Gene Related to Abnormal Brain Development Identified

Using integrative genomics of brain cells, researchers have identified a gene thought to be associated with the types of brain damage that can be caused by inflammation during premature birth, suggesting the presence of a previously unknown mechanism of brain injury.

Premature labor is associated with inflammation in the mother or baby, often due to infection. This can cause damage to the brain that could lead to lifelong conditions (e.g. cerebral palsy, autism or other learning or behavioral difficulties) in up to 30% of pre-term babies. The new study, a collaboration between researchers at King’s College London (London, UK), Inserm (Paris, France) and Paris Diderot University, and Duke-NUS Medical School (Singapore), investigated the role of microglial cells, which control the immune response in the brain, in responding to this inflammation. The research team found a gene, DLG4, expressed in these cells that are thought to be involved in controlling the inflammatory process.

DLG4 is found in different forms in all humans but previously was thought only to play a role in the function of the nervous system. The new finding suggests it is also involved in the process resulting in brain damage in some preterm babies. The study used an integrative approach that included mouse models of inflammation and a genomic analysis of over 500 infant brain scans. It identified differences in the way DLG4 was expressed in microglia in both the mouse models and brain scans.

Whilst the association requires further study to confirm the role of microglia and the DLG4 gene, the result contributes to an existing body of evidence that links the gene with both the immune response and neuropsychiatric diseases such as schizophrenia and autism.

“We have shown that the DLG4 gene is expressed differently in microglia when a brain has been damaged by inflammation,” said David Edwards, professor at King’s College London. Enrico Petretto, associate professor from Duke-NUS Medical School said: “Given the previously acknowledged role of the DLG4 gene in brain diseases such as autism and schizophrenia, our study strengthens the link between the immune response and susceptibility to develop these brain disorders.” Professor Pierre Gressens from Inserm-Paris Diderot University and King’s College London said: “This study identifies for the first time the microglial expression of DLG4, a gene previously considered as expressed in neurons only and highlights the potential role of microglia in different neurodevelopmental disorders.”

The researchers hope to provide a new avenue to study and understand how this inflammation and subsequent brain damage is caused so that measures can be taken and treatments developed to stop or even prevent the inflammation associated with pre-term birth. Identifying effects of mutations in DLG4 may also be useful for diagnostics.

The study, by Krishnan ML et al, was published September 5, 2017, in the journal Nature Communications.

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King’s College London
Inserm
Duke-NUS Medical School