A team of scientists from the Indian Institute of Science (IISc), Bangalore, and the Bangalore Medical College and Research Institute (BMCRI) have discovered the gene responsible for a rare condition called anencephaly - a serious birth defect in which a baby is born without the brain and skull. It is the most lethal form of neural tube defects (NTD), which develops when the baby grows in the womb.
The neural tube is a layer of cells in an unborn baby (foetus) that ultimately develops into the brain and spinal cord. During the first few weeks of pregnancy, one end of the neural tube develops into the brain and its associated neurons. Any disturbance during this critical period leads to malformation of the head. In such instances, the baby is either stillborn or would survive for just a few hours. In India, about two cases of anencephaly are seen for every 1,000 births.
The current study has implicated a gene, TRIM36, as a cause of anencephaly. TRIM36 (Tripartite Motif Containing 36) is one of about 19,000 protein-coding genes, involved in a wide range of biological processes such as cell division, gene regulation and functions related to the nerve cells.
The blood samples of the parents and liver tissue of a 20-week-old affected foetus were used to extract the whole genome. “A total of 77,259 gene variants were extracted, which were then filtered to identify 863 unique novel identical gene variants because of kinship in the family. These were then compared to many databases across the globe and in the lab to finally identify the homozygous (two copies) pathogenic [disease causing] variant in the TRIM36 gene”, explains Prof Arun Kumar from the Department of Molecular Reproduction, Development and Genetics at IISc. “This is the first time that TRIM36 was discovered as the causative gene for anencephaly. No one else has shown it before”, he adds. A previous study has shown the role of this gene in neural tube development in frogs..
Several previous studies have pointed to environmental factors, genetic mutations and malnourishment as causes for anencephaly. Till date, a common variant in the MTHFR gene was thought to be the risk factor for NTD. The MTHFR gene codes for an enzyme (methylenetetrahydrofolate reductase) necessary for the conversion of folate and folic acid (different forms of vitamin B9) into an active form (L-methyl folate) the body can use. The variant in the gene reduces the enzyme activity. During pregnancy, the developing foetus has a high demand for folate; variant in both copies of the MTHFR gene means there is a higher chance of anencephaly and other types of NTDs.
“MHFTR is a risk factor in some but not in all populations. What it means is that even though someone has a variant in this gene, they will not necessarily have anencephaly. It will just increase the chance of having anencephaly, whereas the pathogenic variant (mutation) in TRIM36 is causative of anencephaly”, explains Prof Kumar.
“This basic research has thrown light into gene mutations which were unknown until now and has helped us understand NTDs better. In a clinical setting, parents who are carriers for TRIM36 mutations can be identified and this information can be used for genetic counselling”, says, Dr K.V. Malini, the clinical collaborator of this study from BMCRI.