Study Links Rare Genetic Variant to Late-Onset Ataxia

A multi-institute study has determined that a hidden genetic variation in the FGF14 gene causes a common form of late-onset cerebellar ataxia. The findings could lead to new diagnostics and therapeutics for patients suffering from brain disorder, which interferes with coordinated movement.

“This form of ataxia strikes people relatively late in life, and there are virtually no treatments,” says Stephan Züchner, M.D., Ph.D., co-director of the John P. Hussman Institute for Human Genomics, Chief Genomics Officer for the Miller School of Medicine at University of Miami, and co-senior author on the study. “But now, we know the disease is caused by a single gene, and that should lead to great therapeutic progress.” 

The FGF14 mutation is caused DNA tandem repeat expansion, which has been implicated in only about 50 diseases—including Friedreich’s ataxia and Huntington’s disease—but is suspected to account for many other conditions.

The FGF14 gene is associated with cell growth, tissue repair, and other tasks. While this gene is well-studied, nobody had ever seen these repeat expansions, largely because of how RNA is processed in cells. RNA can be separated into two categories: exons and introns. Exons code for proteins; introns contain non-coding RNA between the exons. Because introns are spliced out of the coding RNA strand, it can be difficult to determine how intronic sequences, such as FGF14’s repeat expansions, impact protein production.

In the study, teams in Miami and in Montreal sequenced complete genomes from French Canadian, German, Australian and Indian families and applied a new computer algorithm to identify repeat expansions. Early access to advanced software tools as well as unique databases of healthy controls allowed the team to boost the ability of short-read genomic sequencing to identify hidden intronic variations. Long-read sequencing was later used to confirm the findings.

One of the next steps will be to understand how these expansions disrupt FGF14. “As best we can tell, these repetitive expansions just make it difficult for the gene to be expressed at normal levels,” says Matt Danzi, Ph.D., associate scientist in Dr. Züchner’s lab. “The affected DNA and RNA gets much larger than usual and interferes with normal RNA processing. Cells end up with a lot less of the protein than they need.”

These findings have already generated a flurry of activity around FGF14 and late-onset ataxia. Identifying the condition’s genetic driver will give scientists and clinicians a critical tool to diagnose more patients. More than 500 families with the variant have been identified to date, and follow-up studies may take that number over a thousand. Repeat expansions in FGF14 may prove to be the most common form of late-onset ataxia.

Identifying anomalies in one gene also means researchers can begin to develop new diagnostic tests, animal models, and eventually therapies to combat it. Treatments being developed for Friedreich ataxia may be used to treat patients with FGF14 expansions. Patients may also benefit from a drug called 4-aminopyridine, which is already being used to treat other neurological conditions.

The findings were published recently in the New England Journal of Medicine.