SLC39A5 dysfunction impairs extracellular matrix synthesis in high myopia pathogenesis

Area of Science:

• Genetics
• Molecular Biology
• Ophthalmology

Background:

• High myopia is a leading cause of visual impairment with high heritability.
• Previous studies identified SLC39A5's genetic role in high myopia and its regulation of the TGF-β pathway.

Purpose of the Study:

• To elucidate the mechanisms of SLC39A5 in high myopia pathogenesis.
• To investigate the link between SLC39A5, zinc transport, and TGF-β signaling in myopia development.

Main Methods:

• Utilized SLC39A5 knockout (KO) human embryonic kidney cells (HEK293).
• Performed RNA-sequencing (RNA-seq) and quantitative reverse transcription PCR (qRT-PCR) to analyze gene expression.
• Assessed cell morphogenesis, migration, and extracellular matrix (ECM) constituent integrity.
• Investigated TGF-β signaling pathway activation, Smad protein stability, and intracellular zinc levels.

Main Results:

• SLC39A5 KO cells exhibited abnormal morphogenesis, migration, and ECM injury.
• Decreased transcription of key ECM genes (COL1A1, COL2A1, COL4A1, FN1, LAMA1) was observed in KO cells.
• TGF-β signaling was inhibited in SLC39A5-depleted cells, with blocked R-Smad phosphorylation.
• Intracellular zinc deficiency due to SLC39A5 depletion destabilized Smad proteins, inhibiting TGF-β signaling and ECM synthesis.

Conclusions:

• SLC39A5 depletion leads to zinc deficiency, which destabilizes Smad proteins.
• This destabilization inhibits TGF-β signaling and downstream ECM synthesis, contributing to high myopia.
• Findings offer insights into the molecular mechanisms underlying myopic development.