Journal
EUROPEAN JOURNAL OF NEUROLOGY
Volume 15, Issue 10, Pages 1111-1117Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1468-1331.2008.02266.x
Keywords
allelic variant; Alzheimer's disease; frontotemporal lobar degeneration; mutation; polymorphism; progranulin
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Funding
- Associazione 'Amici del Centro Dino Ferrari'
- Monzino Foundation
- IRCCS Fondazione Ospedale Maggiore Policlinico
- Associazione per la Ricerca sulle Demenze (ARD)
- Ing. Cesare Cusan
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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 (g100169G > A). 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.100165C > T), 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 -> G > A and IVS7 + 7 -> 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.
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