Mechanisms of pathogenesis of missense mutations on the KDM6A-H3 interaction in type 2 Kabuki Syndrome

Mutations in genes encoding for histone methylation proteins are associated with several developmental disorders. Among them, KDM6A is the disease causative gene of type 2 Kabuki Syndrome, a rare multisystem disease. While nonsense mutations and short insertions/deletions are known to trigger pathogenic mechanisms, the functional effects of missense mutations are still uncharacterized. In this study, we demonstrate that a selected set of missense mutations significantly hamper the interaction between KDM6A and the histone H3, by modifying the dynamics of the linker domain, and then causing a loss of function effect. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.