Spina bifida gene identified in Melbourne study

A breakthrough in the understanding of congenital neural tube defect spina bifida has been made at Royal Melbourne Hospital with the discovery of the responsible gene in the curly-tail mouse model of the disease.

Significantly, the gene has been identified as a highly conserved developmental transcription factor, known as Grhl3 in mice, and found in organisms from Drosophila and Caenorhabditis elegans to humans, says chief investigator Dr Stephen Jane.

The discovery was published this week in Nature Medicine by Jane and the PhD student responsible for the identification of the gene and its role in spina bifida, Dr Stephen Ting.

Studies are also underway to examine the role of the human version of the gene in spina bifida. Jane is collaborating with a US group to look at mutations in a population of 1000 patients with spina bifida.

Ultimately the researchers hope the discovery will lead to pre-natal diagnostic tests and new therapies for the disease, which causes mild to severe lower limb paralysis, bladder and bowel dysfunction, as well as psychosocial difficulties in those affected.

While the incidence of spina bifida has greatly decreased in recent years due to the use of folate supplements by women during pregnancy, it still occurs as a rate of about one in 1000 births. The curly tail mouse has been considered the premier model for this folate resistant, heritable form of the disease, said Jane, but until now the genetic cause of the disease had not been identified.

The identification of the gene will allow researchers to investigate the biological mechanisms leading to neural tube closure at a molecular level. According to Jane, the Grhl3 factor contains both DNA binding and protein dimerisation functional domains. In flies it is responsible for dorsal/ventral and terminal patterning during development and may also play a role in epithelial closure.

"We know some of the genes that are affected by the gene from Drosophila and mouse studies," said Jane. "There is strong evidence that the mechanisms underlying closure of the spinal cord are also in operation in other biological processes, such as healing of wounds. Lessons learnt from the spina bifida gene may therefore impact on conditions as diverse as trauma, skin ulcers and burns.

"We think this is an incredibly exciting avenue of research that we are pushing towards," he said. Preliminary data for the gene's role in skin development was very strong he said, and would be submitted for publication in a major journal shortly.

Another intriguing aspect of the gene is that in curly-tail mice, but not Grhl3 knockout mice, administration of inositol during pregnancy has a mitigating effect on the incidence of spina bifida, suggesting that it may have a similar effect on some mutations in humans. The curly-tail version of Grhl3 is probably not a null mutation, Jane said, and has residual activity that is modified or rescued by inositol in some way.

"It could be a nice, potentially simple way to treat spina bifida," Jane said.