Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia

In Portugal, heterozygous loss-of-function mutations in the progranulin ( ) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific mutational spectrum. The subjects harboring a mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of and the identification of the underlying mutations provided an accurate genetic counselling and allowed the enrolment of subjects with mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.