{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T12:51:44Z","timestamp":1761396704854,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Portuguese national funds","doi-asserted-by":"publisher","award":["PTDC\/MEC-NEU\/4814\/2020"],"award-info":[{"award-number":["PTDC\/MEC-NEU\/4814\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN 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 GRN 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 GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.<\/jats:p>","DOI":"10.3390\/ijms25010511","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T06:37:12Z","timestamp":1704004632000},"page":"511","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Characterization of Progranulin Gene Mutations in Portuguese Patients with Frontotemporal Dementia"],"prefix":"10.3390","volume":"25","author":[{"given":"Maria Ros\u00e1rio","family":"Almeida","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3988-614X","authenticated-orcid":false,"given":"Miguel","family":"T\u00e1buas-Pereira","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar e Universit\u00e1rio de Coimbra, 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8106-7308","authenticated-orcid":false,"given":"In\u00eas","family":"Baldeiras","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]},{"given":"Marisa","family":"Lima","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar e Universit\u00e1rio de Coimbra, 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-593X","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Dur\u00e3es","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar e Universit\u00e1rio de Coimbra, 3004-561 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5791-7149","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Massano","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}]},{"given":"Madalena","family":"Pinto","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"}]},{"given":"Catarina","family":"Cruto","sequence":"additional","affiliation":[{"name":"Neurology Department, Hospital Pedro Hispano, Unidade Local de Sa\u00fade de Matosinhos, 4464-513 Matosinhos, Portugal"}]},{"given":"Isabel","family":"Santana","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s12031-011-9538-y","article-title":"Estimating the Number of Persons with Frontotemporal Lobar Degeneration in the US Population","volume":"45","author":"Knopman","year":"2011","journal-title":"J. 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