Researchers from the University of Miami Miller School of Medicine, McGill University and other institutions have found that a well-hidden genetic variation in the FGF14 gene, called DNA tandem repeat expansion, causes a common form of late-onset cerebellar ataxia, a disorder that interferes with coordinated movement. Tandem repeat expansions are only found in 50 conditions, including Friedreich’s ataxia and Huntington’s disease, but researchers believe they could explain many other conditions.
The paper, Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia, will be published online December 14 in the New England Journal of Medicine. These findings could lead to new diagnostics and therapeutics for patients with late onset ataxia.
“This form of ataxia strikes people relatively late in life, and there is virtually no cure,” said Stephan Züchner, MD, Ph.D., co-director of the John P. Hussman Institute for Human Genomics, director of genomics for the Miller School of Medicine and co-lead author of the study. “But now we know the disease is caused by a single gene, and that should lead to great therapeutic advances.”
Late ataxia is highly concentrated in specific populations, including French Canadians. Co-lead author Bernard Brais, MDCM, M.Phil., Ph.D., director of the Rare Neurological Diseases Group at McGill University in Montreal, treats many patients with this condition. His expertise in ataxia and related disorders and in research on the patient and family registry in Quebec were essential to the success of the study.
The late expansion of ataxia was found in the FGF14 gene, which is associated with cell growth, tissue repair, and other tasks. Although this gene is well studied, no one had ever seen these repeat expansions, largely due to the way RNA is processed in cells.
RNA can be separated into two categories: exons and introns. Exons code for proteins; the introns contain non-coding RNA between the exons. Because introns are separate from the coding RNA strand, it can be difficult to determine how intron sequences, such as FGF14 repeat expansions, impact protein production.
In the study, the Miami and Montreal teams sequenced complete genomes of French-Canadian, German, Australian and Indian families, applying a new advanced computer algorithm to identify repeat expansions. Matt Danzi, Ph.D., an associate scientist in Dr. Züchner’s lab and co-lead author of the paper, spotted the crucial abnormalities in the patients’ genomes. Co-lead author David Pellerin, MD, a McGill researcher, confirmed and characterized these unusual non-protein coding repeat expansions in patients.
Dr. Züchner and his team have earned a solid reputation for solving the genetic mysteries of rare neurological diseases. In this case, they had early access to advanced software tools and prepared unique databases of healthy controls, allowing them to enhance the ability of short-read genomic sequencing to identify hidden intronic variations. Later, the Miami and Montreal teams used long-read sequencing to confirm their findings. One of the next steps will be to understand how these expansions disrupt FGF14.
“As far as we can tell, these repetitive expansions make it difficult for the gene to be expressed at normal levels,” Dr. Danzi said. “Affected DNA and RNA grow much larger than usual and interfere with normal RNA processing. Cells end up with much less protein than they need.”
These findings have already generated a flurry of activity around FGF14 and late ataxia. Identifying the genetic engine of the disease will give scientists and clinicians an essential tool to diagnose more patients. Current efforts have found more than 500 families with the variant, and follow-up studies may bring that number to over a thousand. Repeated expansions in FGF14 may prove to be the most common form of late ataxia.
Additionally, identifying abnormalities in a gene means researchers can begin to develop new diagnostic tests, animal models, and possibly therapies to combat it. Treatments being developed for Friedreich’s Ataxia can be used to treat patients with FGF14 expansions. Patients may also benefit from a drug called 4-aminopyridine, which is already used to treat other neurological conditions.
University of Miami Miller School of Medicine
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