• allelic variant;
  • Alzheimer’s disease;
  • frontotemporal lobar degeneration;
  • mutation;
  • polymorphism;
  • progranulin

Background and purpose:  Progranulin (PGRN) expression is increased in activated microglia in Alzheimer's disease (AD) brain, suggesting a potential role in this pathology.

Methods:  A mutation scanning of exons and flanking regions of PGRN was carried out in 120 patients with sporadic frontotemporal lobar degeneration and 145 with sporadic AD.

Results:  Amongst variants not yet deposited, a novel allelic variant was identified in Exon 1 (g100169A). It leads to an amino acidic change (p.Gly35Arg) and was observed in a patient with late onset AD. In silico analysis predicted that this mutation is possibly damaging. A second variant (g.100165T), resulting in a silent mutation (pAsp33Asp), was found in a patient with semantic dementia and in another with early onset AD. Both variants were absent in 226 controls. In addition, two rare non-pathogenic variants lying very close to PGRN splice-site regions (IVS2 + 7[RIGHTWARDS ARROW]G > A and IVS7 + 7[RIGHTWARDS ARROW]G > A) were observed. Transcriptional analysis in peripheral blood mononuclear cells from patients demonstrated they do not affect exon splicing.

Conclusions:  A novel putative PGRN mutation leading to an amino acidic substitution was identified in a patient with clinical AD.