The rare mutation in the endosome-associated recycling protein gene VPS50 is associated with human neural tube defects

BACKGROUND: 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 VPS50 in embryogenesis and human physiology are poorly understood. RESULTS: We identified a rare missense heterozygous VPS50 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 vps50 gene was expressed throughout the early embryo, especially in the head. Abnormal body axis phenotypes were observed in those vps50 knock-down zebrafishes. Further rescue study in zebrafish suggested that the mutation displayed loss-of-function effects comparing with wild-type VPS50. CONCLUSIONS: These findings thus demonstrated that the functional mutations in VPS50 might contribute to neurodevelopmental disorder and highlighted the critical importance of VPS50 function in cellular and organismal physiology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13039-019-0421-9) contains supplementary material, which is available to authorized users.