title: Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment.
abstract: Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Theuns
authors.forename: E
authors.initials: E
authors.lastname: Marjaux
authors.forename: M
authors.initials: M
authors.lastname: Vandenbulcke
authors.forename: K
authors.initials: K
authors.lastname: Van Laere
authors.forename: S
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: G
authors.initials: G
authors.lastname: Bormans
authors.forename: N
authors.initials: N
authors.lastname: Brouwers
authors.forename: M
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: K
authors.initials: K
authors.lastname: Vennekens
authors.forename: E
authors.initials: E
authors.lastname: Corsmit
authors.forename: M
authors.initials: M
authors.lastname: Cruts
authors.forename: B
authors.initials: B
authors.lastname: De Strooper
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: R
authors.initials: R
authors.lastname: Vandenberghe
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001530:Belgium; D001921:Brain / Q000000981:diagnostic imaging; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D049268:Positron-Emission Tomography; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein
chemical_list: D016564:Amyloid beta-Protein Precursor