AUG 30, 2020 6:15 AM PDT

Transfer RNA Mutations May Be an Overlooked Cause of Disease

WRITTEN BY: Carmen Leitch

Our bodies need vast numbers of proteins to function. Dysfunctional proteins, which can be produced by errors in the genes that encode for them, may cause disease. A lot of disease research has focused on these problematic proteins. They are made when the cell translates them from RNA molecules that have been transcribed from the genome.

The translation of proteins, outlined in the video above, requires molecules called transfer RNAs (tRNAs). There are hundreds of them, and they move amino acids to a cellular structure that generates proteins. There are usually backups of tRNAs available because they are so important. But mutations in tRNAs themselves have often been overlooked in research science. Now more attention is turning their way.

Reporting in Neuron, University of California San Diego researchers identified a mutation in one member of a tRNA gene family that can alter the entire landscape of a cell. The gene, called n-Tr20 is expressed exclusively in the brain, and this mutation can change behavior and brain function.

Disruptions in this gene have been implicated in neurological diseases including autism spectrum disorder and epilepsies. The researchers found that n-Tr20 is involved in the brain's careful orchestration of excitatory and inhibitory neurotransmission, said the first author of the study Mridu Kapur, a postdoctoral scholar in the lab of Professor Susan Ackerman.

"tRNAs have generally been overlooked in the hunt for the genetic causes of disease, but recent whole-genome sequencing projects have revealed that there are many variations in tRNA sequences in the human population," said Kapur. "Our study suggests the enormous potential for tRNA variants to contribute to disease outcomes and phenotypic variability."

When n-Tr20 was removed from mice, they became resistant to seizures. This work could help show how tRNA mutations may not only affect other mutations, but they may also disrupt brain function on their own.

"You can imagine it's like a seesaw--if you push either way you can have problems," said Ackerman, a member of the Section of Neurobiology, Department of Cellular and Molecular Medicine and investigator at the Howard Hughes Medical Institute. "Keeping balance of these two opposing forces is essential for normal function. Shifting one way or another can lead to neurological diseases. It's becoming well accepted in the autism spectrum disorder field that what we are really seeing is an imbalance of excitatory/inhibitory neurotransmission."

Ackerman said genes like n-Tr20 are typically not studied because they are too similar to other genes.

"We never knew a mutation in a multi-copy tRNA gene could do anything like this," said Ackerman. "These findings make you think about people who have diseases with variable symptoms and how much this class of overlooked genes could be playing a role in their disease. So we're seeing this go from a behavior, such as seizure, all the way to the molecular underpinnings causing them."

The researchers now want to know more about the associations between tRNAs and diseases affecting tissues other than the brain.

Sources: AAAS/Eurekalert! via University of California San Diego, Neuron

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  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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