NAA10 is the catalytic subunit of the major N-terminal acetyltransferase complex NatA which acetylates almost half the human proteome. Over the past decade, many NAA10 missense variants have been reported as causative of genetic disease in humans. Individuals harboring NAA10 variants often display variable degrees of intellectual disability (ID), developmental delay, and cardiac anomalies. Initially, carrier females appeared to be oligo- or asymptomatic with X-inactivation pattern skewed towards the wild type allele. However, recently it has been shown that NAA10 variants can cause syndromic or non-syndromic intellectual disability in females as well. The impact of specific NAA10 variants and the X-inactivation pattern on the individual phenotype in females remains to be elucidated. Here we present a novel de novo NAA10 (NM_003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) variant identified in a young female. The 10-year-old girl has severely delayed motor and language development, disturbed behavior with hyperactivity and restlessness, moderate dilatation of the ventricular system and extracerebral CSF spaces. Her blood leukocyte X-inactivation pattern was skewed (95/5) towards the maternally inherited X-chromosome. Our functional study indicates that NAA10 p.(H16P) impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity appears to be intact. Furthermore, cycloheximide experiments show that the NAA10 H16P variant does not affect the cellular stability of NAA10. We demonstrate that NAA10 p.(His16Pro) causes a severe form of syndromic ID in a girl most likely through impaired NatA-mediated Nt-acetylation of cellular proteins. X-inactivation analyses showed a skewed X-inactivation pattern in DNA from blood of the patient with the maternally inherited allele being preferentially methylated/inactivated.

中文翻译：

---

一名患有 NAA10 功能障碍和新型杂合 de novo NAA10 p.(His16Pro) 变异的女孩的严重 ID 综合征和 X 轴失活偏斜 - 病例报告。


NAA10 是主要 N 末端乙酰转移酶复合物 NatA 的催化亚基，可乙酰化几乎一半的人类蛋白质组。在过去的十年中，许多 NAA10 错义变异被报道为导致人类遗传疾病的原因。携带 NAA10 变异的个体通常表现出不同程度的智力障碍 (ID)、发育迟缓和心脏异常。最初，携带者雌性似乎没有症状或无症状，X 失活模式偏向野生型等位基因。然而，最近有研究表明，NAA10 变异也可导致女性综合征性或非综合征性智力障碍。特定 NAA10 变异和 X 失活模式对女性个体表型的影响仍有待阐明。在这里，我们提出了在年轻女性中发现的一种新的从头 NAA10 (NM_003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) 变异。这位 10 岁女孩的运动和语言发育严重迟缓，行为紊乱，多动和烦躁，脑室系统和脑脊液间隙中度扩张。她的血液白细胞 X 失活模式 (95/5) 偏向于母系遗传的 X 染色体。我们的功能研究表明，NAA10 p.(H16P) 会损害 NatA 复合物的形成和 NatA 催化活性，而单体 NAA10 催化活性似乎完好无损。此外，放线菌酮实验表明NAA10 H16P变体不会影响NAA10的细胞稳定性。我们证明 NAA10 p.(His16Pro) 很可能是通过 NatA 介导的细胞蛋白 Nt 乙酰化受损而导致女孩出现严重的 ID 综合征。 X 失活分析显示，患者血液 DNA 中的 X 失活模式存在偏差，母系遗传的等位基因优先甲基化/失活。