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Published on: July 30, 2014
Functional impact of A91V mutation of the PRF1 perforin gene
Natalia Martínez-Pomar1, Nallibe Lanio, Neus Romo
1Department of Immunology, University Hospital of Son Espases, Palma de Mallorca, Spain. natalia.martinez@ssib.es
Abstract:
Perforin (PRF1) gene mutations have been associated with Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2). Substitution p.A91V (c.272C>T) in exon 2 was first described as a neutral polymorphism. Nonetheless, recent clinical evidence and functional assays, suggest a potential pathogenic role for p.A91V, especially in compound heterozygous individuals. Moreover, p.A91V homozygosity has been linked to various pathological states including FHL and lymphocytic leukaemias. In the present report we evaluated the impact of this mutation in a compound heterozygous A91V/G149S 31 year-old asymptomatic female. Functional assays revealed low perforin expression levels, as well as an impaired NK cell-mediated cytotoxicity, partially reconstituted after incubation with IL-2. These results support that p.A91V mutation, associated to another mutated PRF1 allele, may potentially predispose seemingly healthy carriers to suffer a milder FHL2 clinical phenotype, including later onset of the disease. Thus, clinical monitoring of p.A91V carrier individuals bearing another mutation in PRF1 is warranted.
Insights
The PRF1 p.A91V mutation, previously considered neutral, may cause Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) when combined with other PRF1 mutations. This highlights the need for monitoring asymptomatic carriers.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL2) is linked to Perforin (PRF1) gene mutations.
- The PRF1 p.A91V substitution was initially identified as a neutral polymorphism.
Observation:
- Recent studies suggest p.A91V has a pathogenic role, particularly in compound heterozygotes.
- p.A91V homozygosity is associated with FHL and lymphocytic leukemias.
- A 31-year-old asymptomatic female with compound heterozygous A91V/G149S PRF1 mutations was evaluated.
Findings:
- Functional assays showed reduced perforin expression and impaired NK cell cytotoxicity in the patient.
- Cytotoxicity was partially restored by IL-2.
- These findings suggest p.A91V, with another PRF1 mutation, can predispose individuals to a milder FHL2 phenotype.
Implications:
- Asymptomatic carriers of p.A91V with another PRF1 mutation may develop a milder FHL2 phenotype with later onset.
- Clinical monitoring of such individuals is recommended.
- This research underscores the complex genetic landscape of FHL2 and the potential pathogenicity of previously disregarded variants.
