A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology

Brain. 2007 May;130(Pt 5):1360-74. doi: 10.1093/brain/awm069. Epub 2007 Apr 17.


Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Blotting, Western / methods
  • Brain / pathology
  • Case-Control Studies
  • Corpus Striatum / chemistry
  • Corpus Striatum / pathology
  • DNA-Binding Proteins / analysis
  • Female
  • Genotype
  • Hippocampus / chemistry
  • Hippocampus / pathology
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation*
  • Neocortex / chemistry
  • Neocortex / pathology
  • Pedigree
  • Pick Disease of the Brain / genetics*
  • Pick Disease of the Brain / metabolism
  • Pick Disease of the Brain / pathology
  • Progranulins
  • Sequence Analysis, DNA
  • Substantia Nigra / chemistry
  • Substantia Nigra / pathology
  • Ubiquitin / analysis
  • alpha-Synuclein / analysis
  • tau Proteins / analysis


  • DNA-Binding Proteins
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • MAPT protein, human
  • Progranulins
  • Ubiquitin
  • alpha-Synuclein
  • tau Proteins