Mutation Responsible For Spina Bifida Discovered

Severe birth defect like spina bifida that occurs in the earliest stages of an embryo's development is contributed by non-inherited genetic mutations as per an experimental study led by scientists at UCL Great Ormond Street Institute of Child Health, published in the journal Nature Communications.

The mutations that occur in germ cells (parent cell) – the egg and sperm cells, are generally inherited from parent to offspring. But the mutations that do not happen in germ cells, and rather in cells that give rise to specific tissue types are known as mosaic mutations. These are non-inherited genetic mutations and occur randomly during cell divisions in the developing embryo.

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A structural birth defect means that a specific body part is missing or mal-formed during the embryonic development.

‘Severe birth defect like spina bifida that occurs in the earliest stages of an embryo's development is contributed by non-inherited genetic mutations called mosaic mutations. This helps in understanding the ways these mosaic mutations can affect and disrupt cell function (including those of neighboring cells) that causes birth defects.’

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Spina bifida or neural tube defect is a type of birth defect that affects the brain or spinal cord in the first month of pregnancy. It is manifested by nerve damage as a part of the spinal cord remains exposed while in the embryonic stage (in the womb).

Genetic Mutation in Spina Bifida

The team found that 16% of developing spinal cord cells of mouse embryos consisted of a mutation in the gene – Vangl2 (which contains information needed to create spinal cord tissue), which was sufficient to produce spina bifida.

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Neural tube defects are abnormalities that affect the brain, spine and spinal column of the developing embryo and appear during the first month of pregnancy.

The study thereby shifts the burden of those parents who believe their child inherited spina bifida from them via genes, and believe future children could also inherit the condition.

The exact mechanism through which these mosaic mutations occur (though environmental factors may be involved) cannot be drawn completely. Also, the link between prevention of birth defects by taking or not taking folic acid during pregnancy poses a puzzle.

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Low folate levels during pregnancy increase risk of the condition. It is a birth disorder and a severe form of spina bifida where the backbone and spinal canal do not close before birth.

"Some environmental factors are known to increase the risk of these conditions occurring and very few affected individuals or their parents receive a meaningful genetic diagnosis. The discovery that mosaic mutations, which cause spina bifida, may not be inherited from either parent and are not necessarily present in blood or saliva commonly used for genetic testing, may explain why", says Dr. Gabriel Galea, Principle Investigator, UCL Great Ormond Street Institute of Child Health.

Cellular Pathways in Mosaic Mutations

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Earlier it was found that mosaic Vangl2 pathway mutations appeared in 15% of human fetuses with spina bifida, as per the reports from the USA and China. The induced mice model of Vangl2 mutation in a small proportion of cells (which form the developing spinal cord) was utilized by the study team to count the proportion of mutated spinal cells in the normal versus spina bifida group.

The team affirms that the cellular signaling process is surprisingly vulnerable to the uninheritable mosaic mutations. Each neighboring cell is stopped by a mutant cell from functioning to promote spinal cord development thus massively amplifying the effects.

This helps in understanding the ways these mosaic mutations can affect and disrupt cell function (including those of neighboring cells) that causes birth defects.

"We found that the requirement for cells to talk to each other makes them exquisitely vulnerable to mutations in the signaling 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", says, Dr. Gabriel Galea.

Source-Medindia