title: Heterozygous TREM2 mutations in frontotemporal dementia.
abstract: A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects-namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. The mutation frequency and the associated clinical characteristics were analyzed. We identified 8 missense and nonsense mutations in TREM2 exon 2 in 24 subjects. These mutations were more frequent in patients with FTD than in HCs (4.0% vs. 1.0%, p = 0.005). In particular, TREM2 Q33X, R47H, T66M, and S116C mutations were found in FTD and were absent in HCs. These mutations were associated with either the semantic variant of primary progressive aphasia or the behavioral variant FTD phenotypes. The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.
authors.affiliation: Center of Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy. Electronic address: bborroni@inwind.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.affiliation: Center of Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Barone
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Piaceri
authors.affiliation: III Laboratory of Analysis, Brescia Hospital, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Istituto di Ricerca e Cura a Carattere Scientifico Fatebenefratelli, Brescia, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bonvicini
authors.affiliation: Istituto di Ricerca e Cura a Carattere Scientifico Fatebenefratelli, Brescia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.affiliation: Neurology Unit, ValleCamonica Hospital, Brescia, Italy.
authors.forename: Marinella
authors.initials: M
authors.lastname: Turla
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.affiliation: Center of Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Frontotemporal dementia; Frontotemporal lobar degeneration; Mutation; Risk factor; TREM2