Uncovering the Hidden World of Aqueous Humor Proteins for Discovery of Biomarkers for Marfan Syndrome

Abstract

Ectopia lentis is a hallmark of Marfan syndrome (MFS), a genetic connective tissue disorder affecting 1/5000 to 1/10 000 individuals worldwide. Early detection in ophthalmology clinics and timely intervention of cardiovascular complications can be lifesaving. In this study, a modified proteomics workflow with liquid chromatography‐tandem mass spectrometry (LC‐MS/MS)‐based data‐independent acquisition (DIA) and field asymmetric ion mobility spectrometry (FAIMS) to profile the proteomes of aqueous humor (AH) and lens tissue from MFS children with ectopia lentis is utilized. Over 2300 and 2938 comparable proteins are identified in AH and the lens capsule, respectively. Functional enrichment analyses uncovered dysregulation of complement and coagulation‐related pathways, collagen binding, and cell adhesion in MFS. Through weighted correlation network analysis (WGCNA) and machine learning, distinct modules associated with clinical traits are constructed and a unique biomarker panel (Q14376, Q99972, P02760, Q07507; gene names: GALE, MYOC, AMBP, DPT) is defined. These biomarkers are further validated using advanced parallel reaction monitoring (PRM) in an independent patient cohort. The results provide novel insights into the proteome characterization of ectopia lentis and offer a promising approach for developing a valuable biomarker panel to aid in the early diagnosis of Marfan syndrome via AH proteome.

Advances in aqueous humor proteomics for biomarker discovery and disease mechanisms exploration: a spotlight on primary open angle glaucoma

“…A meta database combining data from multiple previous studies also exists ( Yu et al, 2020 ). Beyond these catalogs, individual studies using label-free liquid chromatography-tandem MS (LC-MS/MS) in age-related macular degeneration (AMD) and Marfan Syndrome have reported proteome coverage in excess of 2,300 proteins ( Coronado et al, 2021 ; Shi et al, 2024 ).…”

“…DDA in contrast only fragments and sequences defined precursor ions based on their intensity. Prefractionation of AH samples using high-performance liquid chromatography (HPLC) followed by MS/MS analysis in DIA mode have vastly increased the number of detectable proteins ( Shi et al, 2024 ). Zhang and colleagues recently introduced a Streamlined Workflow based on Anchor-nanoparticles for Proteomics (SWAP) method in conjunction with DIA-MS, which identified ∼1,400 proteins from a minute 5 μL of sample ( Zhang et al, 2023 ).…”