MSH2 and Leigh syndrome: As a result, the cellular amount of a missense protein may be reduced to an insufficient level, which can ultimately cause disease (Ahner et al., 2007; Casadio et al., 2011; Matreyek et al., 2018; Nielsen et al., 2017), as we and others have previously shown for LS-linked variants of MSH2 (Gammie et al., 2007; Arlow et al., 2013; Nielsen et al., 2017).