Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.
Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.
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DOI：
10.1038/s41431-023-01368-y
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发表时间：
2023-07
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--
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--
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氨基末端 (Nt-) 乙酰化 (NTA) 是一种常见的蛋白质修饰，影响人类 80% 的胞浆蛋白。人类必需基因 NAA10 编码 N 端乙酰转移酶 A (NatA) 复合物中的催化亚基 NAA10，还包括辅助蛋白 NAA15。目前尚不清楚该途径中人类遗传变异的全部范围。在这里，我们揭示了人类 NAA10 和 NAA15 变异的遗传图谱。通过基因型优先的方法，一名临床医生采访了 56 名 NAA10 变异个体和 19 名 NAA15 变异个体的父母，这些个体被添加到所有已知病例中（NAA10 的 N = 106 例，NAA15 的 N = 66 例）。尽管这两种综合征之间存在临床重叠，但功能评估表明，具有 NAA10 变异的先证者的总体功能水平显着低于具有 NAA15 变异的先证者。表型谱包括不同程度的智力障碍、里程碑延迟、自闭症谱系障碍、颅面畸形、心脏异常、癫痫发作和视觉异常（包括皮质视觉障碍和小眼症）。一名携带 p.Arg83Cys 变异的女性和一名携带 NAA15 移码变异的女性均患有小眼症。位于 NAA10 C 末端的移码变体对整体功能的影响要小得多，而 NAA10 中具有 p.Arg83Cys 错义的雌性则有显着的损害。总体数据与这些等位基因的表型谱一致，涉及多个器官系统，从而揭示了 NTA 途径改变对人类的广泛影响。
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.
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通讯作者：
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