KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.

KAT5编码一种必需的赖氨酸乙酰转移酶，以前称为TIP60，它参与调节基因表达，DNA修复，染色质重塑，细胞凋亡和细胞增殖。但尚不清楚该基因的变异是否会引起遗传病。在这里，我们研究了三个在KAT5中具有杂合的从头错义变异的个体它们影响正常不变的残基，其中一个在色域（p.Arg53His），两个在乙酰基-CoA结合位点或附近（p.Cys369Ser和p.Ser413Ala）。这三个人都有脑畸形，癫痫发作，整体发育迟缓或智力障碍，以及严重的睡眠障碍。还注意到进行性小脑萎缩。用纯化的变体KAT5进行组蛋白乙酰化测定表明，这些变体降低或消除了所得NuA4 / TIP60多亚基复合物乙酰化染色质中组蛋白H4尾巴的能力。在受影响的单个成纤维细胞中进行的转录组学分析显示，控制发育的多个基因被解除调控。而且，PER1的表达也上调（参与昼夜节律控制的关键基因）与所有个体的睡眠异常一致。总之，主要的错义KAT5变异体会导致组蛋白乙酰化缺陷，并导致多个基因转录失调，从而导致神经发育综合征，伴有睡眠障碍，小脑萎缩和面部畸形，并提示可识别的综合征。