Human Genetics Department, New York State Institute for Basic Research (IBR) in Developmental Disabilities, Staten Island, New York, United States of America.
Biology PhD Program, The Graduate Center, The City University of New York, New York, NY, United States of America.
PLoS One. 2024 May 7;19(5):e0301328. doi: 10.1371/journal.pone.0301328. eCollection 2024.
Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.
N 端（Nt-）乙酰化（NTA）是一种常见的蛋白质修饰，大约影响所有人类蛋白的 80%。人类必需的 X 连锁基因 NAA10 编码 NAA10 酶，它是 N 端乙酰转移酶 A（NatA）复合物的催化亚基。NAA10 存在广泛的遗传变异，包括错义、剪接位点和 C 端移码变异。在小鼠中，Naa10 不是必需基因，因为存在一个同源基因 Naa12，它可以显著挽救 Naa10 敲除小鼠的胚胎致死性，而双敲除（Naa10-/Y Naa12-/-）则是胚胎致死性的。然而，小鼠的表型变异性仍然非常广泛，包括斑驳、骨骼缺陷、体型小、脑积水、肾盂积水和新生儿致死性。在这里，我们在小鼠中用新的遗传等位基因复制了这些表型，但我们证明了它们受遗传背景和环境影响的调节。我们不能复制之前关于杂合子 Naa10-/X 雌性小鼠“母体效应致死性”的报告，但我们确实观察到在不同的动物设施中，在近交遗传背景下，Naa10-/y 雄性小鼠存在少量胚胎致死性。
