Estimating the age of the most common italian grn mutation: Walking back to Canossa Times

Luisa Benussi, Rosa Rademakers, Nicola J. Rutherford, Aleksandra Wojtas, Michela Glionna, Anna Paterlini, Valentina Albertini, Thomas Bettecken, Giuliano Binetti, Roberta Ghidoni

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Mutations in the progranulin gene (GRN) were first implicated in frontotemporal lobar degeneration in 2006. The GRN p.Leu271LeufsX10 mutation is one of the most common GRN mutations worldwide. To gain further insight into the origin of this mutation in Italy, we performed a haplotype sharing analysis (32 families, residents of Lombardy) and refined the GRN p.Leu271LeufsX10 mutation dating. We showed that almost all families (30/32) can be traced to a single founder. We further estimated the age of this mutation using different methods and population growth rates both for Italy and Lombardy. Using DMLE, we dated the origin of this mutation to the Middle Ages, at the turn of the first millennium (phased families only, Italy: 39 and Lombardy: 32 generations ago; all families Italy: 45 and Lombardy 38 generations ago). Mutation dating was slightly postdated using Estiage (phased families only: 15 generations ago; all families: 20 generation ago). From a translational perspective, targeting mutation carriers offers a unique model to test disease-modifying drugs in clinical trials.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - 2013


  • Clinical phenotype
  • FTLD
  • GRN
  • disease haplotypes
  • founder
  • mutation
  • pedigrees
  • progranulin

ASJC Scopus subject areas

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


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