英国弗朗西斯·克里克研究所Gregory M. Findlay团队取得一项新突破。他们认为RNU4-2的饱和编辑揭示了明显的显性和隐性疾病。2026年4月8日，国际知名学术期刊《自然》发表了这一成果。

在这里，课题组研究人员对RNU4-2进行了饱和基因组编辑（SGE），以确定整个基因变异的功能和临床影响。由此得出的SGE功能评分来源于变异对细胞适应性的影响，将ReNU综合征变异与人群中观察到的变异区分开来，并明显优于硅变异效应预测。利用这些数据，该研究组在单核苷酸分辨率上重新定义了ReNU综合征的关键区域，解决了不确定意义变异的变异致病性，并表明SGE功能评分通过表型严重程度和观察到的剪接破坏程度来描述变异。

此外，该课题组确定了影响RNU4-2区域功能的变异，这些区域对与其他剪接体组分的相互作用至关重要。该课题组研究人员发现这些变异是一种新的隐性神经发育障碍，与ReNU综合征不同。总之，这项工作定义了RNU4-2的变异功能，为诊断和治疗发展提供了重要的见解。

据了解，最近，RNU4-2中心18个核苷酸区域的新生变异被证明可以诱导ReNU综合征，这是一种综合征性神经发育障碍，预计会影响全球数十种个体。RNU4-2是一种非蛋白质编码基因，被转录成主要剪接体的U4小核RNA成分。ReNU综合征变异体破坏剪接体功能并改变5'剪接位点选择。

附：英文原文

Title: Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders

Author: De Jonghe, Joachim, Kim, Hyung Chul, Adedeji, Ayanfeoluwa, Leito, Elsa, Dawes, Ruebena, Kajba, Christina M., Cogn, Benjamin, Chen, Yuyang, Blakes, Alexander J. M., Simons, Cas, Rius, Rocio, Alvi, Javeria R., Amblard, Florence, Austin-Tse, Christina, Baer, Sarah, Balton, Elsa V., Blanc, Pierre, Calame, Daniel G., Coutton, Charles, Cunningham, Chloe A., Dargie, Nitsuh, Dipple, Katrina M., Du, Haowei, El Chehadeh, Salima, Glass, Ian, Gleeson, Joseph G., Grunewald, Olivier, Gueguen, Paul, Harbuz, Radu, Jacquemont, Marie-Line, Leventer, Richard J., Marijon, Pierre, Messaoud, Olfa, Sultan, Tipu, Thauvin, Christel, Vincent-Delorme, Catherine, Yilmaz Gulec, Elif, Thevenon, Julien, Mendez, Rodrigo, MacArthur, Daniel G., Depienne, Christel, Nava, Caroline, Whiffin, Nicola, Findlay, Gregory M.

Issue&Volume: 2026-04-08

Abstract: Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome3. ReNU syndrome variants disrupt spliceosome function and alter 5′ splice site selection1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants’ effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development.

DOI: 10.1038/s41586-026-10334-9

Source: https://www.nature.com/articles/s41586-026-10334-9