小柯机器人

美国加州大学Joseph G. Gleeson研究小组报道了皮质发育畸形（MCD）过程中体细胞突变的综合多组学分析。2023年1月12日出版的《自然-遗传学》发表了这项成果。

研究人员描绘了283个脑切除术病人的脑组织遗传图谱，通过对体细胞突变的密集分析与全外显子组和靶向扩增子测序及对小鼠子宫电穿孔功能验证与单核RNA测序相结合，研究人员鉴定了69个突变基因。基因型-表型相关性分析阐明了与不同病理生理学和临床表型相关的特定MCD基因集。突变基因在对照组和患者大脑中特定单细胞水平的时空表达模式表明，在大脑发育过程中突变基因在兴奋性神经源池中起关键作用，并在出生后促进神经元的过度兴奋。

据介绍，皮质发育畸形是胚胎发生过程中发生的与皮质结构和细胞组织局灶性破坏相关的神经系统疾病，主要由体细胞镶嵌突变引起，并导致顽固性癫痫。确定MCD的遗传原因一直是一个挑战，因为在切除的脑组织中这些突变存在于低等位基因并部分与癫痫治疗相关。

附：英文原文

Title: Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Author: Chung, Changuk, Yang, Xiaoxu, Bae, Taejeong, Vong, Keng Ioi, Mittal, Swapnil, Donkels, Catharina, Westley Phillips, H., Li, Zhen, Marsh, Ashley P. L., Breuss, Martin W., Ball, Laurel L., Garcia, Camila Arajo Bernardino, George, Renee D., Gu, Jing, Xu, Mingchu, Barrows, Chelsea, James, Kiely N., Stanley, Valentina, Nidhiry, Anna S., Khoury, Sami, Howe, Gabrielle, Riley, Emily, Xu, Xin, Copeland, Brett, Wang, Yifan, Kim, Se Hoon, Kang, Hoon-Chul, Schulze-Bonhage, Andreas, Haas, Carola A., Urbach, Horst, Prinz, Marco, Limbrick, David D., Gurnett, Christina A., Smyth, Matthew D., Sattar, Shifteh, Nespeca, Mark, Gonda, David D., Imai, Katsumi, Takahashi, Yukitoshi, Chen, Hsin-Hung, Tsai, Jin-Wu, Conti, Valerio, Guerrini, Renzo, Devinsky, Orrin, Silva, Wilson A., Machado, Helio R., Mathern, Gary W., Abyzov, Alexej, Baldassari, Sara, Baulac, Stphanie, Gleeson, Joseph G.

Issue&Volume: 2023-01-12

Abstract: Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

DOI: 10.1038/s41588-022-01276-9

Source: https://www.nature.com/articles/s41588-022-01276-9

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex