Uninherited genetic mutations can cause spina bifida

Genetic mutations that occur naturally during the early stages of an embryo’s development can cause a serious spina bifida birth defect, finds a new experimental study in mice by scientists at UCL.

The research, published in Nature communications, explains for the first time how a ‘mosaic mutation’ – a mutation which is not inherited from either parent (either via the sperm or the egg) but which occurs randomly during cell divisions in the developing embryo – causes spina bifida.

Specifically, the scientists, based at UCL Great Ormond Street Institute of Child Health, found that when a mutation in the Vangl2 gene (which contains the information needed to create spinal cord tissue) was present in 16% of the cells of the in the developing spinal cord of mouse embryos, this was sufficient to produce spina bifida.

The researchers say the findings allow scientists to better understand how and why mosaic mutations can affect and disrupt the functioning of cells, including those of neighboring cells, thereby helping to cause birth defects.

For parents, the findings may help reduce the burden felt by those who believe their child inherited spina bifida from them via genes and believe future children might inherit the disease as well. This is often discussed during genetic counseling.

Spina bifida and current knowledge

Spina bifida is one of a group of birth defects called neural tube defects, affecting the brain or spinal cord. They occur during the first month of pregnancy, often before a woman even knows she is pregnant. People born with this disease suffer nerve damage because part of their spinal cord remains exposed in the uterus.

Advances in recent years now allow surgeons in a few centers around the world, including Great Ormond Street Hospital and University College London Hospital, to perform surgery on fetuses in the womb to reduce neurological consequences. of their condition.

Some neural tube defects can be prevented by taking folic acid supplements before and during early pregnancy, but these conditions continue to affect about one in a thousand pregnancies worldwide.

Researchers say they don’t fully understand why mosaic mutations occur – although environmental factors may be involved – and cannot yet establish a link to whether or not taking folic acid during pregnancy. Despite this, they say folic acid is known to help embryonic cells make DNA and encourage all pregnant women to add folic acid to their diets before conception.

Commenting on the potential causes, lead researcher Dr Gabriel Galea (UCL Great Ormond Street Institute of Child Health) said: “Certain environmental factors are known to increase the risk of these conditions occurring and very few affected people or their parents are given a genetic diagnosis. The discovery that mosaic mutations, which cause spina bifida, cannot be inherited from either parent and are not necessarily present in the blood or saliva commonly used for genetic testing, may explain why. “

Genetic mutations

Genetic mutations occur in every cell throughout development. To go from a fertilized egg to a fetus, each of our cells must replicate and divide to increase in number and develop. Cells have to copy their DNA every time they divide, but errors can occur that change the DNA sequence in daughter cells.

These DNA code errors, called mutations, are then inherited by all cells derived from that cell. If these mutations occur in germ cells – the egg and sperm – they are inherited from parent to offspring. Many mutations do not occur in germ cells, but rather in cells that give rise to specific tissue types. These are known as mosaic mutations.

Experimental study approach

In humans with spina bifida, a number of genetic mutations have been identified, but in many cases it was not known whether they could cause spina bifida.

In this experimental study, the researchers caused a specific mutation, which inactivates a single gene called Vangl2 in mouse embryos. This gene is part of a cell signaling pathway that tells cells which way to face in a tissue. Mutations in this pathway had been identified in people with neural tube defects, and recent reports in the United States and China had previously found mutations in the mosaic Vangl2 pathway in 15% of human fetuses with spina. bifida. For the cell signaling pathway to function normally, cells must interact with their neighbors in order to communicate directional information.

For the study, the researchers induced this Vangl2 mutation in a small proportion of cells that make up the developing spinal cord of mice. This has been done in a number of mouse embryos. The researchers then counted the proportion of spinal cells that harbored this mutation in those that had successfully covered their spinal cord with skin (i.e., had developed normally), compared to those that had a spinal cord. exposed (had spina bifida).

The researchers found that when the mutated Vangl2 gene was present in just 16% of cells in the developing spinal cord, spina bifida occurred.

They say these results show that the cell signaling process is surprisingly vulnerable to inherent mosaic mutations. Each mutant cell prevents each of its neighboring cells from working to promote development of the spinal cord. And each cell has six neighboring cells on average, massively amplifying the effects of each mutant cell.

We have found that the need for cells to talk to each other makes them extremely vulnerable to mutations in the signaling pathway in which Vangl2 works. We now need to understand whether this vulnerability extends to other genes that could cause spina bifida. Detecting these mosaic mutations in living people will require technological advances and careful analysis of the tissue resected during surgery. “

Dr Gabriel Galea, Principal Investigator, Great Ormond Street Institute of Child Health, University College London