GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases

Neurobiol Aging. 2017 May:53:193.e9-193.e16. doi: 10.1016/j.neurobiolaging.2016.12.030. Epub 2017 Jan 9.

Abstract

Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 inNG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bvFTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.

Keywords: Frontotemporal dementia; Phenotype; Progranulin.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Aged, 80 and over
  • Exons / genetics
  • Female
  • Frontotemporal Dementia / genetics*
  • Gene Deletion*
  • Genes, Dominant / genetics
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Haploinsufficiency / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Italy
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Progranulins
  • Real-Time Polymerase Chain Reaction

Substances

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