A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype

Abstract

From our studies, we present evidence that the A91V exchange represents a polymorphism in the perforin gene not causative of the HLH phenotype. We analyzed exon 2 in a series of 86 control DNA samples from healthy unrelated Caucasian individuals by denaturing high-performance liquid chromatography (DHPLC) and found a heterozygous 272C>T transition in 15 cases (17.5%). Additionally, Feldmann et al reported on a homozygous A91V in a nonaffected subject.³ Finally, Molleran Lee et al confirmed the observation of a polymorphism at this nucleotide in the perforin gene by analyzing a large cohort of controls with a heterozygosity of 3% (7 out of 202 investigated cases).⁷ In contrast to these data, Clementi et al described a family including 2 brothers with late onset of the disease and a compound heterozygous pattern of mutations in the perforin gene.⁸ In parallel to a W374X mutation leading to a premature stop, the heterozygous A91V exchange was found in both twins. NK cell activity and perforin expression were markedly reduced in both patients. Taken together, the A91V transition has been described either as polymorphism (Feldmann et al,³ Molleran Lee et al,⁷ and our own observations) or as disease causing mutation in 2 families including 4 patients with late onset of the disease.^1,8 The frequency of this transition differed between the geographic or ethnic origin of the samples. With the assumption of a pathologic role of A91V and an allelic frequency of about 9% in our healthy population, the incidence of HLH should be much higher than observed in Germany. However, the real disease prevalence is not yet determined exactly because of a possible underestimation of the diagnosis due to atypical phenotypic presentations. A reduced perforin expression may also occur in heterozygous carriers or may be due to additional genetic defects in the regulatory region of the gene (eg, exon 1).