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Uninherited mutations in spina bifida

Researchers have found that uninherited mutations that occur randomly during the earliest stages of embryonic development can cause spina bifida.

Spina bifida

Spina bifida is a neural tube defect that continues to affect an average of 1:1000 pregnancies globally. They arise due to failure of the neural tube to close within the early embryo. Mouse models have successfully been able to recapitulate these conditions and have led to the identification of diagnostic and preventative strategies. These models have also identified genes and pathways required for neural tube closure. This includes members of the Wnt/planar cell polarity (PCP) pathway and enzymes of folate metabolism.

Homozygous mutation of core PCP components produces the most severe form of neural defect – craniorachischisis – in which much of the brain and all of the spinal cord remain open. While mutations in core PCP components have been identified in human foetuses, most affected families do not receive an interpretable genetic diagnosis. One explanation is that disease-causing mutations may arise during post-zygotic embryonic development, rather than in the germ line. This results in mosaicism which is not readily detectable with conventional genetic diagnostic methods.

A mosaic mutation

In this study, published in Nature Communications, researchers induced a specific mutation that inactivates the Vangl2 gene in mouse embryos. This gene is one of the core PCP components. The researchers induced this mutation in a small proportion of cells. They then counted the proportion of spinal cells which harboured this mutation in the embryos that developed normally versus those with spina bifida.

The team found that when the mutated Vangl2 gene was present in just 16% of developing spinal cord cells, spina bifida occurred. Their results indicate that the cellular signalling process is surprisingly vulnerable to uninheritable mosaic mutations. Each mutant cell prevents the other neighbouring cells from functioning to promote spinal cord development. 

Dr Gabriel Galea, Principle Investigator, stated:

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

This study provides a framework to understand the consequences of mosaic mutations on congenital structural malformations. Moreover, their findings may begin to explain why patients with non-syndromic neural tube defects rarely receive a relevant genetic diagnosis.

Image credit: By wildpixel –

More on these topics

Embryo / Genetic Variants / Mosaicism / Spina Bifida