Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation.
Bottom Line: 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.
Affiliation: Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium.Show MeSH
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Mentions: In this work, we identify a novel and unusual APP mutation in a Belgian patient showing early onset AD and seen in the University Hospital in Leuven. This mutation –E682K– is located at the β′-site within the Aβ sequence (Fig 1F). We examined the effect of the E682K mutation on the proteolytic processing of APP and found that this mutation caused significant increases in total Aβ and in Aβ1–42/40 levels. We further analysed APP processing in neuronal cultures by short metabolic labelling experiments demonstrating that β′-site cleavage is a major processing event of wild-type (WT) human APP in neuronal cultures. The E682K mutation blocked this processing step and consequentially shifted BACE1 cleavage towards the β-site. The data demonstrate the functional significance of β′-site cleavage in preventing overproduction of Aβ, which may potentially cause AD.
Affiliation: Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium.