New Study Shows DNA Sequence Protects Against Spinocerebellar Ataxia
Article Summary
- Miller School researchers have shown that a specific DNA sequence protects people from developing spinocerebellar ataxia 27B.
- Spinocerebellar ataxia 27B is a rare, neurodegenerative condition caused by tandem repeat expansions in the FGF14 gene.
- One-third of all people don’t have the DNA sequence that protects against spinocerebellar ataxia 27B.
Researchers at the University of Miami Miller School of Medicine, McGill University and other institutions have shown that a specific DNA sequence in the FGF14 gene prevents the expansion of genetic variants called tandem repeats, protecting people from developing spinocerebellar ataxia 27B (SCA27B).
The findings may help identify families who are at higher risk for the debilitating condition and eventually lead to new therapies to prevent tandem repeat expansions. The study was published in Nature Genetics.
Gene Patterns Gone Awry
Spinocerebellar ataxia 27B is a rare, neurodegenerative condition that causes uncoordinated movements, balance problems, vertigo, double vision and other issues. Caused by tandem repeat expansions in the FGF14 gene, the disease is particularly common in French Canadians.
Tandem repeat expansions are simple genetic patterns in genes that can expand dozens or even hundreds of times, disrupting gene function. These anomalies have been linked to more than 50 neurodegenerative conditions.
Most people have no more than 30 repeats in the FGF14 gene. In spinocerebellar ataxia 27B, the GAA repetitive sequence is expanded more than 300 times. The research team had previously shown that FGF14 expansions can grow when passed down from parents to children and, over several generations, can eventually cause disease.
Identifying a Key DNA Sequence
This study shows, for the first time, that a short DNA sequence located next to the repeat expansion prevents intergenerational growth of the FGF14 repeat. Remarkably, one-third of all people do not have this protective element. Their children are at risk for a growing expansion.
“While always suspected for repeat expansion disorders, this is the first time such an element has been identified,” said Stephan Züchner, M.D., Ph.D., co-director of the John P. Hussman Institute for Human Genomics, chief genomics officer for the Miller School and co-senior author on the study. “Astoundingly, this rather common sequence does not appear in any of the popular reference genomes.”
This paper stems from a years-long collaboration with co-senior author Bernard Brais, MDCM., Ph.D., of the Rare Neurological Diseases Group at McGill University in Montreal. The Miami and McGill groups jointly discovered the cause of spinocerebellar ataxia 27B in a paper published in the New England Journal of Medicine. The current finding is a significant extension of this earlier study.
The current study rose from an insight by first author David Pellerin, M.D., M.Sc., a neurogenetics research fellow in the Züchner lab and first author on the paper. Having examined hundreds of patient samples, Dr. Pellerin began seeing unusual patterns in the FGF14 gene sequence. These patterns were not recorded on the reference genome, the template that shows what the human genome should look like.
The data was unusually clearcut, showing that people with the protective string had fewer GAA repeats and did not develop spinocerebellar ataxia. Those who had the disease completely lacked the sequence.
“When David first brought it to us, I was very skeptical,” said Matt Danzi, Ph.D., associate scientist in the Züchner lab and corresponding author on the study. “It seemed unlikely that he picked out this completely novel pattern with all the data noise surrounding it. But he was 100% correct, and around two-thirds of the population are being protected by this sequence, which nobody had ever heard of before.”
Working Toward Greater Understanding, Effective Therapies
Drs. Zuchner, Brais and others are working with the SCA27b Foundation to develop models to better understand the disease and possibly test therapies. Bill Nye (The Science Guy), who has spoken about the spinocerebellar ataxia 27B in his family, has also shown great interest in this work.
Discovery is leading to many new questions. Dr. Zuchner and colleagues now want to understand how the sequence provides its protection. The team believes the sequence stabilizes the GAA repeats and prevents them from causing disease but more work is needed to truly grasp these mechanisms. In addition, this work might offer clues to other tandem repeat expansion diseases, such as Huntington’s disease and Friedreich ataxia.
“This raises the question of whether we’re missing similar phenomena with other repeat expansions,” said Dr. Zuchner. “This is the first time we’ve seen this type of protective sequence. There may be others.”
Tags: Dr. Stephan Zuchner, Gene sequencing, genetics, John P. Hussman Institute for Human Genomics, spinocerebellar ataxia