An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression

Abstract

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disease of early childhood manifested by hypercytokinemia and organ infiltration of macrophages and activated lymphocytes, and it is characterized by a fulminant clinical course. The molecular mechanism underlying this disease appears to be a deregulation of apoptosis of activated T cells and macrophages. Approximately 20-40% of patients with familial hemophagocytic lymphohistiocytosis reported worldwide had a perforin gene mutation. We report herein a novel perforin variant in the homozygous state in an Omani boy who was diagnosed 44 days after birth. Sequence analysis of the perforin gene coding region revealed a 12-base pair deletion (codon 284-287) resulting in the deletion of four amino acids in the membrane attack complex domain of the protein. This deletion maintains the reading frame of the perforin mRNA. Both parents were heterozygotes for this molecular defect. Flow-cytometric analysis revealed intracellular perforin expression at the lower end of the normal range in the cytotoxic T cells (CD3 + /CD8 + ) and (CD3 + /CD56 + ) and in around 50% of the natural killer cells (CD3 -/CD56 + ). This is an additional example of a perforin variant which is associated with a significant level of cellular perforin expression and thus confirms that drastic reduction in its expression is not a constant feature in familial hemophagocytic lymphohistiocytosis type 2. Am.

Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations

“…Although these might be considered as in-frame deletions,47 all nine patients had a very severe clinical picture, characterised by very early onset and absent perforin expression and natural killer activity, thus suggesting that these mutations disrupt the protein function.…”

Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic omani patients

“…Together, these data from diverse populations suggest that mutations in this specific region of the PRF1 gene are prone to result in the FHL phenotype. The next novel mutation is a homozygous 12 base pair inframe deletion (codons 284-287) with residual perforin expression and had already been reported and hence will not be discussed further [28]. The remaining two novel alleles (518C?T and 563C?T) were found only in a heterozygous state.…”

Pathology of the Liver in Familial Hemophagocytic Lymphohistiocytosis

“…By contrast, missense perforin mutations, which can be inherited as homozygous or compound heterozygous alleles, have more varied effects on perforin expression and/or function. 10,11,16,22,30,31,38,42,44,46,47 Infant no. 3, a compound heterozygote for 2 perforin mutations (150delG/A893G, nucleotide change), had diminished NK cell activity and markedly decreased perforin expression by immunohistochemical staining and by flow cytometry.…”

“…16,29,30,49 Over 60 disease-associated perforin mutations have been described to date, and the spectrum of perforin alterations includes missense, nonsense, deletion, and insertion mutations. 16,21,31,44,45,49 A nonsense or deletion/insertion mutation that introduces a premature stop codon is predicted to give rise to a truncated, misfolded, and nonfunctional protein leading to its intracellular retention and degradation. This occurred in infant no.…”