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Researchers discover gene mutations linked to spinocerebellar ataxia

A global hunt for the cause of a crippling inherited nerve disorder has found its target. The discovery opens the door for better diagnosis and treatment of this particular disease – but also for better understanding of why nerves in the brain’s movement-controlling center die, and how new DNA-mapping techniques can find the causes of other diseases that run in families.

In a new paper in the Annals of Neurology, a team from Taiwan, France and the University of Michigan Health System report that mutations in the gene KCND3 were found in six families in Asia, Europe and the United States that have been haunted by the same form of a disease called spinocerebellar ataxia or SCA. The disease causes progressive loss of balance, muscle control and ability to walk.

The new paper finds the disease gene in a region of chromosome 1 where a Dutch group had previously shown linkage with a form of SCA called SCA19, and the Taiwanese group on the new paper had shown similar linkage in a family for a form of the disease that was then called SCA22.

The Dutch group has just published results in the same issue of the journal, zeroing in on the same gene as the U-M/Taiwanese/French groups.

The gene governs the production of a protein that allows nerve cells to “talk” to one another through the flow of potassium. Pinpointing its role as a cause of ataxia will now allow more people with ataxia to learn the exact cause of their disease, give a very specific target for new treatments, and perhaps allow the families to stop the disease from affecting future generations.

But the findings also have significance beyond ataxia. The researchers also show that when KCND3 is mutated, it causes not only poor communication between nerve cells in the cerebellum – but also the death of those cells. It’s information that could aid research on other neurological disorders involving balance and movement.

Margit Burmeister, Ph.D., the U-M geneticist who helped lead the work, notes that the gene could not have been found without a great deal of DNA detective work – and the cooperation of the families who volunteered to let researchers map all the DNA of multiple members of their family tree.

“We combined traditional genetic linkage analysis in families with inherited diseases with whole exome sequencing of an individual’s DNA, allowing us to narrow down and ultimately identify the mutation,” she says. “This new type of approach has already resulted in many new gene identifications, and will bring in many more.”

U-M neurologist Vikram Shakkottai, M.D., Ph.D., an ataxia specialist and co-author on the paper, notes that the new genetic information will help patients find out the specific cause of their disease – a reassuring thing in itself.

But he and his colleagues are already working to find drugs that might alter potassium flow, and provide a treatment for a group of diseases that currently are only treated with supportive care such as physical activity and balance training as patients deteriorate.

“Many of the families who come to our clinic for treatment don’t have a recognized genetic mutation, so it’s important to find new genetic mutations to explain their symptoms,” says Shakkottai, an assistant professor in the U-M Department of Neurology. “But at the same time, this research is helping us understand a common mechanism of nerve cell dysfunction in progressive and non-progressive disease.”

Some forms of ataxia, called episodic, do not cause progressive worsening of symptoms – but past research has shown potassium and calcium channel mutations to be at the root of them, too.

Burmeister is a member of the U-M Molecular & Behavioral Neuroscience Institute and a professor in the departments of Human Genetics, Computational Medicine & Bioinformatics and Psychiatry at the U-M Medical School. Jun Li, Ph.D., an assistant professor of human genetics and CMB, led the exome sequencing using the U-M Medical School’s DNA Sequencing Core.

The U-M researchers worked with partners at the National Yang-Ming University School of Medicine in Taipei, Taiwan, and the Taipei Veterans General Hospital, as well as teams at the University of Tokyo and the Hopital Pitie-Salpetriere in Paris. Each center had identified one family that mapped near SCA19, previously also known as SCA22, and gotten their permission to study their DNA in depth.

The family studied at U-M is of Ashkenazi Jewish heritage, and Burmeister notes that other families of this background with unexplained ataxias may turn out to have the KCND3 mutation.

The Dutch team that is publishing its findings about KCND3 at the same time studied families in the Netherlands. They found that mutations on the gene are responsible for SCA 19, which until now had no specific cause known.

“In other words, mutations in this gene are not uncommon and present all over the world,” says Burmeister. “This means that in the future, this gene should be tested for mutations as part of a clinical genetic test panel for patients with ataxia symptoms. Because a generation can be skipped, it may even be relevant in some sporadic cases – those where the patient isn’t aware of any other family members with a similar disease.”

While a test is not quite available yet, it should be soon through testing laboratories that partner with clinics such as U-M’s.

At the same time, families affected by ataxia who don’t yet know the cause might be eligible to volunteer for U-M research.


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