Abstract
Abstract
Familial hemophagocytic lymphohistiocytosis (FHL) is generally an autosomal recessive disease of early childhood characterized by uncontrolled T cell and macrophage activation leading to a fatal accumulation of activated T lymphocytes and histiocytes in different tissues. Immune regulation is severely impaired in these patients (both CTL and NK cells) and defects in perforin gene expression, an important component of the lytic granules, were the first defects identified in these patients. So far, FHL genetics have identified a locus at chromosome 9q22 (not molecularly defined yet), at chromosome 10q21-22 (where mutations in perforin gene have been described in 20% of FHL patients), at chromosome 17q25 (where mutations in the Munc13-4 gene have been found) and most recently at chromosome 6q24 (where mutations in the syntaxin-11 gene have been found). We described previously that MEF-null mice, which lack the ETS-transcription factor also known as ELF-4 (located at Xq26.1), have impaired NK cell development and function, and no NK cell perforin gene expression. We also showed that MEF regulates the human perforin proximal promoter via two ETS binding sites and showed that MEF is bound to the perforin promoter in vivo, using chromatin immunoprecipitation. Subsequently, we initiated a study of MEF gene integrity in male patients that have been studied and lacked perforin gene mutations. In addition to a known polymorphism in exon 9 (503 C→T) present in approximately 30% of unrelated patients and leukemic cell lines, we found a nucleotide change in exon 9 of MEF (408, C→T) in a male FHL patient from Denmark. The mutation found in the son, who was diagnosed with FHL and received a BMT at 12 years of age, was also seen in the patient’s grandmother, mother and one sister (heterozygous). Mutation 408 leads to an amino acid change (Val→Met) in a region located between the Ser/Thr and Pro rich domains in the C-terminal portion of MEF. We generated a MEF-mutant (MEFVal→Met) protein; it has a reduced capacity to activate the perforin gene promoter (only 30–40% of the wild type). MEFVal→Met does not have a dominant negative effect, when co-transfected with wild type protein, which could account for the FHL phenotype found in the male only. We are further examining the biology of this mutation in MEF-null cells to see if it can contribute to FHL pathology. Transcription factor abnormalities, such as the MEF mutation in this family, should be evaluated to help explain the pathogenesis of FHL in different patients.