All variants associated with MORC2 neurodevelopmental disorder are missense and cluster in the gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATP binding domain and the transducer-like domain, which together form the ATPase module of MORC2 (aa 1-494).
Genetic complementation experiments to assess the functional consequences of pathogenic MORC2 variants in HUSH-mediated silencing showed all mutants to be hyperactivating. This finding mirrors the effects observed with the mutants previously associated with MORC2-neuropathies. Similar to other GHKL-type ATPases, ATP binding and hydrolysis by MORC2 functions as a conformational switch. Upon ATP binding, the ATPase module dimerizes and becomes active, allowing for HUSH complex activity leading to transcriptional repression. Assessing the functional effects of different MORC2 variants, Douse et al. (2015) showed that, in the setting of normal ATP-dependent dimerization, neuropathic mutations resulting in weaker ATPase activity hyperactivated HUSH-mediated silencing.