Leveraging single-cell transcriptomics of developing rat ocular outflow tissues to prioritize congenital glaucoma...

Area of Science:

• Ophthalmology
• Developmental Biology
• Genetics

Background:

• Abnormal development of the trabecular meshwork (TM) and Schlemm's canal (SC) can lead to congenital glaucoma, a vision-impairing condition.
• Understanding the genetic basis of TM and SC development is crucial for diagnosing and treating early-onset glaucoma.

Purpose of the Study:

• To identify genes critical for the development of the aqueous humor outflow pathway (AHOP) structures.
• To investigate gene expression patterns in developing TM and SC tissues.
• To find novel candidate genes for congenital and childhood glaucoma.

Main Methods:

• Single-cell RNA sequencing was performed on rat AHOP tissues during key developmental periods.
• Transcriptomic profiles of limbal cells were analyzed to identify distinct cell types, including TM and SC.
• Gene expression data was compared between AHOP cells and other limbal tissues, and interrogated for known glaucoma-associated genes.

Main Results:

• 13 general cell types and specific TM/SC cell subtypes were identified from 86,653 limbal cells.
• 395 genes showed enhanced expression in TM/SC cells compared to other limbal tissues.
• 82% of Mendelian childhood glaucoma genes were enriched in SC/TM cells, versus 8% of complex late-onset glaucoma genes.

Conclusions:

• The identified 395 selectively expressed genes are strong candidates for causing congenital/childhood glaucoma.
• This transcriptomic dataset is a valuable resource for understanding AHOP development and early-onset glaucoma genetics.
• Findings can inform the development of polygenic risk scores and therapeutic strategies for glaucoma.