#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research. From February 5 – April 16, 2022, a team of talented students from Columbia University’s M.A. in Biotechnology program is taking over the Rare Roundup section of the #ScienceSaturday blog! What topics do you want to learn more about? Send suggestions to our team at impact@kif1a.org.
KIF1A-Related Research
Zika Virus Infection of Sertoli Cells Alters Protein Expression Involved in Activated Immune and Antiviral Response Pathways, Carbohydrate Metabolism and Cardiovascular Disease
Today we are sharing a recent paper that details the role of KIF1A not in neurological disease but in… Zika virus infection? While this may seem out of the blue, this is not the first time we’ve reported on literature describing KIF1A’s role in viral infection. In fact, KIF1A and other kinesin motor proteins are known to be important cellular machinery that viruses must manipulate to successfully infect an organism’s cells. In this paper the authors aimed to identify ways in which Zika viral infection leads to proteomic changes in a cell type called “Sertoli cells” (a cell type found in the testes). What exactly is a proteomic change? We can think of this as a change that causes a cell to alter the way in which proteins are produced in response to cellular environmental changes. This could mean less of a certain type of protein is produced, while the production of another protein is increased. In this study, we learn that Zika viral infection leads to the downregulation of KIF1A and other kinesin proteins like KIF11, meaning less of these proteins are produced. This information helps us understand the relationship between viral infection and kinesin proteins such as KIF1A. Want to learn more about kinesin motor proteins in our bodies? Check out the video below!
Rare Roundup
Welcome to the #ScienceSaturday Takeover portion of today’s post! Meet our guest bloggers from Columbia University, Aaron, Pragya, Keyue, Rakshitha, and Hazel, here.
Understanding Uncertainty: Variants of Uncertain Significance
In this edition of #ScienceSaturday we’re exploring a topic that arises frequently in the KIF1A and rare disease community: Variants of Uncertain Significance (VUS). Genetic testing can often end the long and frustrating “diagnostic odyssey” that patients and families endure while searching for answers to explain their medical conditions. But genetic testing doesn’t always reveal concrete answers. Let’s help you understand what we do know about VUSs.
First, what’s the difference between a variant and a mutation?
Well, context, mostly. Our genomes are made up of billions and billions of base pairs of DNA. While the vast majority of these are the same across all humans, a miniscule amount differ (0.01%). What you may not know is that such a difference occurs once in every thousand letters of the genome on average. However, because of the negative connotation of the word “mutation,” the human genetics community has started to use a new term: “variant.” The term variant underlines the fact that not all variants are harmful.
How do we tell the difference between harmful and harmless variants?
Sometimes it can be difficult to tell whether a variation is harmful or harmless. The mass screening of genes is called Next Generation Sequencing (NGS). NGS genetic testing involves looking closely at our DNA code, which consists of 4 letters (ATGC) in different sequences. Our genetic blueprint contains a large length of DNA, a small proportion of which are genes (our genes control how we function day-to-day). When the DNA letters are mixed up, the gene may function differently.
Most variants are harmless and in fact make you a unique presence from others. Surprisingly, a few gene variants may benefit some individuals, depending on when and where they occur. For example, a variant could potentially increase our natural defense against a bacterial strain. On the other end of the spectrum, some gene variants could be definitively associated with a genetic disorder like KIF1A Associated Neurological Disorder (KAND), and they are rigorously studied through the scientific data available. Based on their capabilities of causing disorders, these variants are classified into five major categories:
- Pathogenic
- Likely pathogenic
- Variants of uncertain significance
- Likely benign
- Benign
Sometimes NGS doesn’t provide a clear answer. Instead, testing reveals you have a VUS, or variant of uncertain significance. That means you have a variant with unknown effect on your health, and you may wonder how that can be. Well, you can think of variants like mushrooms. Most mushrooms are innocuous, but some are more or less poisonous. Your VUS is like a newly discovered mushroom. You can’t tell if it is poisonous or not just by looking, since it’s never been found before. It must be carefully studied to figure this out. The same is true for VUSs.
Researchers can analyze the function of VUSs in the lab to see if such an error in the gene will affect how the gene works. For example, KIF1A encodes a motor protein that transports cargos in neurons, and our Research Network designs experiments to measure the motility of KIF1A variants. Some variants do not show an affect on the function of the KIF1A gene—it operates just fine. For other variants, it is very clear that the variant negatively impacts the function of the gene. In addition, numerous computational tools are popping up to predict potential effects of an unknown variant. However, none of these methods can give us a 100% certain answer, and they take time.
What if you or a loved one is diagnosed with a VUS in KIF1A?
It’s important to work closely with a genetic counselor to help you understand what the VUS might mean for you or your family. Not all KIF1A variants lead to KIF1A Associated Neurological Disorder. If a child is diagnosed with a VUS, it is helpful to have mom and dad tested as well to see if either of them have the same variant. If a parent shares a variant with their child, but the parent does not have symptoms that the child is experiencing, it is less likely that the VUS is pathogenic (or it would have likely affected the parent). Every family with a KIF1A variant listed on their genetic report should contact the research and clinical team led by Dr. Wendy Chung at Columbia University. They have reviewed well over 150 genetic reports with KIF1A, and can help you and your family understand how a KIF1A variant may or may not be your answer.
Who do I contact with questions?
Email kif1a_study@cumc.columbia.edu to connect with the team at Columbia University, and email impact@kif1a.org to speak with our staff and family volunteers. Regardless of whether or not you have a definite pathogenic KIF1A mutation, or you have a VUS, the KIF1A community is here to support you and help you find the answers you need and deserve.
Additional Resources
A final note on variants and mutations:
It is important to note that while in the context of humans the term has generally progressed from “mutation” to “variant,” this isn’t necessarily the case in genetics outside of humans. So, for example, if you see someone describing a change in the DNA in a mouse as a mutation, the concept is still the same as a variant.
It’s also important to state that the definition of a variant is different in virology than it is in human genetics. We have all been hearing lots about the omicron variant, for example. In virology the term variant refers to a virus which has changes in the DNA, while in humans a variant is the change in the DNA. A virus variant is defined by one or many mutations; confusing, we know!