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首页> 外文期刊>The American Journal of Human Genetics >De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay
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De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay

机译：KAT6A，赖氨酸乙酰基转移酶基因的从头废话突变，导致包括小头畸形和全球发展延迟的综合症。

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摘要

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.
机译：通过组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）酶的染色质重塑会影响基本的细胞过程，包括细胞周期，细胞分化，代谢和凋亡。与组蛋白乙酰化和脱乙酰化有关的基因中无意义的突变导致多种先天性异常，大多数个体表现出显着的发育延迟，小头畸形和畸形。在这里，我们报告了由临床外显子组测序（CES）鉴定的四个独立家族中的KAT6A（也称为MOZ，MYST3）的从头杂合无意义突变引起的综合征。在三个个体中观察到相同的从头无意义突变（c.3385C> T [p.Arg1129 *]），第四个人具有附近的从头无意义突变（c.3070C> T [p.Arg1024 *]）。这些变体均未出现在1,815个内部外显子组或公共数据库中。这四个先证者的共同特征包括原发性小头畸形，整体发育迟缓（包括严重的言语迟缓）和颅面畸形，以及更多变化的特征，例如进食困难，心脏缺陷和眼部异常。我们进一步证明，KAT6A突变导致H3K9和H3K18乙酰化失调，并改变了P53信号传导。通过组蛋白和非组蛋白乙酰化，KAT6A影响多个细胞过程，并说明了乙酰化在调节发育和疾病中的复杂作用。

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