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Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type – amino acid (AA) substitutions – despite the diversity of coding variants that cause disease. We have recently used Deep Indel Mutagenesis (DIM) to generate the first comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aß) peptide that aggregates into fibrils in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). We combined DIM with a selection method that reports on the rate of amyloid nucleation, i.e. the mechanism by which Aß fibrils form in the first place. The resulting comprehensive atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aß aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but we identify likely pathogenic variants in all classes of mutations. Overall, mutations that increase the propensity of the peptide to aggregate into amyloid fibrils are highly enriched in the polar N-terminus of Aß, a region that remains unstructured in mature Aβ fibrils and – as a result – has been largely under-studied. This first comparative atlas highlights the importance of including diverse mutation types in MAVEs, while providing important mechanistic insights into amyloid nucleation.

Publié le novembre 28, 2022