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Neurodevelopmental disorders resulting from rare genetic mutations can lead to atypical cognitive function, intellectual disability and developmental delays. However, we do not know why and how it happens. Scientists suspected a mutation in a protein complex to be responsible for a group of rare genetic diseases. Researchers at the Salk Institute have now identified the molecular mechanism linking this mutation to the abnormal development of the nervous system. The results of the team, published in Molecular cell On July 30, 2019, bring researchers closer to an understanding of neurodevelopmental disorders, such as Nicolaides-Baraitser syndrome and others.
"For the first time, we have been able to characterize the mechanism of a known genetic mutation involved in neurodevelopmental disorders," says Assistant Professor Diana Hargreaves, Lead Author and Development Chair Richard Heyman and Anne Daigle .
The root cause is linked to a complex of proteins called SWI / SNF complex, involved in the regulation of DNA and, when it is mutated, badociated with Nicolaides-Baraits syndrome, with Coffin-Siris syndrome , to autism and even to some cancers. These complexes repackage and reshape the DNA in the nucleus to allow or prevent access to the genes. And yet, scientists do not know how mutations in individual subunits of the SWI / SNF complex affect its function.
"We sought to understand how a single mutation in the SMARCA2 subunit affected brain development," said Fangjian Gao, the journal's first author and postdoctoral researcher at Salk. "We expected to see an effect on the neurodevelopmental pathways, but we did not know how, in particular."
Scientists have turned to cell cultures in a box to model the growth patterns of brain cells reached compared to normal brain cells. They used the CRISPR gene editing technique to mimic the SMARCA2 mutation observed in Nicolaides-Baraits syndrome. In particular, researchers found that healthy cells had minimal activity of SMARCA2. The cells carrying the mutation, however, exhibited a dramatic increase in SMARCA2 activity and a capacity significantly altered to generate neuronal precursors, called neural progenitor cells. In this highly activated state, SMARCA2 has affected the operation of the normal SWI / SNF complex. This led to a domino effect with changes in gene expression leading to abnormal brain development.
"By better understanding this mutation of SMARCA2, we have been able to exploit what looks like a fundamental developmental process that could be disrupted in pathological conditions such as autism or even cancer," said Mr. Hargreaves.
Other writers included Nicholas J. Elliott, Josephine Ho and Maxim N. Shokhirev of Salk, as well as Alexzander Sharp of the University of California at San Diego.
The work was funded by the Helmsley Trust, the National Institutes of Health (9R35 GM128943-01 and R00 CA184043-03) and the V Foundation for Cancer Research (V2016-006).
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Material provided by Salk Institute. Note: Content can be changed for style and length.
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