NAA10是主要的N-末端乙酰转移酶复合物NatA的催化亚基,其乙酰化几乎一半的人类蛋白质组。在过去的十年里,据报道,许多NAA10错义变异是人类遗传疾病的病因.携带NAA10变体的个体通常表现出不同程度的智力残疾(ID),发育迟缓,和心脏异常.最初,携带者雌性似乎是寡症或无症状的,X失活模式偏向野生型等位基因。然而,最近有研究表明,NAA10变异体可引起女性的综合征性或非综合征性智力障碍。特定NAA10变体和X失活模式对雌性个体表型的影响仍有待阐明。
在这里,我们提出了一种新颖的从头NAA10(NM_003491.3)c。[47A>C];[=](p。[His16Pro];[=])在年轻女性中发现的变体。这个10岁的女孩严重延迟了运动和语言发育,多动和不安的行为受到干扰,心室系统和脑外CSF间隙的适度扩张。她的血液白细胞X失活模式向母体遗传的X染色体倾斜(95/5)。我们的功能研究表明,NAA10p。(H16P)损害了NatA复合物的形成和NatA催化活性,而单体NAA10催化活性似乎是完整的。此外,环己酰亚胺实验显示NAA10H16P变体不影响NAA10的细胞稳定性。
我们证明NAA10p。(His16Pro)在女孩中引起严重的综合征ID,很可能是通过受损的NatA介导的细胞蛋白Nt-乙酰化作用。X失活分析显示,患者血液中DNA的X失活模式偏斜,母系遗传等位基因优先甲基化/失活。
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.