Role of single gene linked to epilepsy, autism identified: Study

Lynchpin has been identified as the only gene that has previously been found to be a driving force in the rare syndrome associated with epilepsy, autism and developmental disability.

Researchers say the DDX3X gene generates a cellular machinery called helicase, whose task is to disassemble RNA’s hairpins and cul-de-sac so that its code can be read by cell protein-making machinery.

Duke researchers say DDX3X generates a cellular machine called the gene helicase, whose task is to break down the RNA’s hairpins and cul-de-sac so that its code can be read by cell protein-making machinery. 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 remove both copies of a gene in a female mouse, it causes massive microcephaly, where the brains are drastically reduced in size,” said Debra Silver, associate professor of molecular genetics and microbiology at the Duke School of Medicine. Who led the research team. “But removing a single copy will probably more closely mimic what’s happening in human patients,” Silver said.

In other words, defects caused by defective DDX3X are dosage-dependent – depending on how badly the mutation affects the production of helicases, the syndrome may change. The findings appear in the open access journal eLife on June 28.

When the DDX3X mutation is changed in early development, Silver said, “you don’t get more neurons over time because this gene is required for the production of neurons from the progenitor cells.” “And it helps divide the ancestors properly.”

While it usually takes 15 hours or more for the nerve precursor cell to divide, the mutated DDX3X can make that process even longer, Silver said. “And over time this means that if these nerve precursors take longer to divide, you fall behind and the brain doesn’t develop properly.”

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In a previous study published by the team in March 2020, using genetic models of 107 developmentally disabled children around the world, researchers found that half the DDX3X mutations completely disrupted the gene, while the other half made it more poorly functioning.

DDX3X mutations are now considered to account for 1 to 3 percent of women with intellectual disabilities, but the mutations are always ‘de novo’, meaning they occurred spontaneously during development rather than inherited from the parents.

In previous studies, almost all of the females were female, leading researchers predicted that DDX3X loss in males would be fatal because they carry only one copy of the gene. In this work, however, Silver’s team has found that a fellow gene carrying the male Y chromosome, DDX3Y, fulfills some of the functions of the gene.

To do this work, the Silvers Lab, led by Maria Hoy, developed a new method for profiling of all new progenitor cells in the brain of living animals, which may lead to an important understanding of protein synthesis in the brain. He said.

Silver said some RNAs that reduce translation by damaging DDX3X have roles in brain development. “So it helps us figure out what I call a network of RNAs. Its translation depends on this gene. And molecularly, it starts to give us tips on how DDX3X can disrupt brain development.”

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DDX3X has also been implicated in neurodegeneration, some cancer progression and innate immune responses. Understanding the cellular processes in the developing brain and the molecular targets of DDX3X can help illuminate the underlying cause of many disorders, Silver said.

“We know that more than 800 families worldwide are diagnosed with DDX3X syndrome,” Silver said. “It’s definitely an important gene with hundreds of mutations. There’s really tons to learn about how DDX3X regulates brain development.”

“We hope this research will improve understanding based on DDX3X syndrome and related disorders,” Silver said. “In the long run it may help the development of treatments.”

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