By: Josh Baxt | June 28, 2024 | 6 min. read |
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Summary of the article
- Miller School researchers have shown that a specific DNA sequence protects people from developing 27B spinocerebellar ataxia.
- Spinocerebellar ataxia 27B is a rare neurodegenerative condition caused by recurrent, successive enlargements in FGF14 gene.
- One third of all people lack the spinocerebellar ataxia protective DNA sequence 27B.
Researchers at the University of Miami Miller School of Medicine, McGill University and other institutions have shown that a specific DNA sequence in FGF14 The gene prevents the expansion of genetic variants called tandem repeats, protecting people from developing spinocerebellar ataxia 27B (SCA27B).
The findings could help identify families that are at higher risk for the debilitating condition and eventually lead to new therapies to prevent recurrent, consecutive expansions. The study was published in Genetics of Nature.
Gene patterns are gone
Spinocerebellar ataxia 27B is a rare, neurodegenerative condition that causes uncoordinated movements, balance problems, dizziness, double vision and other problems. Caused by repeated consecutive expansions in FGF14 gene, the disease is particularly common in French Canadians.
Single repeat expansions are simple genetic patterns in genes that can expand tens or even hundreds of times, disrupting gene function. These abnormalities have been linked to more than 50 neurodegenerative conditions.
Most people don’t get more than 30 reps in FGF14 gene. In spinocerebellar ataxia 27B, the GAA repeat sequence is expanded more than 300-fold. The research team had previously shown this FGF14 expansions can increase when passed from parents to children and, over several generations, can cause disease.
Identification of a key DNA sequence
This study shows, for the first time, that a short DNA sequence located near the repeat expansion prevents the intergenerational growth of FGF14 repeat. Surprisingly, a third of all people do not have this protective element. Their children are at risk for increased enlargement.
“While repeat expansion disorders are always suspected, this is the first time such an element has been identified,” said Stephan Züchner, MD, Ph.D., co-director of the John P. Hussman Institute for Human Genomics, chief officer of the genome. for the Miller School and co-senior author on the study. “Surprisingly, this fairly common sequence does not appear in any of the popular reference genomes.”
This paper stems from a multi-year collaboration with co-senior author Bernard Brais, MDCM., Ph.D., of the Rare Neurological Disease 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 previous study.
The current study arose from an insight by first author David Pellerin, MD, M.Sc., a neurogenetic researcher in Züchner’s lab and first author on the paper. After examining hundreds of patient samples, Dr. Pellerin began to see unusual patterns in the FGF14 gene sequence. These patterns were not recorded in the reference genome, the template that shows what the human genome should look like.
The data were remarkably clear, showing that people with the protective strand had fewer GAA repeats and did not develop spinocerebellar ataxia. Those who had the disease were completely missing 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 impossible that he would choose this completely new model with all the data noise surrounding him. But he was 100% correct, and about two-thirds of the population is being protected by this sequence, which no one had ever heard of before.”
Working towards greater understanding, effective therapy
Dr. 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) also showed great interest in this work, who spoke about spinocerebellar ataxia 27B in his family.
The discovery is leading to many new questions. Dr. Zuchner and colleagues now want to understand how the sequence ensures its protection. The team believes the sequence stabilizes the GAA repeats and prevents them from causing disease, but more work is needed to truly understand these mechanisms. Additionally, this work may provide clues to other repeat expansion diseases, such as Huntington’s disease and Friedreich’s ataxia.
“This raises the question of whether we are missing similar phenomena with other repeat expansions,” said Dr. Zuchner. “This is the first time we have seen this kind of defensive sequence. There may be others.”
Label: Dr. Stephan Zuchner, Gene sequencing, genetics, John P. Hussman Institute for Human Genomics, spinocerebellar ataxia
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