Researchers have unravelled how mutations in a single gene can cause abnormal brain development in fetuses and babies.
Although scientists had previously discovered the link between mutations in the gene that codes for a protein called Trabid and microcephaly, it was unknown how these mutations caused the developmental disorder. An Australian research team in Parkville, Victoria, discovered the mechanism underpinning how these mutations affect neuronal development.
Dr Grant Dewson, co-lead author of the study published in eLife and laboratory head at the Walter and Eliza Hall Institute (WEHI) of Medical Research said, 'While previous research has indicated [that] there could be a link between defects in Trabid and microcephaly, our study is the first to provide evidence for the gene's function in neuronal guidance – filling a vital knowledge gap.'
The gene that codes for the Trabid protein is called Zranb1. The research team inserted the same Zranb1 mutations that are found in microcephaly patients into mouse models and monitored their brain development.
They found fewer neurons and supportive cells, called glia, in certain brain regions of the mice harbouring the Zranb1 mutations compared with their healthy littermates. In particular, the brain region that controls motor function exhibited fewer neurons, which may help explain the movement symptoms that many microcephaly patients experience.
'Healthy neurons extend long processes called axons in a directional, ordered manner. In our study, we found the neurons from models with defective Trabid project axons that migrate with a wayward trajectory,' Dr Dewson explained. 'Cells in the developing brain must migrate to the right location. If the address is missed, developmental defects can occur.'
The research team discovered that the microcephaly-associated Zranb1 mutations prevent interactions between Trabid and other proteins in the brain. These interactions are imperative for neuronal migration and normal brain development.
In Australia, around one in 2000 babies are born with microcephaly and there is currently no cure or disease-modifying therapies available. In the future, the team hopes that detecting defects in the Trabid protein early could help identify babies at risk of developing microcephaly which could allow for early intervention.
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