De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay

Abstract

Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

“…Related to the cerebral defects, Morf is important for regulating neural stem cells [72,73]. These findings shed some light on defects characteristic of developmental disorders due to mutations in the MOZ and MORF genes [74][75][76][77][78][79]. The phenotypes observed with these mutant mice indicate that although they are interchangeable in various molecular and cell-based studies in vitro [26,34,36], MOZ and MORF have quite distinct functions in vivo.…”

“…Importantly, two recent studies have also identified recurrent MOZ gene mutations in previously unrecognized syndromes that display intellectual disability and global developmental delay (Fig. 1B) [78,79].…”

“…3A) [36]. The bromodomain of BRPF1 has acetyllysine-binding ability [57], whereas the PZP modules of BRPF1 and BRPF2 recognize the unmodified N-terminus of histone H3 [46,58] and the second PHD finger of BRPF2 is also known to bind directly [78,79,130,134]. Abbreviations: CBP, CREB-binding protein; p300, E1A-associated p300 kDa protein (paralogous to CBP); TIF2, transcription intermediary factor 2 (known to bind p300 and CBP).…”

Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

“…Heterozygous mutations in MOZ have been identified in patients with microcephaly and global developmental delay, including intellectual disability and cardiac defects (5,6). Notably, MOZ has also been shown to play important roles in cardiac septum development (78).…”

“…Lysine acetyltransferase 6 (KAT6) belongs to the MYST family and has been linked to cell cycle regulation and leukemia (2)(3)(4). In addition, mutations and misregulation of the human KAT6 genes, MOZ/MORF, have been identified in solid tumors and patients with developmental disorders (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). To gain better understanding of the roles of KAT6 HATs in human diseases, it is critical to know how their functions are regulated.…”