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Researchers Identify Genetic Anomaly That Causes a Common Congenital Birth Defect

A team of researchers from A*STAR have identified a mutated gene which causes severe brain and spinal congenital birth defects in humans, providing a much-needed genetic framework for understanding and potentially treating them.

Researchers from the Agency for Science, Technology and Research’s (A*STAR) Institute of Medical Biology (IMB) and the Institute of Molecular and Cell Biology (IMCB) have identified a mutated gene whose malfunction impairs brain formation in the developing foetus.

Neural tube defects (NTDs) are severe birth defects of the brain and spine and are the most common birth defects observed in humans. They occur when the neural tube does not form properly when the brain is developing in the womb, and take various forms, such as spina bifida or anencephaly, the absence of the brain and skull.

NTDs account for four percent of all congenital birth defects in Singapore, with an average of 42 cases a year. While detection of NTDs at the early stages of pregnancy has improved over the last few years, they are still traumatic experiences for the expecting family.

The majority of NTDs are believed to be sporadic and caused by environmental factors such as a deficiency of folic acid and vitamins. While animal models have been able to identify several genetic pathways associated with anencephaly in mice, the genetic aetiology in humans is still unclear.

The team’s study, published in the Journal of Experimental Medicine, identified a biallelic germline mutation, deleting 21 base pairs in the NUAK2 gene in a family with three consecutive foetuses presenting with anencephaly using whole exome sequencing. This gene, which encodes a serine/threonine kinase, was known to be associated with cancer but had never been associated with genetic disease in humans.

Collaborators at Imperial College London and Turkey’s Koç University demonstrated that this mutation killed the enzymatic activity of NUAK2 in vitro and in patient’s cells using kinase assays.

While most of the studies on NTDs use animal models, Professor Bruno Reversade’s team at IMB and Dr Toh Yi-Chin’s team at the National University of Singapore established in vitro 2D and 3D human models to study anencephaly. After reprogramming foetus skin cells into induced Pluripotent Stem cells (iPSCs), the team differentiated iPSCs into disease-relevant cell lineages to study the mechanisms underlying NTDs. Using neural progenitor cell assays as well as cerebral organoids (or minibrains), the scientists observed downregulation of the Hippo-YAP signalling pathway, as well as significant changes in the actomyosin network, affecting cell shape and contraction. These results suggest that the Hippo signalling axis governs neural tube morphogenesis and establishes NUAK2 as an essential kinase for human brain development.

Dr Carine Bonnard, Scientific Project Manager, IMB, and Head of Operations, Asian Skin Biobank, Skin Research Institute of Singapore (SRIS), the first author and co-corresponding author of this study said, “I hope that our genetic finding and research approach will provide guidance to physicians and help families affected by birth defects. Our study also shows the importance of developing new in vitro models to study human diseases in a dish rather than using animal models.”

The corresponding author Professor Bruno Reversade, Research Director at IMB and IMCB, added, “this study provides a long sought-after genetic framework for understanding one of the most common birth defects in human babies. It may serve as a stepping stone for therapeutic intervention in the future”. [APBN]