Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings

Biol Psychiatry. 2008 May 15;63(10):946-52. doi: 10.1016/j.biopsych.2007.08.015. Epub 2007 Oct 22.


Background: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease.

Methods: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects.

Results: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects.

Conclusions: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • DNA Mutational Analysis
  • DNA-Binding Proteins / metabolism
  • Dementia / genetics*
  • Dementia / metabolism
  • Dementia / pathology
  • Female
  • Gene Expression / physiology*
  • Genetic Predisposition to Disease*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intranuclear Inclusion Bodies / pathology
  • Male
  • Mutation / genetics*
  • Neuropsychological Tests
  • Progranulins
  • RNA / metabolism*
  • Retrospective Studies
  • Sequence Analysis
  • Ubiquitin / metabolism
  • alpha-Synuclein / metabolism
  • tau Proteins / genetics


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