University of Manchester scientists have used lab-grown human retinas to uncover how subtle genetic changes in a key protein cause a rare eye condition present from birth.
The study, published in the journal BBA: Molecular Basis of Disease, focuses on ocular coloboma. This condition affects approximately 1 in 5,000 births and is responsible for about 10% of childhood blindness.
Coloboma occurs when the optic fissure in a developing eye fails to close properly. The defect often appears alongside other issues like cleft lip or palate.
The role of YAP1
Researchers focused their investigation on YAP1, a protein that acts as a cellular switch to guide organ formation and tissue health. While scientists previously linked YAP1 changes to coloboma, the reason why some individuals develop severe defects while others remain unaffected remained a mystery.
To solve this, the team used human retinal organoids—miniature, lab-grown versions of the developing human retina. By reducing YAP1 activity in these models, they observed significant disruptions in how early retinal cells grow and develop.
Disrupting the protein reduced the activity of genes essential for retinal cells to maintain their identity. This slowdown in cell development provides a mechanical explanation for how the eye's formation fails.
"These findings give us a much clearer picture of how small genetic changes can have major effects during eye development," said lead author Dr. Cerys Manning.
Using computer modeling alongside experimental data, the team found that the specific location of a genetic change determines how much it disrupts YAP1 function. This explains the wide variation in severity among patients carrying the same gene.
Dr. Manning noted that identifying these precise variants allows doctors to better interpret genetic results in patients. The study also demonstrates how retinal organoids can serve as an ethical alternative to animal models in medical research.