Impaired NK cell cytotoxicity in multiple myeloma caused by the homozygous A91V polymorphism in the perforin gene: a case report

Abstract

We describe a 58-year-old man diagnosed with IgG/Kappa multiple myeloma (International Staging System III) treated for eight years with polychemotherapy (VAD schee) and autologous peripheral hematopoietic stem cell transplantation. The patient studied was homozygous C272T polymorphism (PRF1272T/T) by analysis of perforin gene by direct sequencing. This SNP is considered pathogenic and leads to the substitution of the amino acid alanine for valine in codon 91 of the perforin protein. The cytotoxic lymphocytes (CLs) of the patient and of the healthy wild homozygous individual were evaluated for their cytotoxic capacity. Our results show that PRF1272T/T effector cells had significantly reduced ability to induce specific lysis of K562 cells. The NK cells of the patient had three times less intracellular perforin than observed in the wild-type individual. The gene expression of PRF1 and FAS did not differ between the individuals, however the expression of GZMB was approximately 2.5 times higher in the patient. It was also observed that the T-BET expression was approximately 1.7-fold higher and IFN-γ expression was 4.5-fold higher in the PRF1272T/T patient. In conclusion, functional analysis of the CLs of the patient revealed a significant decrease in their cytolytic capacity as well as the amount of perforin present in NK cell granules.