Affiliations: [a] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| [b] U.O. Neurologia, Azienda Ospedaliero Universitaria di Modena, Modena, Italy
| [c] Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy
| [d] IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
Correspondence:
[*]
Correspondence to: Benedetta Nacmias, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy Viale Pieraccini 6, 50139 Florence, Italy. Tel.: +39 0557948910; Fax: +39 0552758265; E-mail: [email protected].
Abstract: Background:Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer ’s disease (AD) patients. Objective:Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2, and APP). In addition, Microtubule-associated protein tau (MAPT) gene was studied too. All patients underwent an extensive neuropsychological battery. Methods:Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. Results:Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. Conclusions:Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD.
