Mitochondria Polymorphism in Neurofibromatosis Type 1

Abstract

Abstract : NF1 is characterized clinically by the development of plexiform and multiple cutaneous neurofibromas. There is no correlation between the numbers, size or prevalence of neurofibromas and the type of mutations in the NF1 gene, suggesting a role for genetic modifiers. Genetic polymorphism in mitochondria could cause variability in the observed tumor phenotype in NF1. Here, we analyzed somatic mitochondrial DNA mutations in cutaneous and plexiform neurofibromas to determine if certain mutations are found predominantly in tumors. We found somatic mutations in 9 of 18 plexiform neurofibromas and 9 of 19 cutaneous neurofibromas. All mutations detected were in the hypervariable D-loop region, where origin of replication and transcriptional regulators are located. Most mutations appeared to be homoplasmic in the tumors. In addition, pre-existing soamtic mtDNA mutations were detected in healthy skin of NF1 patients. Our analysis found that these pre-existing somatic mtDNA mutations accumulate in the tumor, suggesting a selection for the mutated mitochondria in all cell types present in neurofibromas. In a second ongoing set of experiments we analyze the proportion of germ line mitochondrial DNA variants in a cohort of 500 NF1 patients with high numbers and low numbers of cutaneous neurofibromas.