Understanding phenotype variability in frontotemporal lobar degeneration due to granulin mutation

Cristian Bonvicini, Elena Milanesi, Andrea Pilotto, Nadia Cattane, Enrico Premi, Silvana Archetti, Alessandro Padovani, Massimo Gennarelli, Barbara Borroni

Research output: Contribution to journalArticlepeer-review


Phenotype in patients with granulin (GRN) mutations is unpredictable, ranging from behavioral variant frontotemporal dementia (bvFTD) to agrammatic variant of primary progressive aphasia (avPPA). To date the wide clinical variability of FTLD-GRN remains unexplained. The aim of the study was to identify genetic pathways differentiating phenotypic expression in patients carrying GRN mutations. Patients carrying the same GRNT272SfsX10 mutation were enrolled, a careful clinical assessment was carried out, and the diagnosis of either bvFTD (n= 10, age= 63.9 ± 9.4) or avPPA (n= 6, age= 58.8 ± 4.7) was done. Microarray gene expression analysis on leukocytes was performed. Genes differentially expressed between the groupswere validated by real time polymerase chain reaction considering an age-matched healthy controls group (n= 16, age= 58.4 ± 10.7). We further considered a group of FTD with no GRN mutations (GRN-) (n= 21, 13 bvFTD, and 8 avPPA) for comparisons. Real-time polymerase chain reaction (PCR) confirmed asignificant decrease in leukocytes mRNA messenger RNA (mRNA) levels of RAP1GAP in bvFTD patients ascompared with avPPA (p= 0.049). This finding was specific for patients with GRN mutations, as we did not observe this pattern in FTD GRN-patients (p= 0.99). The alteration of RAP1GAP mRNA levels may explain the clinical variability of GRN-FTLD patients. This is the first report linking a molecular pathway tospecific phenotype expression in FTLD-GRN. To understand the clinical relevance of our early results itwill be mandatory to extend the observation to other clinical and neuropathological series.

Original languageEnglish
Pages (from-to)1206-1211
Number of pages6
JournalNeurobiology of Aging
Issue number5
Publication statusPublished - May 2014


  • AvPPA
  • BvFTD
  • Frontotemporal dementia
  • Genetic modulation
  • GRN mutations
  • Phenotype variability

ASJC Scopus subject areas

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


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