MID1 的 RING 结构域缺失会导致发育中的人类大脑出现模式化缺陷。

IF 3.3 2区 生物学 Q1 BIOLOGY
Life Science Alliance Pub Date : 2024-01-18 Print Date: 2024-04-01 DOI:10.26508/lsa.202302288
Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, Susann Schweiger
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引用次数: 0

摘要

X 连锁型 Opitz BBB/G 综合征(OS)是一种单基因疾病,其症状在胚胎发育早期就已出现。OS是由X连锁基因MID1中的致病变体引起的。除了包含E3泛素连接酶活性的N端真正有趣的新基因(RING)结构域外,疾病相关变体分布于整个基因座。通过使用基因组编辑的人类诱导多能干细胞系,我们在此表明,含有MID1 RING结构域的同工酶缺失会导致人类脑器官组织出现严重的模式化缺陷。我们观察到,神经源性缺陷突出,神经组织减少,同时脉络丛样结构增加。转录组分析表明,很早就出现了模式化通路的失调,甚至在神经诱导之前就已出现。值得注意的是,观察到的表型与在 MID1 完全敲除的器官组织中观察到的表型形成鲜明对比,这表明存在一种不同的机制来支撑模式化缺陷。这些表型的严重性和早期发病可能是没有携带编码 N 端 RING 结构域的 MID1 基因第 1 外显子致病变体的患者的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Absence of the RING domain in MID1 results in patterning defects in the developing human brain.

The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.

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来源期刊
Life Science Alliance
Life Science Alliance Agricultural and Biological Sciences-Plant Science
CiteScore
5.80
自引率
2.30%
发文量
241
审稿时长
10 weeks
期刊介绍: Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.
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