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.

Lrpap1 deficiency leads to myopia through TGF-β-induced apoptosis in zebrafish

“…TGF-β plays a role in regulating the ECM and acts in many diseases, including myopia [ 38 – 40 ]. Previous studies have shown that TGF-β is downregulated in the context of scleral tissues with myopia and associated with ECM degradation and fibroblast transformation via the increase in levels of MMP2 or α-SMA [ 41 – 43 ]. However, bFGF and TGF-β were reported to jointly regulate ocular development in a chick model; TGF-β may be an inhibitor of bFGF, leading to axial elongation and diopter change [ 44 ].…”

Analysis of the Association of Two SNPs in the Promoter Regions of the PPP2R5C and SLC39A5 Genes with Litter Size in Yunshang Black Goats

“…SLC39 proteins are important transporter proteins for the transport of metal ions from extracellular or intracellular organelles into the cytoplasm [ 14 ]. SLC39A5 , one of the key components of SLC39 protein, also plays an important role in the transport of metal ions such as zinc ions across the cell membrane [ 15 ]. SLC39A5 has been shown to play an important role in Zn + transport within intestinal epithelial cells in vivo, maintaining systemic homeostatic control [ 16 ].…”

Myopia: Mechanisms, Interventional Strategies, and Clinical Evidence

“…11 Others have focused on underlying biological mechanisms-the cellular and molecular transduction of visual signals to understand what ultimately drives ocular growth and tissue remodeling. 9 While we continue exploring fundamental mechanisms, clinical interventions are under development and in clinical trials to gauge efficacy. These clinical evaluations include contact lenses that modulate retinal defocus, orthokeratology, and more.…”

“…More recently, funded work addresses gene and protein expression to understand signals that drive ocular growth. 8,9 Although we are making progress, there is much to do.…”

“…Tom Norton and colleagues have provided insights on the effects of spectral composition and its impact on ocular growth 11 . Others have focused on underlying biological mechanisms—the cellular and molecular transduction of visual signals to understand what ultimately drives ocular growth and tissue remodeling 9 …”