DNA sequence prevents genetic variations from expanding and causing disease
A recent study published in Nature Genetics led by Dr. Bernard Brais from The Neuro and Dr. Stephan Zuchner from the University of Miami’s Miller School of Medicine has discovered a genetic mechanism that protects people from developing a type of spinocerebellar ataxia, a mechanism that one third of the population lack.
Spinocerebellar ataxia 27B is a rare neurodegenerative condition, characterized by episodes of uncoordinated gait, vertigo, and double vision that become permanent around the age of 60. As reported by the group in the New England Journal of Medicine in 2023, it is caused by tandem repeat expansions in the FGF14 gene. Spinocerebellar ataxia 27B is now considered one of the most common causes of ataxia worldwide and is particularly common in Québec, with more than 120 patients identified to date.
In this most recent study, the research team discovered that a short DNA sequence in the FGF14 gene blocks the expansion of tandem repeats, preventing spinocerebellar ataxia 27B.
Previous studies by the team showed that FGF14 expansions can continue to grow when passed down from parents to children, from mother to children in particular, and over several generations can eventually reach a size that causes disease. This most recent study shows for the first time that a short DNA sequence located next to the repeat expansion prevents intergenerational growth of the FGF14 repeat. A third of humans do not have this protective element and so are at risk of transmitting to their children an enlarged expansion.
These findings may help identify families who are at higher risk for this debilitating condition and could eventually lead to new therapies to prevent tandem repeat expansions. The study was published on June 27, 2024, making the journal cover.
“This discovery underlines how the exponential growth of high-quality human DNA sequencing, when studied by young investigators mastering these new techniques – such as Dr. David Pellerin, who will return to The Neuro after his fellowship training, and Dr. Matt Danzi in Miami – can lead to major, high impact discoveries,” says Dr. Brais.
“While we always suspected such stabilizing sequences for repeat expansion disorders, this is the first time such an element has been identified,” says Dr. Zuchner. “Astoundingly, this rather common sequence does not appear in any of the popular reference genomes.”