Study of the Week: Mosaic Mutations Can Cause Spina Bifida and Other Birth Defects

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice

We previously published about this research in a story titled “Mosaic Mutations May Cause Spina Bifida,” which can be found here. The study was originally published in the research journal Nature Communications. You can view the fully study text here.

What Happened?

While there are several known risk factors for spina bifida, a specific cause of this birth defect hasn’t been identified. With that being said, a steady stream of research has come to light in recent years that associates naturally occurring mutations that appear in the early stages of an embryo’s development can trigger severe congenital defects, particularly those affecting the neural tube. The researchers sought to understand how certain mutations called mosaic mutations— which occur during development and are not inherited from a parent— can cause spina bifida.

The research used mouse embryos for study and focused on the Vangl2 gene, which plays a critical role in spinal cord development. The scientists focused specifically on a process called neural fold elevation, which takes places during another process called spinal neurulation. The presence of a Vangl2 deletion mutation (which was triggered by the researchers in the study) in only 16 percent of the developing spinal cord cells (also called neuroepithelial cells) was sufficient to cause spina bifida to appear. This findings demonstrated that even an alteration affecting a small percentage of cells is sufficient to cause developmental problems.

The research demonstrates how mosaic mutations can have a major impact on the function of not only the cells that carry the mutation, but the neighboring cells as well. The fact of the matter is that in general, mosaic mutations, also called post-zygotic mutations, are not at all uncommon during development. Overall, genetic testing is generally not a part of diagnosis in spina bifida specifically because the mutations behind it cannot be detected in the saliva or blood.

About Spina Bifida

Spina bifida is a birth defect in which the back bone does not fully close around the spinal cord. The area most typically affected is the lower back, but it can also appear along the mid back or neck. There are several different types which vary in their severity. The defect has been linked to a combination of environmental and genetic factors. Some risk factors include family history, folic acid deficiency during the pregnancy, diabetes, obesity, using anti-seizure medication, white or Hispanic descent, and alcohol consumption. Females are more susceptible than males. Symptoms range widely in severity but can include poor walking or inability to walk, abnormal eye movement, leg weakness or paralysis, club foot, scoliosis, skin conditions, poor kidney function, and incontinence. Some patients may have neurological abnormalities or learning disabilities. Treatment typically involves surgery. To learn more about spina bifida, click here.

Why Does it Matter?

The findings from this study represent the clearest revelation yet of a specific process occurring during development that can be directly linked to the appearance of neural tube defects such as spinal bifida. While the condition was more or less understood to not be inherited, parents of people born with it can now know for sure that they are not responsible for passing along the disease.

For families impacted by spina bifida, genetic counseling can be valuable in helping them understand the role of genes in spina bifida. Women who are trying to become pregnant may also take a folic acid supplement as this can reduce the chance of spina bifida occurring. However, the researchers point out that they still don’t exactly understand why these mosaic mutations appear and that more study of them is necessary. It is possible that some of the environmental factors previously linked to the condition, such as diabetes, obesity, or the use of anti-seizure medication, could be connected to them. 

The scientists were surprised by how susceptible the cellular signaling process was to mosaic mutations. Since each mutated cell has six cells around it and can prevent them from functioning, the impact of these mutations is greatly magnified. Future research will aim to understand if this vulnerability is relevant in other genes that could be linked to spina bifida, which may require careful tissue analysis using samples from humans instead of mice. 

Check back the Monday of each week for the next installment in this series.

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