A single gene that was previously found to be the driving force in a rare syndrome linked to epilepsy, autism and developmental disability has been identified as a linchpin in the formation of healthy neurons.

Duke researchers say the gene, DDX3X, forms a cellular machine called a helicase, whose job it is to split open the hairpins and cul-de-sacs of RNA so that its code can be read by the protein-making machinery of the cell. This gene is carried on the X chromosome, so females have two copies of the gene and males have only one.

“If you remove both copies of the gene in a female mouse, that results in a massive microcephaly where the brains are severely reduced in size,” said Debra Silver, PhD, an associate professor of molecular genetics and microbiology in the Duke School of Medicine who led the research team. “But the removal of a single copy is probably more closely mimicking what’s happening in human patients,” Silver said.

Put another way, the defects caused by faulty DDX3X are dosage-dependent — the syndrome can vary depending on how badly the production of helicases is affected by mutations. The findings appear June 28 in the open access journal eLife.

When DDX3X is altered by a mutation in early development, “you don’t get as many neurons over time because this gene is required for the production of neurons from progenitor cells,” Silver said. “And it is also helping the progenitors to divide properly.”

If it normally takes a nerve precursor cell 15 hours or so to divide, a mutated DDX3X may make that process take even longer, Silver said. “And what that means over time, if these neural precursors are taking too long to divide, is you fall behind, and the brain doesn’t develop properly.”

In a previous study the team published in March 2020, , using genetic samples from 107 developmentally disabled children from around the world, the researchers found that half of the DDX3X mutations disrupted the gene completely, but the other half only made it work more poorly.

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