title: Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.
abstract: Frontotemporal lobar degeneration (FTLD) recognises high familial incidence, with up to 50% of patients reported to have a family history of similar dementia. It has been reported that mutations within progranulin (PGRN) gene are a major cause of FTLD in the USA and worldwide, counting for 5-10% of FTLD and for 20-25% of familiar FTLD cases. The aim of the present study was to define the role of PGRN genetic variations in a large sample of consecutive patients with FTLD in Italy. Two-hundred forty-three FTLD patients were investigated. Each subject performed a clinical and neuropsychological evaluation, a functional and structural brain imaging, and the diagnosis was confirmed by at least 1 year follow-up. PGRN sequencing was performed in all FTLD patients and in 121 healthy age-matched controls drawn from the same geographic area. Only one PGRN pathogenetic mutation was found, consisting of a four-base pair deletion in the coding sequence of exon 8 (delCACT). This mutation was recognised in four patients, being the overall frequency of mutations in our clinical series of 1.64%. Considering only patients with a well-known family history for dementia, the frequency of this mutation was 6%. Moreover, four missense mutations within intron regions (g.100474G>A, g.100674G>A, g.101266G>A, g.102070G>A) were found. The frequency of these genetic variations did not differ in patients compared to controls, and they did not influence on clinical FTLD phenotype. In conclusion, this study supports a lower frequency of PGRN mutations amongst FTLD patients in Italy compared to literature data and further underlies the genetic heterogeneity of FTLD.
authors.affiliation: Department of Neurology, University of Brescia, Brescia, Italy. bborroni@inwind.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.forename: Antonella
authors.initials: A
authors.lastname: Alberici
authors.forename: Chiara
authors.initials: C
authors.lastname: Agosti
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Bigni
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bellelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Diego
authors.initials: D
authors.lastname: Di Lorenzo
authors.forename: Luigi
authors.initials: L
authors.lastname: Caimi
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
mesh_terms: D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007438:Introns; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins