Scientists at UHN have made a significant discovery about a rare debilitating brain disorder called hypomyelinating leukodystrophy-15 (HLD15). This new understanding could help develop better treatments for the disease.
The research team, co-led by Dr. Grace Yoon, a Clinical Geneticist at The Hospital for Sick Children, affiliated with Krembil Brain Institute, found a crucial mutation in a gene called EPRS1. This gene normally helps produce an important protein, but when it’s mutated, it doesn’t work correctly, leading to severe problems with thinking and movement.
Dr. Yoon explained, "We found that this pathogenic variant affects how a part of the cell’s machinery, called mRNA, is modified and used to make proteins. This is a novel mechanism not previously linked to genetic disorders."
The team studied two siblings with HLD15 and discovered that the causative DNA change prevents the mRNA from working properly, which means the body can’t make the necessary proteins. This causes the severe symptoms that are seen in HLD15 patients.
This discovery has far-reaching implications. It not only sheds light on how genetic changes can affect RNA modifications and protein synthesis but also suggests a new therapeutic approach. What makes this discovery even more exciting is that the researchers found a way to fix the problem in the lab. They used special molecules to correct the mRNA’s function, pointing to the potential for personalized RNA-based therapies.
"This research gives hope to individuals affected by HLD15 and indicates that similar mechanisms might be involved in other genetic disorders," said Dr. Yoon. "By targeting these mRNA issues, we can create more precise treatments."
This work was supported by The National Institutes of Health, the American Heart Association, the Krembil Research Institute, and UHN Foundation.
Dr. Grace Yoon is a Professor at the Department of Molecular Genetics, University of Toronto and a staff physician in the Division of Clinical and Metabolic Genetics, with a cross-appointment in the Division of Neurology at The Hospital for Sick Children.
Khan D, Ramachandiran I, Vasu K, China A, Khan K, Cumbo F, Halawani D, Terenzi F, Zin I, Long B, Costain G, Blaser S, Carnevale A, Gogonea V, Dutta R, Blankenberg D, Yoon G, and Fox PL. Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6 A site accessibility. doi: doi.org/10.1038/s41467-024-48549-x.