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.

中文翻译：

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MID1 中 RING 结构域的缺失会导致人类大脑发育中的模式缺陷。

X 连锁形式的 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形成。OS 是由 X 连锁基因MID1中的致病性变异引起的。疾病相关变异分布在整个基因座中，但包含 E3 泛素连接酶活性的 N 端真正有趣的新基因 (RING) 结构域除外。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 结构域的异构体的缺失会导致人脑类器官的严重模式缺陷。我们观察到显着的神经源性缺陷，神经组织减少，脉络丛样结构随之增加。转录组分析揭示了模式通路在很早的时候就出现了失调，甚至在神经诱导之前。值得注意的是，观察到的表型与 MID1 全敲除类器官中观察到的表型形成鲜明对比，表明存在一种独特的机制来导致图案缺陷。这些表型的严重程度和发病较早可能是导致患者不存在编码 N 末端 RING 结构域的MID1基因外显子 1 致病性变异的原因。