Genetic disorders such as hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) can be tough to grasp. This is largely because research on rare diseases is lacking. At the Foundation to Fight H-ABC, one of our goals is to educate affected families and interested advocates. That’s why we wanted to take this opportunity to provide an overview of the TUBB4A gene, looking at…
What this gene actually is
When it was discovered
What causes a mutation in the gene
How the gene relates to H-ABC
What research is being done
By learning about this gene, you can gain a deeper understanding of the role it plays in related disorders such as H-ABC.
Let’s get started…
What Is TUBB4A?
TUBB4A, which stands for tubulin beta-4a, is one of the many genes that code for proteins. This gene provides instructions for making beta-tubulin (β-tubulin)—a protein found primarily in the brain, specifically the basal ganglia and the cerebellum. β-tubulin belongs to a family of proteins that form and organize structures known as microtubules.
A Brief Introduction to Microtubules
As mentioned above, β-tubulin is one of two proteins that make up microtubules. The other protein is alpha-tubulin (α-tubulin), which is produced from the TUBA1A gene.
Here’s a simplified explanation of how microtubules are created:
The β-tubulin and α-tubulin proteins join to form a dimer.
These dimers then form polymers—long, repeating chains of molecules.
The polymers are then put into a sheet and rolled up to create a tube.
Essentially, microtubules are rigid, hollow cylinders composed of tubulin. These microtubules are a key component of the cytoskeleton, which is a network of filaments that exists in the cytoplasm of eukaryotic cells.
What do microtubules do?
The main purpose of microtubules is to support and give shape to the cell. However, they serve a few other important functions. For example, as the brain develops, microtubules help transport nerve cells to the right location. This process is known as neuronal migration.
When Was the Gene Discovered?
To give you a brief history, the gene was identified by researchers back in 1984 and originally designated as 5-beta. Since then, a lot of information about this gene has come to light…
In 2010, a group identified eight major β-tubulins, including TUBB4A, which they referred to as TUBB4. Then, in 2013, another group examined the presence of this gene in the brain, discovering the highest expression to be in the cerebellum; this part of the brain plays an important role in muscle control and movement. That same year, researchers performed gene mapping and traced the gene to chromosome 19p13.3.
What Causes a TUBB4A Gene Mutation?
In most cases, a change in the TUBB4A gene is a random mutation. Typically, neither parent is a carrier, which means the chances of having multiple children with the mutation is low. However, if a parent does carry the mutation in some cells (usually due to mosaicism, when a person has two or more genetically different sets of cells), they could pass it along to their children.
How Does This Gene Relate to H-ABC?
The connection between this gene and H-ABC is simple: A mutation in this gene is what causes the disorder.
H-ABC is a type of TUBB4A-related leukodystrophy, a disease that affects the white matter of the brain. The 52 conditions labeled as leukodystrophies disrupt the growth or maintenance of the myelin sheath. This protective layer insulates nerve cells and allows messages to be transmitted between cells. In the case of H-ABC, hypomyelination occurs. This means the body doesn’t produce myelin at normal levels, so the process of forming that protective layer can’t be completed. Additionally, the condition reduces the size and function of the basal ganglia and cerebellum. However, it’s worth noting that not all individuals with the gene defect have every aspect of H-ABC; some have hypomyelination but not atrophy of the parts of the brain mentioned above.
When there’s a mutation in this gene, it alters single protein building blocks—also known as amino acids—in the β-tubulin. In most cases, H-ABC presents when the mutation results in the replacement of one amino acid with another. An example would be the replacement of aspartate with asparagine. It’s believed that these kinds of mutations change the structure of β-tubulin, which then affects the formation or structural integrity of the microtubules it helps form.
How does it all tie together?
At this time, it’s still unclear how such genetic changes cause the symptoms of TUBB4A-related leukodystrophy, with some examples including…
Seizures
Deafness
Involuntary movements
Poor coordination
Speech problems
Difficulty eating
Loss of balance
Attention problems
However, researchers suspect that problems with microtubules affect neuronal migration or the transport of key substances within neurons. This may lead to the dysfunction and loss of these cells in the brain—the white matter in particular.
What Research Is Being Done on TUBB4A and Leukodystrophies Such as H-ABC?
As stated before, researchers have uncovered quite a bit about the TUBB4A gene. Because of their efforts, we know what the gene does, where it’s located, and how it can affect the body when a mutation is present.
Now we need to figure out how to treat and prevent the diseases that result from its mutation. This is what researchers are working on now. The good news is doctors and scientists have already made significant headway by…
Completing cellular-level research of H-ABC
Researching the biological makeup of this disorder
Developing a natural history study
Although genetic disorders such as H-ABC aren’t easy to fight, gene therapy has proven itself to be a promising method of curing cellular-level diseases. This can be done in one of three ways:
Reduce the expected toxicity to cells from the mutated tubulin by using an approach that captures RNA before it becomes proteins (antisense oligos or ASOs). The advantage of this type of approach is a relatively well-established treatment for certain neurodegenerative conditions.
Out-compete the mutant tubulin through overexpression of wild type (i.e., correct) TUBB4A in the cell via adeno-associated virus (AAV). This is a specific virus engineered to deliver the correct mutation to targeted cells.
Correct the mistake in the tubulin gene through a highly novel gene-editing approach that can correct spelling mistakes in genes (using CRISPR to correct the mutation at the DNA level). This approach is still very new.
Once the doctors and scientists involved in this research determine the best approach for gene therapy, we can proceed to the next step—getting FDA approval to conduct a clinical trial.
However, it’s important to note that clinical research can’t move forward without proper funding. That’s why we need to generate greater awareness of H-ABC and other leukodystrophies caused by a TUBB4A mutation.
Takeaway
Genetic disorders such as H-ABC can be hard to understand at first. That’s why it helps to get some background information. Once you trace the condition back to its source, you begin to see how the tiniest defect can have a major impact. In this case, you can see how a defective TUBB4A gene can lead to a debilitating disease like H-ABC.
Take this opportunity to learn more about the gene responsible for H-ABC. And be sure to share this information with others. By giving related leukodystrophies such as H-ABC the attention they deserve, we can help experts perform additional research so they can find a cure.