A mutation in the 5′-UTR of GRN gene associated with frontotemporal lobar degeneration: Phenotypic variability and possible pathogenetic mechanisms

Gianfranco Puoti, Maria Cristina Lerza, Maria Giulia Ferretti, Orso Bugiani, Fabrizio Tagliavini, Giacomina Rossi

Research output: Contribution to journalArticlepeer-review

Abstract

Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non-fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5′ splice site A > G in the 5′-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5′ splice site A > G mutation widens the GRN regions affected by null mutations, including the 5′-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.

Original languageEnglish
Pages (from-to)939-947
Number of pages9
JournalJournal of Alzheimer's Disease
Volume42
Issue number3
DOIs
Publication statusPublished - 2014

Keywords

  • Frontotemporal lobar degeneration
  • GRN
  • haploinsufficiency
  • mutation
  • phenotype
  • progranulin

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology
  • Medicine(all)

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