciences, 366, 387-394. doi:10.1016/j.amjms.2023.07.005. https://pubmed.ncbi.nlm.nih.gov/37467895/

2. Canna, Scott W, Marsh, Rebecca A. . Pediatric hemophagocytic lymphohistiocytosis. In Blood, 135, 1332-1343. doi:10.1182/blood.2019000936. https://pubmed.ncbi.nlm.nih.gov/32107531/

3. Zhu, Guang-Hua, Zhang, Li-Ping, Li, Zhi-Gang, Wang, Tian-You, Zhang, Rui. 2020. Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on 1366 subjects. In World journal of pediatrics : WJP, 16, 598-606. doi:10.1007/s12519-020-00351-7. https://pubmed.ncbi.nlm.nih.gov/32198610/

4. Sidore, Carlo, Orrù, Valeria, Cocco, Eleonora, Cucca, Francesco, Zoledziewska, Magdalena. 2020. PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity. In Multiple sclerosis (Houndmills, Basingstoke, England), 27, 1332-1340. doi:10.1177/1352458520963937. https://pubmed.ncbi.nlm.nih.gov/33566725/

5. Alfaraidi, Albaraa T, Alqarni, Abdulaziz A, Aqeel, Mohammed T, Albalawi, Turki A, Hejazi, Ahmed S. 2021. Familial Hemophagocytic Lymphohistiocytosis Secondary to PRF1 Mutation. In Case reports in hematology, 2021, 7213939. doi:10.1155/2021/7213939. https://pubmed.ncbi.nlm.nih.gov/35003815/

6. Stadermann, Alina, Haar, Markus, Riecke, Armin, Müller, Matthias, Witte, Hanno. 2024. Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene. In International journal of molecular sciences, 25, . doi:10.3390/ijms25052762. https://pubmed.ncbi.nlm.nih.gov/38474010/