Undeveloped genetic mutations can cause spina bifida

Naturally occurring genetic mutations in the earliest stages of embryo development can cause the true birth defect of spina bifida, a new experimental study in mice led by UCL scientists has found.

The research, published in Nature Communication, explaining for the first time how a ‘mosaic mutation’ – a mutation that is not inherited from one parent (either through sperm or an egg cell) but occurs randomly during cell divisions in the embryo developing – causing spina bifida.

In particular, the scientists, based at the UCL Great Ormond Street Institute of Child Health, found that a mutation in the Vangl2 gene (which contains information needed to form spinal cord) was present in 16% of the spinal cell development of mouse cells, this was sufficient to produce spina bifida.

Researchers say the findings add to scientists’ understanding of how and why mosaic mutations can affect cell activity, including those of nearby cells , helping to cause birth defects.

For parents, the findings could help reduce the burden that people believe their child has acquired spina bifida from them through genes, and who believe that children in the future may suffer from their condition. possession. This is often discussed during genetic counseling.

Spina bifida and current experience

Spina bifida is one of a group of birth defects called neural tube defects, affecting the brain or spine. They occur in the first month of pregnancy, often before a woman even knows she is pregnant. People born with this condition suffer zero damage because part of their spinal cord is exposed while they are in the womb.

Advances in recent years are now allowing surgeons in a few centers around the world, including at Great Ormond Street Hospital and London University College Hospital, to perform fetal surgery in the abdomen to reduce the neurological effect of their condition.

Some neural tube defects can be prevented by taking folic acid products before and during pregnancy, but these conditions still affect about one in every thousand pregnancies throughout the year. universe.

Researchers say they do not fully understand why mosaic mutations occur – although environmental factors may be involved – and cannot yet make a connection by taking (or not) folic acid during pregnancy. Despite this, they claim that folic acid is known to help embryonic cells make DNA and encourage all expectant mothers to add folic acid to their diet from before they are born.

Commenting on the possible causes, the Chief Inspector, Dr Gabriel Galea (UCL Institute of Child Health Great Ormond Street), said: “Some environmental factors are known to increase risk that these conditions occur and very few individuals or their parents receive the meaning of genetic diagnosis. The finding that mosaic mutations, caused by spina bifida, may not be found by one parent, and are not present in blood or saliva commonly used for genetic testing, may explain why. “

Genetic mutations

Genetic mutations occur in all cells through development. To grow from a fertilized egg cell to a fetus, each of our cells must reproduce and divide to increase in number and growth. Cells have to copy their DNA every time they divide, but errors can occur that alter the DNA sequence in the daughter cells.

These DNA code errors, called mutations, are then inherited by every cell that comes from that cell. If these mutations occur in germ cells – the egg and sperm cells – they are inherited from parents to children. Many mutations do not occur in germ cells, but in cells that cause certain types of tightness. These are called mosaic mutations.

Experimental study approach

In people with spina bifida several gene mutations have been identified, but in many cases it was not known if they could cause spina bifida.

In this experimental study, researchers induced a specific mutation, which activates a single gene called Vangl2 in mouse embryos. This gene is part of a cell signaling pathway that tells cells how they look inside a tissue. Variations in this pathway have been identified in people with neural tube defects, and recent reports from the US and China found Vangl2¬-pathway mutation mutations in 15% of human fetus with spina bifida. For the cell signaling pathway to function normally, cells must interact with their neighbors to communicate management information.

For the study, researchers observed this mutation of Vangl2 in a small proportion of cells that form the spinal cord of mice. This was done in several mouse embryos. Researchers then counted the proportion of spinal cells that damaged this movement in those that had successfully covered the spine with skin (i.e. developed normally). ), compared with those with an open spine (called spina bifida).

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

They say, these results show that the cellular signaling process is remarkably vulnerable to the unstable mosaic mutations. Each mutant cell stops all nearby cells from working to promote spinal development. And there are on average six adjacent cells in each cell, greatly increasing the effect of each mutant cell.

We found that the requirement for cells to talk to each other makes them highly vulnerable to mutations in the signaling pathway in which Vangl2 works. We now need to understand whether this vulnerability extends to other genes that can cause spina bifida. Detection of these mosaic mutations in living beings requires technological advances and careful examination of affected joints during surgery. “

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