In mouse embryos, 16% of cells in the spinal cord only require a specific mutation for spina bifida, which causes lifelong disability. This mutation occurs early in fetal development and is therefore not communicable, reveals British researchers in the journal Nature communication.

Spina bifida, a common defect associated with genetic defects

Every year, around 150 babies are born with spina bifida in France. This malformation occurs as a result of a defect of the neural tube closure, a fetal structure becoming the brain and spinal cord. In most cases, the deformity is not identified until the second ultrasound, around the fifth month of pregnancy. The only consequences are abortion or lifetime disability.

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The causes of spina bifida are not well understood, but taking vitamin B9 (or folic acid) reduces the risk by 70%. Genes useful for closing the neural tube and using vitamin B9 have already been identified as being involved in the occurrence of malformation. Among them, the VANGL2 gene, required for the correct orientation of cells of the neural tube and therefore for subsequent closure, has been specifically identified. Recent reports in the United States and China also found “mosaic” mutations of VANGL2 with spina bifida in 15% of human embryos.

Strangely, these mutations are not identified in most affected families. For researchers, this may be explained by mutations occurring during fetal development, and therefore will not be transmitted by parents. This type of mutation is called “mosaicism”.

It only takes 16% of cells in the future backbone to be mutated.

To verify the importance of VANGL2 in spina bifida, researchers caused its mutation in mouse embryos, and especially in cells that make up the developing spinal cord. Researchers then counted the proportion of vertebrate cells carrying this mutation in mouse embryos, compared to those that had developed normally, whose spinal cord was exposed, characteristic of spina bifida.

Researchers then discovered that for spina bifida, only 16% of the mutated VANGL2 gene was required to exist to grow spinal cord cells (“neuroepithelial”) cells. Cells communicate with each other, and one’s faults can affect their neighbors. Without the VANGL2 gene, cells no longer know in which direction to grow, and disrupt their 5 to 6 neighboring cells, amplifying the initial defect. “We have found that the need for cells to talk to each other makes them particularly vulnerable to mutations in VANGL2. Now we need to understand whether this vulnerability extends to other genes that can cause spina bifida.“, Explains Gabriel Galia, the first author of this work.