SNARE proteins comprise a conserved protein family responsible for catalyzing membrane fusion during vesicle traffic. Syntaxin18 (STX18) is a poorly characterized endoplasmic reticulum (ER)-resident t-SNARE. Recently, together with TANGO1 and SLY1, its involvement was shown in ER to Golgi transport of collagen II during chondrogenesis. We report a fetus with a severe osteochondrodysplasia in whom we identified a homozygous substitution of the highly conserved p.Arg10 to Pro of STX18. CRISPR/Cas9-mediated Stx18 deficiency in zebrafish reveals a crucial role for Stx18 in cartilage and bone development. Furthermore, increased expression of multiple components of the Stx18 SNARE complex and of COPI and COPII proteins suggests that Stx18 deficiency impairs antero- and retrograde vesicular transport in the crispant stx18 zebrafish. Taken together, our studies highlight a new candidate gene for a recessive form of osteochondrodysplasia, thereby possibly broadening the SNAREopathy phenotypic spectrum and opening new doors toward future research avenues. © 2023 American Society for Bone and Mineral Research (ASBMR).

中文翻译：

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人类和斑马鱼的突触融合蛋白 18 缺陷揭示了早期软骨和骨骼发育的关键作用

SNARE 蛋白包含一个保守的蛋白家族，负责在囊泡运输过程中催化膜融合。Syntaxin18 (STX18) 是一种尚不清楚的内质网 (ER) 驻留 t-SNARE。最近，它与 TANGO1 和 SLY1 一起参与了软骨形成过程中内质网到高尔基体 II 型胶原蛋白的转运。我们报告了一个患有严重骨软骨发育不良的胎儿，我们在该胎儿中发现了高度保守的 p.Arg10 与 STX18 Pro 的纯合替代。斑马鱼中 CRISPR/Cas9 介导的 Stx18 缺陷揭示了 Stx18 在软骨和骨骼发育中的关键作用。此外，Stx18 SNARE 复合体以及 COPI 和 COPII 蛋白的多种成分表达增加表明，Stx18 缺陷会损害脆脆stx18斑马鱼的前向和逆行囊泡运输。总而言之，我们的研究突出了隐性骨软骨发育不良的一个新候选基因，从而可能扩大 SNAREopathy 表型谱，并为未来的研究途径打开新的大门。© 2023 美国骨与矿物质研究学会 (ASBMR)。