title: A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.
abstract: Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aβ42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Luedecke
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jos S
authors.initials: JS
authors.lastname: Becktepe
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan T
authors.initials: JT
authors.lastname: Lehmbeck
authors.affiliation: MVZ Dr. Eberhard & Partner, Dortmund, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Finckh
authors.affiliation: MVZ Dr. Eberhard & Partner, Dortmund, Germany.
authors.forename: Raina
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahn
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: k.boelmans@uke.uni-hamburg.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Boelmans
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D053764:Presenilin-1
keywords: Cosegregation analysis; Early-onset Alzheimer disease; Missense mutation; Presenilin 1