title: Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing.
abstract: Autosomal dominant Alzheimer's disease (AD) is caused by mutations in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 genes and is mostly associated with early-onset form of AD (EOAD), whereas very few mutations were also found in late-onset AD (LOAD) cases. Because of the clinical overlapping between AD and other degenerative dementias such as frontotemporal dementias, a wide-spectrum genetic analysis should be envisaged in the differential diagnosis of this group of disorders. We used next-generation sequencing techniques to analyze 10 genes involved in dementia on a cohort of 20 EOAD and 20 LOAD cases. We found 5 rare coding variants (frequency <1%). PSEN1 H214N mutation, identified in a case of familial EOAD and PSEN1 R220P, found in a case of familial LOAD, are predicted to be pathogenic. These findings confirm the contribution of PSEN1 genetic variants also to LOAD, underlining the need of extending the genetic screening of presenilin mutations to LOAD patients. Two variants in microtubule-associated protein tau and 1 in progranulin appeared to be benign polymorphisms, showing no major contribution of these genes to AD.
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piccoli
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Electronic address: grossi@istituto-besta.it.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Division of Neurology, Geriatric Hospital, INRCA IRCCS, Ancona, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Rossi
authors.affiliation: Division of Neurology, Geriatric Hospital, INRCA IRCCS, Ancona, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelliccioni
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Amato
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; Mutation; PSEN1; Targeted exome sequencing