Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies
Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies
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DOI：
10.1016/j.ajhg.2018.03.004
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发表时间：
2018-05-03
影响因子：
9.8
通讯作者：
Lyon, Gholson J.
中科院分区：
文献类型：
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作者：
Cheng, Hanyin;Dharmadhikari, Avinash V.;Lyon, Gholson J.
N-α-乙酰化是一种常见的共翻译蛋白质修饰，对人类正常的细胞功能是必不可少的。我们以前发现了一种X连锁的婴儿致死性孟德尔病的遗传基础，涉及NAA10中的C.109T>；C(p.Ser37Pro)错义变体，它编码N末端乙酰转移酶A(NatA)复合体的催化亚单位。NatA复合体的辅助亚基NAA15是NAA10的二聚体结合伙伴。通过全外显子组或基因组测序(WES/WGS)和靶向测序分析，我们鉴定了来自33个无关家庭的38个个体，包括25个不同的从头或遗传的NAA15基因可能的基因干扰(LGD)变体，并对其进行了表型分析。NAA15中携带LGD变异的受影响个人的临床特征包括不同程度的智力残疾、言语和运动里程碑延迟以及自闭症谱系障碍。此外，一些受试者还会出现轻微的颅面畸形、先天性心脏畸形和癫痫发作。来自两个个体的细胞系的RNA分析显示，带有LGD变体的转录本降解，可能是由于无意义介导的衰退所致。在酵母中的功能测试证实了NAA15中的两个LGD变体的有害影响。进一步支持单倍体功能不全的机制，涉及NAA15及其周围基因的拷贝数变异(CNV)缺失的个体可呈现轻度智力残疾、轻度变形特征、运动迟缓和生长减慢。我们认为，NatA介导的N-末端乙酰化(NTA)缺陷会导致人类不同程度的神经发育障碍，支持NatA复合体在正常人类发育中的重要性。
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.