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Newly identified mutations in SCA19/22 and their dysfunctions

Written by Sophia Leung Edited by Dr. Marija Cvetanovic

While the mutant proteins in SCA19/22 lose part of their innate functions and properties, they also disrupt the key functions of the normal healthy protein.

The underlying mechanism of the hereditary property of SCA19/22 is elusive. In this study, the researchers investigated the molecular properties of four different mutations found in patients with SCA19/22. They looked at how these mutant proteins affect the normal protein if they are both present in the cell. They found that the mutant proteins are not only non-functional (do not work properly), but that in their presence, the normal protein’s function is also diminished. Furthermore, while the production and proper localization of these mutant proteins are found to be defective, they also bring the same decline to the normal protein. This adds to their disease-causing properties. This study is significant in that it offers a molecular investigation into mutant proteins associated with SCA19/22 that was previously lacking. It also provides evidence that may explain the hereditary property of the disease.

A number of mutations in the gene KCND3 has been associated with SCA19/22. The gene makes the voltage‐gated potassium ion (K+) channel subunit KV4.3. In general terms, the gene makes a protein that functions to allow potassium ions to pass through the membrane of nerve cells. Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through their membrane to orchestrate normal functioning. One could imagine the disruption to any channels, a partial obstruction or a total blockage, could perturb the overall output of the cell.

Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through to orchestrate normal functioning. (Photo by Rajesh Kavasseri / Unsplash)

In this study, the researchers found that the normal KV4.3 channel protein detectably allows potassium ions to pass through. But little to no ions can pass through the SCA19/22 mutant KV4.3 channels. Even under the assistance of a “helper” protein, which normally enhances the function of this channel, only one of the mutant channel proteins shows improvement. This indicates that the SCA19/22 causing mutations result in a reduced function of mutated KV4.3 channels.

In human cells, there are two copies of every gene. This means that patients with SCA19/22 can have either one normal copy and one mutated copy, or two copies of the mutated gene. In the case when the patient has both the normal and mutated copy, how does the mutated channel affect the function of the normal channel in a cell? Could the normal channel make up for the mutated one? Or would the mutant channel bring down the function of the normal one? This is an important question because it tells us how the disease is inherited: if one mutated copy is enough to cause the disease, the chance for the child of patients with SCA19/22 inheriting the disease is a lot higher. This is called dominant inheritance.

They found that when both normal and mutant channels were present in cells, the function of normal protein was reduced as well. Taken together, the mutant channel’s presence partially cancels out the functioning of the normal protein, supporting the dominant inheritance hypothesis.

Another question the authors explored is whether SCA19/22 mutations affect the production of the mutated KV4.3 channels. If the cells cannot produce as many mutant channels as it could the normal channel, then there would be fewer KV4.3 channels present in the cells. This could explain the decline in function. Using biochemical assays, the researchers found that the cell cannot produce as many mutant channels (lower by 21-46%). Even when cells produced mutant channels, they were degraded faster than the normal channel. This means at any given time, the overall level of the mutant channel in the cell is reduced.

Ion channels function on the surface of the cell to transport ions through the cell membrane. For this reason, the localization of channel proteins on the cell surface is essential. The researchers measured the amount of channel protein on the cell surface. They found that both the mutant and normal channels surface protein levels are also reduced. Taken together, there is less of mutant channel produced and also the produced channels are not successfully transported to their destination, making the level of working channels drastically lowered. This line of evidence further supports the dominant inheritance hypothesis.

This study has not only revealed previously unexplored potential mechanisms of SCA19/22 and its inheritance, it has also provided evidence on the fundamental properties of the potassium channel KV4.3. The family of channel KV4.3 belongs to, the KV4, is widely expressed in the brain in different cell types. Therefore, the current study may have implications for a wide range of disorders.

Key Terms

Potassium channel: A small molecule made up of protein that usually locates on cell membrane that allows potassium ions to pass through.

Hereditary: A word used to describe in biology, for example, a disease or a feature, that can be passed on from a parent to their child.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Hsiao, C. T., et al., Novel SCA19/22‐associated KCND3 mutations disrupt human KV4. 3 protein biosynthesis and channel gating. Human mutation, 2019. 40(11), p.2088-2107. (

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