The genetic cause of a very rare neurodevelopmental disorder called Nicolaides-Baraitser syndrome is known, but we’ve had a limited understanding of how the gene error leads to the severe symptoms. The disease can cause intellectual disability, cognitive disorders, and developmental delays. The genetic mutation that causes it has been shown to impact an important protein complex. The findings have been reported in Molecular Cell and are outlined in the following video.
"For the first time, we have been able to characterize the mechanism of a known gene mutation implicated in neurodevelopmental disorders," said the senior study author Assistant Professor Diana Hargreaves, the Richard Heyman and Anne Daigle Endowed Developmental Chair at Salk.
The protein complex the mutation disrupts is called SWI/SNF (for SWItch/Sucrose Non-Fermentable), which normally plays a role in gene regulation through the structural rearrangement of DNA. The genome is a huge molecule that has to be carefully packaged so it will fit in the nucleus of the cell, and so cellular machinery will be able to access the right parts of it at the right time. Mutations in the SWI/SNF complex have been linked not only to Nicolaides-Baraitser syndrome but also to some cancers, syndromic intellectual disability, autism, and another neurodevelopmental disease called Coffin-Siris syndrome. It’s still unclear how all the different mutations in the various subunits of the complex disrupt its function, however.
"We sought to understand how a single mutation in the SMARCA2 subunit affected brain development," explained Fangjian Gao, the first author of the report and a postdoctoral fellow at Salk. "We expected to see some effect on the neurodevelopmental pathways, but we were not sure how, specifically."
In this study, the researchers used the CRISPR gene-editing tool to modify cells growing in the lab, so they modeled the SMARCA2 mutation seen in Nicolaides-Baraitser syndrome patients. While healthy cells had very little SMARCA2 activity, the mutated cells were found to have far higher levels of SMARCA2 expression. The ability of the mutant cells to generate neuronal precursors was also impaired significantly. These precursors or progenitor cells are vital to normal development. In this way, the mutation in SMARCA2 triggers a change in gene expression that seems to ultimately disrupt the brain.
"By better understanding this mutation in SMARCA2, we have tapped into what looks like a core developmental process that could be perturbed in disease states such as autism or even cancer," noted Hargreaves.