Modifiers of GRN-Associated Frontotemporal Lobar Degeneration

Trends Mol Med. 2017 Oct;23(10):962-979. doi: 10.1016/j.molmed.2017.08.004. Epub 2017 Sep 7.


Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.

Keywords: age of onset; frontotemporal dementia; frontotemporal lobar degeneration; modifiers; progranulin; therapy.

Publication types

  • Review

MeSH terms

  • Clinical Trials as Topic
  • Frontotemporal Lobar Degeneration / genetics*
  • Frontotemporal Lobar Degeneration / metabolism
  • Frontotemporal Lobar Degeneration / physiopathology*
  • Frontotemporal Lobar Degeneration / therapy*
  • Haploinsufficiency*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Loss of Function Mutation*
  • Progranulins


  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins