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Updated: Jul 10, 2026
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Biobanking of Human Aqueous and Vitreous Liquid Biopsies for Molecular Analyses
Published on: September 11, 2023
Deep Proteomic Analysis With Machine Learning Identifies Aqueous Humor Biomarkers of ADAMTSL4-associated Congenital
Xinyao Chen1,2,3, Xin Shen1,2,3, Wannan Jia1,2,3
1Eye Institute and Department of Ophthalmology, Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
Investigative Ophthalmology & Visual Science
|July 9, 2026
Summary
This study reveals key protein changes in aqueous humor of patients with ADAMTSL4-associated congenital ectopia lentis (CEL). These findings offer insights into the molecular mechanisms driving this rare eye condition.
Area of Science:
- Ophthalmology
- Proteomics
- Genetics
Background:
- Congenital ectopia lentis (CEL) is a rare inherited eye disorder.
- Mutations in the ADAMTSL4 gene are a known cause of CEL.
- The specific molecular alterations in the aqueous humor (AH) of patients with ADAMTSL4-associated CEL remain largely uncharacterized.
Purpose of the Study:
- To systematically characterize aqueous humor (AH) proteomic alterations in ADAMTSL4-associated congenital ectopia lentis (CEL).
- To identify disease-related molecular features and potential biomarkers for ADAMTSL4-associated CEL.
- To elucidate the underlying molecular mechanisms of this rare ocular disorder.
Main Methods:
- Deep data-independent acquisition (deep DIA) mass spectrometry was used to profile AH proteomes from pediatric CEL patients with ADAMTSL4 mutations.
- Functional enrichment, gene set enrichment analysis, and weighted gene co-expression network analysis (WGCNA) were employed to analyze differentially expressed proteins (DEPs).
- Machine learning prioritized candidate biomarkers, which were confirmed using intelligent parallel reaction monitoring (iPRM) and correlated with clinical data. Transcriptional changes were assessed in cellular and zebrafish models.
Main Results:
- Deep DIA quantified 1865 AH proteins, identifying 265 DEPs enriched in extracellular matrix (ECM) remodeling, complement-coagulation cascades, and lipid transport pathways.
- WGCNA identified protein modules significantly associated with ocular phenotypes.
- Six candidate biomarkers were prioritized, with four (APOC2, AMBP, KLKB1, ENPP2) confirmed by iPRM. APOC2, KLKB1, and ENPP2 correlated with axial length or choroidal thickness. Downregulation of ENPP2, MYDGF, and CA2, and upregulation of LCAT were observed in knockdown models.
Conclusions:
- This study provides a high-resolution proteomic profile of the aqueous humor in ADAMTSL4-associated CEL.
- Coordinated molecular alterations in ECM disruption, complement-coagulation activation, and lipid homeostasis were identified.
- The findings offer integrated molecular insights and potential candidate biomarkers for understanding and potentially diagnosing this rare ocular disorder.
