Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features

Celeste M. Karch, Lubov Ezerskiy, Veronica Redaelli, Anna Rita Giovagnoli, Pietro Tiraboschi, Giuseppe Pelliccioni, Paolo Pelliccioni, Dimos Kapetis, Ilaria D'Amato, Elena Piccoli, Maria Giulia Ferretti, Fabrizio Tagliavini, Giacomina Rossi

Research output: Contribution to journalArticlepeer-review


GRN, the gene coding for the progranulin (PGRN) protein, was recognized as a gene linked to frontotemporal lobar degeneration (FTLD). The first mutations identified were null mutations giving rise to haploinsufficiency. Missense mutations were subsequently detected, but only a small subset has been functionally investigated. We identified missense mutations (C105Y, A199V, and R298H) in FTLD cases with family history and/or with low plasma PGRN levels. The aim of this study was to determine their pathogenicity. We performed functional studies, analyzing PGRN expression, secretion, and cleavage by elastase. GRN C105Y affected both secretion and elastase cleavage, likely representing a pathogenic mutation. GRN A199V did not alter the physiological properties of PGRN and GRN R298H produced only moderate effects on PGRN secretion, indicating that their pathogenicity is uncertain. In the absence of strong segregation data and neuropathological examinations, genetic, biomarker, and functional studies can be applied to an algorithm to assess the likelihood of pathogenicity for a mutation. This information can improve our understanding of the complex mechanisms by which GRN mutations lead to FTLD.

Original languageEnglish
Pages (from-to)215.e1-12
JournalNeurobiology of Aging
Publication statusPublished - Feb 2016


  • Adult
  • Aged
  • Aged, 80 and over
  • Cellobiose
  • Cohort Studies
  • Female
  • Frontotemporal Lobar Degeneration
  • Gene Dosage
  • Genetic Association Studies
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Middle Aged
  • Mutation, Missense
  • Case Reports
  • Journal Article
  • Research Support, N.I.H., Extramural


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