Connecting the dots between genetics and disease in SCA13

Written by Dr. David D. Bushart  Edited by Dr. Carolyn J. Adamski

How one research group worked to identify previously unknown causes of SCA13, and what we can learn from their strategy.

With so many different causes of cerebellar ataxia, how are doctors able to make an accurate diagnosis? This is an extremely important question for doctors, research communities, and patients. For doctors, knowing the underlying genetic cause for a case of ataxia is critical not only for formulating a more specific treatment plan, but also for performing informed genetic screens to determine if a patient’s family members are at risk for developing ataxia. For researchers, knowing what causes a certain type of ataxia allows for the development of new treatment strategies. And for patients, an accurate diagnosis can, importantly, provide peace-of-mind.

Unfortunately, getting to this point of diagnosis can still be a difficult task in a lot of cases – up to 20 percent of ataxia cases do not have a confirmed genetic cause (Hadjivassiliou et al., Journal of Neurology, Neurosurgery, and Psychiatry 2016). This is clearly an area for improvement in the field of ataxia research. Fortunately, many research groups are making efforts to improve our knowledge of the many different causes for cerebellar ataxia, how frequently they appear, and how we might be able to better treat them.

two puzzle pieces being connected together by hands
Two puzzle pieces being connected together, much like how researchers connect pieces of data together to understand disease. Photo by Pixabay on Pexels.com

Though there are many studies that are continuously being performed and are constantly improving our knowledge of the specific causes of cerebellar ataxia, this summary will focus on the work of one group (Figueroa et al., PLoS One 2011). The research team, led by Dr. Stefan Pulst at the University of Utah, sought to better identify the frequency of different genetic mutations causing SCA13, a rare, dominantly-inherited form of spinocerebellar ataxia caused by mutations in a gene called KCNC3.

What is KCNC3, and why is it important?

The KCNC3 gene is responsible for making a protein called Kv3.3, which is a type of ion-channel protein. Ion-channels allow ions – in this case, potassium – into and out of nerve cells, which produces an electrical current and makes these nerve cells function properly. Because this electrical current is how nerve cells communicate with one another, these channels are very important for the function of the brain. In particular, Kv3.3 is known to be very important in a group of nerve cells called Purkinje cells, which are located in the cerebellum and help control movement.

Normally, Purkinje cell function is very consistent, due to the proper function of Kv3.3 and many other ion-channel proteins; however, in SCA13, Kv3.3 is not able to perform its job correctly. Some researchers believe that without proper Kv3.3 function, Purkinje cell function can become abnormal, which might explain why movement is impaired in SCA13 patients (though there is still some debate on this topic). Kv3.3 is important in other regions of the brain as well, which might cause additional symptoms that are sometimes seen in SCA13, including seizures and intellectual impairment. Still, there is much to learn about Kv3.3’s role in SCA13: it is currently unclear exactly how often this type of genetic mutation is responsible for causing cerebellar ataxia, for instance.

How often could mutations in KCNC3 be the cause of undiagnosed ataxia?

In this study, Figueroa and colleagues worked with patients who were diagnosed with cerebellar ataxia of unknown genetic cause, along with healthy, unaffected individuals, to determine how frequently mutations in KCNC3 might be an underlying cause of ataxia. In order to do this, these researchers sequenced DNA from 327 patients diagnosed with unknown cerebellar ataxia and 142 unaffected individuals, then examined each subject’s genetic code at the KCNC3 gene. This is possible since we know the specific DNA sequence of KCNC3, which was informed by previous efforts to sequence the human genome. Now, researchers can compare DNA sequencing results to the known DNA blueprint for every gene, including KCNC3. In genetic disorders, very small changes to DNA can cause large effects in cells that manifest as disease. These small variants in DNA are the focus of Figueroa and her colleagues’ work in this study.

Of the different changes to the KCNC3 gene found in this study, one of these changes, called p.Gly263Asp, was further investigated to determine whether it can cause a large cellular effect. Researchers found that this particular genetic change causes subtle alterations in the function of Kv3.3; however, they also determined that this change was unlikely to have enough of an effect to completely explain symptoms of ataxia. On the other hand, they determined that another identified change, p.Arg423His, is likely to be important in symptom development. This is because it had been previously identified in a separate family with a history of ataxia. Since multiple cases of SCA13 caused by this same p.Arg423His change have been identified throughout the world, this particular DNA region seems to be important for doctors to consider when diagnosing SCA13 in the future. Overall, the results of this study indicate that some genetic changes in KCNC3 are likely to be underlying causes for SCA13, while other genetic variations may not change the function of the Kv3.3 channel protein. In individuals with genetic variants of KCNC3 that do not cause changes in Kv3.3 function, it is more likely that changes in a separate, unknown gene are the cause of their ataxia.

Conclusion

Overall, Figueroa and colleagues determined that genetic changes in KCNC3 appear very rarely in patients with cerebellar ataxia. In addition, they found that it is even less common that these DNA variations are the direct cause of ataxia. Since this study was performed in 2011, several other genetic changes in KCNC3 have been discovered to cause SCA13 (Subramony et al., Cerebellum 2013; Khare et al., PLoS One 2017; Khare et al., Cerebellum 2018), which indicates that KCNC3 should continue to be screened when performing genetic diagnoses of patients with cerebellar ataxia. It is helpful to know the exact genetic variants in KCNC3 that cause disease so that they can be more easily identified in future genetic screens of ataxia patients. Although the study did not definitively identify a large number of disease-causing genetic changes in KCNC3, it laid a strong foundation for the continued study of KCNC3 in cerebellar ataxia. To this day, research is being performed to better identify and characterize the ways that this gene can be affected in ataxia. Studies like this are of the highest importance to the ataxia community, as they help in our continued effort to improve diagnosis and treatment strategies for the diverse causes of cerebellar ataxia.

Key Terms

Dominantly-inherited: Inheriting an abnormal gene from one parent will cause the disease.

Gene: A unit of heredity made up of DNA that fully or partially controls the development of specific traits.

DNA sequencing: A method to look at the specific sequence of an individual’s DNA. By comparing this DNA sequence to a known reference sequence, researchers can identify small changes in specific regions of DNA.

Purkinje cell: A type of neuron in the cerebellum. They are some of the largest cells in the brain. They help regulate fine movement.  Purkinje cell loss/pathology is a common feature in cerebellar ataxia.

Ion-channel: A specialized protein that allows ions (charged molecules) to pass into and out of nerve cells.

Conflict of Interest Statement

Dr. David D. Bushart is a postdoctoral researcher at the University of Michigan, and has no conflicts of interest with the studies referenced in this article.

Dr. Carolyn J. Adamski, a postdoctoral researcher at Baylor College of Medicine, edited this article and has no conflicts of interest with the studies referenced in this article.

Citation of Article Reviewed

Figueroa K.P., et al., Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PLoS One, 2011 Mar; 6(3): doi: 10.1371/journal.pone.0017811

References

Hadjivassiliou M., et al., Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. Journal of Neurology, Neurosurgery, and Psychiatry, 2016 Dec; 88: p 301-309.

Subramony S.H., et al., Comprehensive phenotype of the p.Arg420his allelic form of spinocerebellar ataxia type 13. Cerebellum, 2013 Dec; 12(6): pp 932-926

Khare S., et al., A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLoS One, 2017 May; 12(5): doi: 10.1371/journal.pone.0173565

Kahre S., et al., C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity. Cerebellum, 2018 Oct; 17(5): pp 692-697.