title: Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation.
abstract: BACE1 cleaves the amyloid precursor protein (APP) at the β-cleavage site (Met(671) -Asp(672) ) to initiate the generation of amyloid peptide Aβ. BACE1 is also known to cleave APP at a much less well-characterized β'-cleavage site (Tyr(681) -Glu(682) ). We describe here the identification of a novel APP mutation E682K located at this β'-site in an early onset Alzheimer's disease (AD) case. Functional analysis revealed that this E682K mutation blocked the β'-site and shifted cleavage of APP to the β-site, causing increased Aβ production. This work demonstrates the functional importance of APP processing at the β'-site and shows how disruption of the balance between β- and β'-site cleavage may enhance the amyloidogenic processing and consequentially risk for AD. Increasing exon- and exome-based sequencing efforts will identify many more putative pathogenic mutations without conclusive segregation-based evidence in a single family. Our study shows how functional analysis of such mutations allows to determine the potential pathogenic nature of these mutations. We propose to classify the E682K mutation as probable pathogenic awaiting further independent confirmation of its association with AD in other patients.
authors.affiliation: Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium.
authors.forename: Lujia
authors.initials: L
authors.lastname: Zhou
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.forename: Annelies
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: David
authors.initials: D
authors.lastname: Demedts
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D050505:Mutant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human