De Novo Mutations of the Gene Encoding the Histone Acetyltransferase KAT6B Cause Genitopatellar Syndrome

Abstract

Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.

KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer

“…[18][19][20]. Data mining of the Cancer Cell Line Encyclopedia copynumber variation data derived from a lower resolution SNP microarray (21) confirmed the presence of the KAT6B homozygous deletion in NCI-H1963 ( Supplementary Fig.…”

Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos

“…Related to this, the MORF gene is mutated in three developmental disorders, Noonan syndrome-like disorder, 24 Ohdo syndrome, 25 and Genitopatellar syndrome, 26,27 with the common characteristic of intellectual disability. Specific expression in the neocortex, hippocamus, and cerebullum of mouse Brpf1 (Table S1; Fig.…”

“…The MOZ and MORF genes are rearranged in hematological malignancies and the MORF gene is subject to chromosome translocation in uterine leiomyomata. 4,22,23 In addition, MORF is mutated in different developmental disorders, including Noonan syndrome-like disorder, 24 Ohdo syndrome, 25 and Genitopatellar syndrome, 26,27 so another important issue is whether BRPF1 serves a "modifier" of these diseases. Molecular and cell-based studies suggest that this may be the case.…”

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

“…Notably, MOZ has also been shown to play important roles in cardiac septum development (78). Dominant mutations in MORF are associated with Noonan syndrome, Say-Barber-Biesecker-YoungSimpson syndrome, genitopatellar syndrome, and blepharophimosis-ptosis-epicanthus inversus syndrome (7)(8)(9)(10)(11)(12). The common phenotypes shared between at least two of these four syndromes include abnormal facial features, intellectual disability, congenital heart defects, and genital anomalies.…”

“…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.…”