Role of a single gene linked to epilepsy, autism identified: study

A single gene that was previously shown to be the driving force behind a rare syndrome linked to epilepsy, autism and developmental disabilities has been identified as central to the formation of healthy neurons.

Researchers say the gene, DDX3X, forms a cellular machine called helicase, whose job is to open the hairpins and dead ends of RNA so that its code can be read by the machinery for making cell proteins.

Duke researchers say the gene, DDX3X, forms a cellular machine called helicase, whose job is to open the hairpins and dead ends of RNA so that its code can be read by the machinery of production of cell proteins. This gene is carried on the X chromosome, so females have two copies of the gene and males have only one.

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“If you delete both copies of the gene in a female mouse, it results in massive microcephaly where brain size is dramatically reduced,” said Debra Silver, PhD, associate professor of molecular genetics and microbiology at Duke School of Medicine. . who led the research team. “But the deletion of a single copy probably more closely mimics what happens in human patients,” Silver said.

In other words, the defects caused by defective DDX3X are dose-dependent – ​​the syndrome can vary depending on how severe the helicase production affected by the mutations is. The results appear June 28 in the open-access journal eLife.

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

While it normally takes about 15 hours for a nerve precursor cell to divide, mutated DDX3X can make that process even longer, Silver said. “And what that means over time, if those neural precursors take too long to divide, you’re falling behind and the brain isn’t developing properly.”

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In a previous study published by the team in March 2020, using genetic samples from 107 children with developmental disabilities from around the world, researchers found that half of DDX3X mutations completely disrupt the gene, but the other half only made it work worse.

DDX3X mutations are now thought to cause 1-3% of intellectual disabilities in women, but the mutations are almost always “de novo”, meaning they occurred spontaneously during some developmental phase. , rather than being inherited from parents.

The children in the previous study were almost all female, leading researchers to speculate that loss of DDX3X in males would be fatal, as they carry only one copy of the gene. But in this work, Silver’s team discovered that a companion gene carried by the male Y chromosome, DDX3Y, may perform part of the gene’s function.

To do this work, Silver’s lab, led by Mariah Hoye, developed a novel approach to profiling all newly made proteins from progenitor cells in the brain of a living animal, a technique that could lead to an important understanding of the protein synthesis in the brain, she said.

Some of the RNAs whose translation is reduced by damage to DDX3X also play a role in brain development, Silver said. “So that’s helping us uncover what I would call an RNA network that depends on this gene for translation. And that’s starting to give us clues as to how, at the molecular level, DDX3X can disrupt brain development. “

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DDX3X has also been implicated in neurodegeneration, the progression of certain cancers, and innate immune responses. Silver said understanding the cellular processes and molecular targets of DDX3X in the developing brain could help shed light on the basis of many disorders.

“We know of over 800 families worldwide who have been diagnosed with DDX3X syndrome,” Silver said. “This is definitely an important gene, with probably hundreds of mutations. There really is a lot to learn about how DDX3X controls brain development.”

“We hope this research can improve understanding of the basis of DDX3X syndrome and associated disorders,” Silver said. “In the longer term, this may contribute to the development of therapies.”

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