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01-04-2017 | Original Article

Truncation of the MSH2 C-terminal 60 amino acids disrupts effective DNA mismatch repair and is causative for Lynch syndrome

Authors: Eva Wielders, Elly Delzenne-Goette, Rob Dekker, Martin van der Valk, Hein te Riele

Published in: Familial Cancer | Issue 2/2017

Abstract

Missense variants of DNA mismatch repair (MMR) genes pose a problem in clinical genetics as long as they cannot unambiguously be assigned as the cause of Lynch syndrome (LS). To study such variants of uncertain clinical significance, we have developed a functional assay based on direct measurement of MMR activity in mouse embryonic stem cells expressing mutant protein from the endogenous alleles. We have applied this protocol to a specific truncation mutant of MSH2 that removes 60 C-terminal amino acids and has been found in suspected LS families. We show that the stability of the MSH2/MSH6 heterodimer is severely perturbed, causing attenuated MMR in in vitro assays and cancer predisposition in mice. This mutation can therefore unambiguously be considered as deleterious and causative for LS.

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Title: Truncation of the MSH2 C-terminal 60 amino acids disrupts effective DNA mismatch repair and is causative for Lynch syndrome
Authors: Eva Wielders
Elly Delzenne-Goette
Rob Dekker
Martin van der Valk
Hein te Riele
Publication date: 01-04-2017
Publisher: Springer Netherlands
Published in: Familial Cancer / Issue 2/2017
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-016-9945-x

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