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: We next analysed the effects of the E682K mutation on APP processing in further detail. In primary neuronal cultures, this mutation increased C99 and sAPPβ levels two- to three-fold (Fig 2), which correlates well with the overall increases in Aβ levels as measured by ELISAs. Similar effects were observed in transiently transfected CHO cells, in which the E682K mutation caused a two- to three-fold increase in C99 and sAPPβ levels (Fig S1 of Supporting Information). These data show that the E682K mutation increased Aβ generation by favouring the β-site cleavage of APP. In contrast to the E682K mutation, the ‘Flemish’ A692G mutation did not significantly affect the β-secretase processing (as measured by C99 and sAPPβ generation), confirming that the increased Aβ generation with this mutant is caused by a different mechanism. It has indeed been shown that the ‘Flemish’ mutation affects an inhibitory domain in the APP sequence that modulates γ-secretase activity (Tian et al, 2010).
Affiliation: Department for Developmental and Molecular Genetics, VIB, Leuven, Belgium.