近日，美国雷迪儿童基因组医学研究所教授Kimberley F. Tolias及其课题组报道了从头编码突变对脑脊膜膨出的贡献。2025年3月26日出版的《自然》杂志发表了这项成果。

研究小组假设纯化选择下的新生突变增加了发生脑膜脊髓炎的风险。

在这里，课题组人员招募了851名出生时需要分流的三联脑膜脊膜囊肿患者和732名对照三联脑膜脊膜囊肿患者，发现大约22.3%的受试者出现了可能的基因破坏或破坏性错义突变，其中28%的变异估计会导致疾病风险。具有破坏性新生突变的187个基因共同定义了包括肌动蛋白细胞骨架和基于微管的过程、Netrin-1信号传导和染色质修饰酶在内的网络。基因验证表明，在非洲爪蟾胚胎中部分或完全丧失功能，信号受损和神经管关闭缺陷。他们的研究结果表明，新生突变对脑膜脊髓膨出风险起着关键作用，并强调了人类胚胎发生中神经管闭合所需的关键途径。

据了解，脊膜膨出（也称为脊柱裂）被认为是一种由神经管关闭失败引起的遗传复杂疾病。脑膜脊膜膨出患者表现为神经运动障碍和频繁的脑积水，需要脑室分流术。一些基因已被提出与疾病易感性有关，但除此之外仍未得到解释。

附：英文原文

Title: The contribution of de novo coding mutations to meningomyelocele

Author: Ha, Yoo-Jin Jiny, Nisal, Ashna, Tang, Isaac, Lee, Chanjae, Jhamb, Ishani, Wallace, Cassidy, Howarth, Robyn, Schroeder, Sarah, Vong, Keng loi, Meave, Naomi, Jiwani, Fiza, Barrows, Chelsea, Lee, Sangmoon, Jiang, Nan, Patel, Arzoo, Bagga, Krisha, Banka, Niyati, Friedman, Liana, Blanco, Francisco A., Yu, Seyoung, Rhee, Soeun, Jeong, Hui Su, Plutzer, Isaac, Major, Michael B., Benoit, Batrice, Pos, Christian, Heffner, Caleb, Kibar, Zoha, Bot, Gyang Markus, Northrup, Hope, Au, Kit Sing, Strain, Madison, Ashley-Koch, Allison E., Finnell, Richard H., Le, Joan T., Meltzer, Hal S., Araujo, Camila, Machado, Helio R., Stevenson, Roger E., Yurrita, Anna, Mumtaz, Sara, Ahmed, Awais, Khara, Mulazim Hussain, Mutchinick, Osvaldo M., Medina-Bereciartu, Jos Ramn, Hildebrandt, Friedhelm, Melikishvili, Gia, Marwan, Ahmed I., Capra, Valeria, Noureldeen, Mahmoud M., Salem, Aida M. S., Issa, Mahmoud Y., Zaki, Maha S., Xu, Libin, Lee, Ji Eun, Shin, Donghyuk, Alkelai, Anna, Shuldiner, Alan R., Kingsmore, Stephen F., Murray, Stephen A., Gee, Heon Yung, Miller, W. Todd, Tolias, Kimberley F.

Issue&Volume: 2025-03-26

Abstract: Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

DOI: 10.1038/s41586-025-08676-x

Source: https://www.nature.com/articles/s41586-025-08676-x