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SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis.

ABSTRACT: High myopia is one of the leading causes of visual impairment worldwide with high heritability. We have previously identified the genetic contribution of SLC39A5 to nonsyndromic high myopia and demonstrated that disease-related mutations of SLC39A5 dysregulate the TGF-β pathway. In this study, the mechanisms underlying SLC39A5 involvement in the pathogenesis of high myopia are determined. We observed the morphogenesis and migration abnormalities of the SLC39A5 knockout (KO) human embryonic kidney cells (HEK293) and found a significant injury of ECM constituents. RNA-seq and qRT-PCR revealed the transcription decrease in COL1A1, COL2A1, COL4A1, FN1 and LAMA1 in the KO cells. Further, we demonstrated that TGF-β signalling, the regulator of ECM, was inhibited in SLC39A5 depletion situation, wherein the activation of receptor Smads (R-Smads) via phosphorylation was greatly blocked. SLC39A5 re-expression reversed the phenotype of TGF-β signalling and ECM synthesis in the KO cells. The fact that TGF-β signalling was zinc-regulated and that SLC39A5 was identified as a zinc transporter urged us to check the involvement of intracellular zinc in TGF-β signalling impairment. Finally, we determined that insufficient zinc chelation destabilized Smad proteins, which naturally inhibited TGF-β signalling. Overall, the SLC39A5 depletion-induced zinc deficiency destabilized Smad proteins, which inhibited the TGF-β signalling and downstream ECM synthesis, thus contributing to the pathogenesis of high myopia. This discovery provides a deep insight into myopic development.

SUBMITTER: Dong S

PROVIDER: S-EPMC8419198 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis.

Dong Shanshan S Tian Qi Q Zhu Tengfei T Wang Kangli K Lei Ganting G Liu Yanling Y Xiong Haofeng H Shen Lu L Wang Meng M Zhao Rongjuan R Wu Huidan H Li Bin B Zhang Qiumeng Q Yao Yujun Y Guo Hui H Xia Kun K Xia Lu L Hu Zhengmao Z

Journal of cellular and molecular medicine 20210724 17

High myopia is one of the leading causes of visual impairment worldwide with high heritability. We have previously identified the genetic contribution of SLC39A5 to nonsyndromic high myopia and demonstrated that disease-related mutations of SLC39A5 dysregulate the TGF-β pathway. In this study, the mechanisms underlying SLC39A5 involvement in the pathogenesis of high myopia are determined. We observed the morphogenesis and migration abnormalities of the SLC39A5 knockout (KO) human embryonic kidne ...[more]

PMID: 34302427

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Dataset Information

SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis.

Publications

SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis.

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