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A rare genetic disorder caused by mutations in proteins that control RNA metabolism

Hairpin loop from pre-mRNA. Highlighted are the nucleobase (green) and the ribose-phosphate skeleton (blue). Note that this is a single strand of RNA that wraps around itself. Credit: Vossman / Wikipedia

In the paper published today Nature CommunicationsAn international collaborative group led by researchers at the UPMC Children’s Hospital in Pittsburgh has identified a genetic cause of rare neurological disorders characterized by developmental delay and loss of coordination, or ataxia.

Discovered by scientists, this disorder is caused by mutations in a protein called GEMIN5, one of the key components of a protein complex that controls RNA metabolism in neurons. Mutations in GEMIN5 were previously unrelated to any genetic disease.

“It’s like building a house,” said Dr. Udai Panday, an associate professor of pediatrics, human genetics, and neurology at the University of Pittsburgh School of Medicine. “You take out the most important bricks at the base and the entire building collapses.”

GEMIN5 is part of a protein complex that regulates a number of important cellular processes, including the development of special by-products from nerve cells called dendrites and axons. Interestingly, mutations in another important protein in the complex called the survival motor neuron protein cause another catastrophic disorder, spinal muscular atrophy.

To collect materials for the study, Pittsburgh researchers contacted pediatricians, geneticists, and neurologists around the world and eventually collected data from 30 patient families in 12 countries. ..

Since it is impossible to isolate living neurons from humans, researchers needed to come up with another way to take samples for future testing. They collected blood samples from pediatric patients referred to a neurogenetic clinic with undiagnosed neurological symptoms. Blood samples were then processed to isolate cells, carefully tinkered in the laboratory, and reprogrammed into neurons.

After comparing the genetic material of reprogrammed neurons from a sick child with that of an unaffected relative, scientists found 26 mutations in the GEMIN5 gene that damage the neurological symptoms of the disease to protein structure. Associated with.

“Children came to the clinic with non-specific symptoms such as developmental delay and gait abnormalities. Their doctors performed all possible tests, including an assessment of the child’s metabolic function, but it was helpful. There was no brief explanation of their condition, “said Deeparajan. , MD, Associate Professor of Pediatrics, University of Pittsburgh, Neurologist at UPMC Children’s Hospital, and co-lead author of the study. “It wasn’t until extensive genomic analysis that we discovered that these patients had mutations in the GEMIN5 gene.”

“Many hereditary disorders appear to be rare individually, but are relatively common collectively,” added Rajan, director of the Neurogenetics Clinic at UPMC Children’s Hospital. “We can now use next-generation technologies to help diagnose previously undiagnosed children. Each discovery of a new gene will better understand each of these diseases. It’s the beginning of a journey for. “

Additional experiments more clearly associated damage to the GEMIN5 protein with disease symptoms. Scientists say that depleting analogs of the fruit fly’s human neuronal GEMIN5 protein is fatal if it occurs early in the fruit fly’s life cycle, and that if such disruption occurs later, its development. I have found that it delays significantly.

“The most exciting part of being a researcher is working on a project that helps the family directly,” Pandy said. “Our study hopes that neurologists will consider testing for GEMIN5 mutations and that the laboratory will include GEMIN5 in testing for ataxia. Although it is difficult to identify and treat hereditary disorders, If a cure is found, it makes a big difference in someone’s life. ”


Breakthrough discovery of genes that cause severe neurological conditions


For more information:
Nature Communications (2021). DOI: 10.1038 / s41467-021-22627-w

Courtesy of the University of Pittsburgh

Quote: A rare genetic disease (May 7, 2021) caused by mutations in proteins that control RNA metabolism is https: //medicalxpress.com/news/2021-05-rare-genetic-disease-mutations-protein. Obtained from html on May 7, 2021

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A rare genetic disorder caused by mutations in proteins that control RNA metabolism

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