Shi Zhiwen, Chen Shuxia, Han Xiao, Peng Rui, Luo Jin, Yang Luming, Zheng Yufang, Wang Hongyan
1Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, 200011 China.
2Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, 200032 China.
Mol Cytogenet. 2019 Feb 20;12:8. doi: 10.1186/s13039-019-0421-9. eCollection 2019.
Tight control of endosome trafficking is essential for the generation of a normally patterned embryo. Recent studies have found that VPS50 is a key ingredient in EARP which is required for recycling of internalized TfRs to the cell surface and dense-core vesicle maturation. However, the role of in embryogenesis and human physiology are poorly understood.
We identified a rare missense heterozygous mutation (p. Gly169Val) in NTDs by high-throughput sequencing. In vitro functional analysis demonstrated that the p. Gly169Val was a loss-of-function mutation, delaying transferrin recycling and altering its interaction with VPS53. Using WISH during zebrafish embryogenesis, we demonstrated that gene was expressed throughout the early embryo, especially in the head. Abnormal body axis phenotypes were observed in those knock-down zebrafishes. Further rescue study in zebrafish suggested that the mutation displayed loss-of-function effects comparing with wild-type .
These findings thus demonstrated that the functional mutations in might contribute to neurodevelopmental disorder and highlighted the critical importance of function in cellular and organismal physiology.
内体运输的严格调控对于正常模式胚胎的形成至关重要。最近的研究发现，VPS50是EARP中的关键成分，EARP是内化的转铁蛋白受体（TfRs）循环至细胞表面和致密核心囊泡成熟所必需的。然而，其在胚胎发生和人类生理学中的作用仍知之甚少。
我们通过高通量测序在神经发育障碍（NTDs）中鉴定出一种罕见的错义杂合突变（p.Gly169Val）。体外功能分析表明，p.Gly169Val是一种功能丧失突变，延迟了转铁蛋白循环并改变了其与VPS53的相互作用。在斑马鱼胚胎发生过程中使用全胚胎原位杂交（WISH），我们证明该基因在整个早期胚胎中表达，尤其是在头部。在那些该基因敲低的斑马鱼中观察到了异常的体轴表型。在斑马鱼中的进一步拯救研究表明，与野生型相比，该突变表现出功能丧失效应。
这些发现因此证明该基因的功能突变可能导致神经发育障碍，并突出了其功能在细胞和机体生理学中的关键重要性。
