Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04109 Leipzig, Germany.
Am J Hum Genet. 2018 Dec 6;103(6):1045-1052. doi: 10.1016/j.ajhg.2018.10.026.
We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs20), c.1348C>T (p.Arg450), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
我们描述了三个家庭中的六个人，他们都携带有 PUS7 基因的三个纯合蛋白截断变异：c.89_90del（p.Thr30Lysfs20）、c.1348C>T（p.Arg450）和倒数第二个外显子 15 的缺失。所有这些个体都有智力残疾、言语迟缓、身材矮小、小头畸形和攻击性行为。PUS7 编码 RNA 非依赖性假尿嘧啶核苷合成酶 7。假尿嘧啶化是 RNA 中最丰富的转录后修饰，主要被认为稳定 RNA 的二级结构。我们表明，与疾病相关的变异导致 PUS7 对 tRNA 和 mRNA 底物的活性丧失。此外，果蝇中的 pus7 基因敲除导致多种行为缺陷，包括活动增加、定向障碍和攻击性，这支持了神经缺陷是由 PUS7 变异引起的。我们的发现表明，PUS7 的 RNA 假尿嘧啶化对于正常的神经元发育和功能至关重要。
