PDF(Pubmed)
Abstract：
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.
摘要：
OpitzBBB/G综合征（OS）的X连锁形式是一种单基因疾病，其症状在胚胎发育早期建立。OS是由X连锁基因MID1的致病变异引起的。疾病相关变异分布在整个基因位点，除了包含E3泛素连接酶活性的N端真正有趣的新基因（RING）域。通过使用基因组编辑的人类诱导多能干细胞系，我们在这里表明，缺乏含有MID1的RING结构域的同种型会导致人脑类器官的严重模式缺陷。我们观察到明显的神经源性缺陷，神经组织减少，脉络丛样结构随之增加。转录组分析揭示了早期模式通路的失调，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，表明存在形成图案缺陷的独特机制。这些表型的严重程度和早期发作可能潜在地解释了在编码N末端RING结构域的MID1基因的外显子1中没有携带致病性变体的患者。
