PRION PROTEIN CODON 129 POLYMORPHISM MODIFIES AGE AT ONSET OF FRONTOTEMPORAL DEMENTIA WITH THE C.709-1GA PROGRANULIN MUTATION

摘要

Frontotemporal lobar degeneration due to mutations in the progranulin gene (PGRN) presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and MAPT genotypes and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and MAPT genotypes and age at onset of the disease; while we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least one valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative.