Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant-a case report
Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant-a case report
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DOI：
10.1186/s12881-020-01091-1
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发表时间：
2020-07-22
影响因子：
--
通讯作者：
Arnesen, Thomas
中科院分区：
文献类型：
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作者：
Bader, Ingrid;McTiernan, Nina;Arnesen, Thomas
背景NAA 10是N-末端乙酰转移酶复合物NatA的催化亚基，该复合物乙酰化几乎一半的人类蛋白质组。在过去的十年中，许多NAA 10错义变体被报道为人类遗传疾病的病因。携带NAA 10变异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，携带者女性似乎是寡核苷酸或无症状的X-失活模式偏向野生型等位基因。然而，最近已经表明，NAA 10变异体也可以导致女性的综合征或非综合征性智力残疾。具体的NAA 10变体和X-失活模式对女性个体表型的影响仍有待阐明。在这里，我们提出了一种新的de novoNAA 10（NM_003491.3）c. [47A> C];[=]（p. [His 16 Pro];[=]）在年轻女性中鉴定出的变异。这名10岁的女孩有严重的运动和语言发育迟缓，行为障碍伴多动和坐立不安，脑室系统和脑外CSF空间中度扩张。她的血液白细胞X-失活模式偏向（95/5）母系遗传的X-染色体。我们的功能研究表明，NAA 10 p.（H16 P）损害NatA复合物形成和NatA催化活性，而单体NAA 10催化活性似乎是完整的。此外，放线菌酮实验表明，NAA 10 H16 P变体不影响NAA 10的细胞稳定性。讨论和结论我们证明，NAA 10 p。（His 16 Pro）导致一个女孩的综合征ID的严重形式，最有可能通过受损的NatA介导的细胞蛋白质的N-乙酰化。X-失活分析表明，从血液中的患者与母系遗传的等位基因被优先甲基化/失活的DNA的X-失活模式倾斜。
Background 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. Case presentation Here we present a novel de novoNAA10(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. Discussion and conclusions 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.