Background: Kabuki syndrome is a congenital developmental disorder that is characterized by distinctive facial gestalt and skeletal abnormalities. Although rare, the disorder shares clinical features with several related craniofacial syndromes that manifest from mutations in chromatin-modifying enzymes. Collectively, these clinical studies underscore the crucial, concerted functions of chromatin factors in shaping developmental genome structure and driving cellular transcriptional states. Kabuki syndrome predominantly results from mutations in KMT2D, a histone H3 lysine 4 methylase, or KDM6A, a histone H3 lysine 27 demethylase.
Aims: In this review, we summarize the research efforts to model Kabuki syndrome in vivo to understand the cellular and molecular mechanisms that lead to the craniofacial and skeletal pathogenesis that defines the disorder.
Discussion: As several studies have indicated the importance of KMT2D and KDM6A function through catalytic-independent mechanisms, we highlight noncanonical roles for these enzymes as recruitment centers for alternative chromatin and transcriptional machinery.
Keywords: KMT2D; Kabuki syndrome; MLL4; craniofacial and skeletal disorder; histone methylase.
© 2023 The Authors. Birth Defects Research published by Wiley Periodicals LLC.