Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

Hum Mutat. 2007 Apr;28(4):416. doi: 10.1002/humu.9484.


Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Case-Control Studies
  • Conserved Sequence
  • DNA Mutational Analysis
  • Dementia / genetics*
  • Dementia / metabolism
  • Dementia / pathology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense*
  • Progranulins
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Tertiary


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