Characterization of novel progranulin gene variants in Italian patients with neurodegenerative diseases

Anna Bartoletti-Stella, Silvia De Pasqua, Simone Baiardi, Ilaria Bartolomei, Giacomo Mengozzi, Giuseppe Orio, Francesca Pastorelli, Silvia Piras, Roberto Poda, Alberto Raggi, Michelangelo Stanzani Maserati, Martina Tarozzi, Rocco Liguori, Fabrizio Salvi, Piero Parchi, Sabina Capellari

Research output: Contribution to journalArticlepeer-review


Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.

Original languageEnglish
Pages (from-to)145.e7-145.e15
JournalNeurobiology of Aging
Publication statusPublished - Jan 2021


  • Frontotemporal dementia
  • Neurodegenerative diseases
  • Progranulin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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