英国牛津大学Nicola Whiffin.研究小组的最新研究发现，RNU4-2 snRNA的新生变异导致一种常见的神经发育综合征。相关论文于2024年7月11日发表在《自然》杂志上。

研究人员发现非编码RNA RNU4-2是神经发育障碍（NDD）综合症的致病基因。RNU4-2 编码U4小核RNA (snRNA)，它是主要剪接体U4/U6.U5三-snRNP复合物的重要组成部分。研究人员在RNU4-2中发现了一个18 bp的区域，该区域与U4/U6 snRNA双链中的两个结构区域（T环和茎III）相映射，在普通人群中该区域的变异非常少，但研究人员在115名NDD患者中发现了该区域的杂合变异。大多数个体（77.4%）具有相同的高发性单碱基插入（n.64_65insT）突变。在54个确诊的个体中，从头变异全部出现在母系等位基因上。

研究证明，与RNU4-1和其他U4同源物相比，RNU4-2在发育的人类大脑中高度表达。通过RNA测序，研究展示了RNU4-2变异个体的5'剪接位点是如何遭到系统性破坏的，这与该区域在剪接体激活过程中的已知作用相一致。最后，研究人员估计这18 bp区域的变异可解释0.4% NDD患者的病因。这项工作强调了非编码基因在罕见疾病中的重要性，并将为全球成千上万NDD患者的诊断提供依据。

据了解，约有60%的NDD患者在经过全面基因检测（主要是蛋白质编码基因检测）后仍不能确诊。大型基因组测序技术提高了人们在非编码基因组中发现新诊断结果的能力。

附：英文原文

Title: De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author: Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, DSouza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., DSouza, Precilla, Danecek, Petr, Dlot, Emmanule C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, Franois, Leito, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J.

Issue&Volume: 2024-07-11

Abstract: Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5’ splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

DOI: 10.1038/s41586-024-07773-7

Source: https://www.nature.com/articles/s41586-024-07773-7