Sites in the Brain Where RNA Is Edited Could Help to Better Understand Neurodevelopment and Disease

 

Researchers at Mount Sinai have determined new avenues for understanding molecular and cellular mechanisms of brain development and how they affect both disease and health by cataloging sites in the brain where RNA is modified. As an individual ages, the RNA editing rate in the brain increases. This modification happens throughout one's lifetime through a process known as adenosine-to-inosine (A-to-I) editing. With this they could explore the implications across a range of aging and neurodevelopmental disorders. Because there are so many already identified A-to-I sites, it can be difficult to determine which sites are physiologically important. The researchers were able to narrow it down to about 10,000 sites that have potential functional roles from early fetal development through advanced aging. These sites will help get a better understanding of brain neurodevelopment through a lens of A-to-I RNA modifications.  

While DNA is widely known as the genetic blueprint of all human and other living things, RNA is responsible for carrying out the instructions to create functioning proteins. When modifications accumulate on RNA, it can alter the way a protein functions. These A-to-I changes are introduced by a group of ADAR enzymes whose edits have been known to have an important physiological role in early fetal development by regulating neuronal signaling and synaptic transmission. All of this shows that in the course of a lifetime, thousands of individual edits will accumulate in the RNA in the brain and will likely produce functional ramifications as a person ages.  

The data collected by the Mount Sinai study was from more than 800 individuals covering all stages of pre and postnatal development. The broad data can create a timeline to depict how A-to-I editing changes over time. The work uncovered by the researchers can now provide many avenues for future studies and offer insight into the role of RNA editing in the promotion of health and disease.  

Researchers discover new neurodevelopmental disorder

After discovering its link to a tumor suppressor gene, Australian researchers have found a novel neurodevelopmental condition. The Murdoch Children's Research Institute (MCRI) conducted an international research team that linked a known tumor suppressor gene to a novel neurodevelopmental disease, putting an end to the diagnostic journey for 32 families throughout the world. Variations in the FBXW7 gene were linked to the newly identified disorder, which causes “mild to severe developmental delay, intellectual disability, hypotonia, and gastrointestinal problems,” according to the study. Because the FBXW7 gene regulates cell life-cycle, cell growth, and cell survival, the research team hypothesized that abnormal cell proliferation during brain development could underpin the wide range of brain abnormalities seen in this new disorder, according to Murdoch Children's researcher Dr Sarah Stephenson. According to this article, The researchers employed cutting-edge diagnostic methods, genomic sequencing, and global data sharing platforms to find 35 persons, ages 2 to 44, from 32 families in seven countries who had variations in the FBXW7 gene that were linked to a hitherto unknown neurodevelopmental disease. Almost all of those impacted experienced developmental delays and intellectual disabilities ranging from mild to severe; 62% had decreased muscle tone, 46% had eating and constipation issues, and 23% had seizures. Variable underlying anatomical variations affecting the cerebellum, nerve fibers, and white matter were also shown by brain imaging. The researchers next used a fly model to lower the gene's expression, which impaired the flies' capacity to jump in response to a stimulus. This backed with the theory that the 28 FBXW7 mutations were to blame for the disease. It also reinforced the importance of the gene in development in general and in the brain in particular. Professor Tiong Tan of Murdoch Children's Hospital, who is also a clinical geneticist at Victorian Clinical Genetics Services (VCGS), said the findings demonstrated the power of undiagnosed disease programs that use new genomic sequencing technologies as well as international data sharing and collaboration to provide diagnoses to children and families who have been searching for answers for years. Rare Diseases Now (RDNow) has devised a pathway for children who remain unidentified after a genomic test such as exome sequencing, building on the scientific and clinical experience of MCRI and VCGS. Recently studies have found that this diagnosis is a dominant condition, which means the person who is affected has a 50 percent chance of passing it off to the offsprings. Even though its a high risk, this also gives a good certainty to the families, as this gives them a better understanding of the this new condition, and have a better knowledge of what to do in the future, if they were to have offsprings. Professor Tan also stated that the next stage would be to test these findings in human stem cells, which would then be engineered into brain cells for laboratory research, in order to gain a better knowledge of how the brain was damaged in this condition.

“Researchers Discover New Neurodevelopmental Disorder.” ScienceDaily, ScienceDaily, 7 Apr. 2022, https://www.sciencedaily.com/releases/2022/04/220407121608.htm.

Taylor, Michelle. “Researchers Discover New Neurodevelopmental Disorder.” Lab Equipment, 8 Apr. 2022, https://www.laboratoryequipment.com/584965-Researchers-Discover-New-Neurodevelopmental-Disorder/.

Influence of Genetic Background on Severity of Neurodevelopmental Disorders

(Explanation of picture. As shown, individuals with the same primary variant associated with a certain disease show completely different symptoms. This is due to differences in their genetic background (More information in blog))










In this article by Genetic Engineering and Biotechnology News, writers highlight a study done by researchers from Penn State which link variations in a person's genetic background to the severity of neurodevelopmental disorders, such as autism.

Many genetic variants have been known to increase a person's vulnerability to various neurodevelopmental disorders, however, a problem lies when two people with the same variant show different symptoms. Researchers from Penn State shed light to this problem by revealing the key role of a person's genetic background. To study this, the team took 757 individuals who had a deletion along a gene band, which has been linked to several neurodevelopment disorders, and 233 of their parents and/or siblings.

After analyzing sequences and other data, the research team found that the accumulation of mutated genes elsewhere lead to the severity of a disorder made vulnerable by the main genetic variant. This explains the discrepancy of why a parent and child who share the same primary variant show different symptoms (e.g. the parent may be normal, while the child displays the disorder). Higher mutations are partly dictated by family history. A child who has a history of family members with neurodevelopmental disorders are at an increased risk of being born with a higher number of mutations in the genetic background, making their disorder more severe.

At the conclusion of the research team's study, they emphasize the need for genetic background testing of individuals who show neurodevelopment disorders, as well as their parents, to draw a more conclusive pathway of treatment and disease management.

I believe research in this area of genetics should be continued and expanded upon. By doing so, it dispels the misconception that a single gene variant dictates the manifestation of symptoms. To add, screening for mutations in one's genetic background should be one of the main course of action in determining treatment, since they influence the severity of the disorder to such a high degree.

Link to actual published article
Additional article exploring topic

Researchers pinpoint gene responsible for neurodevelopmental disorders, including autism

Researchers at McMaster University have pinpointed genes that are correlated with neurodevelopmental disorders, that include autism. Karun Singh, researcher, and co-author at Mcmaster stem cell and cancer research institute said:"Our studies reveal that in complex brain disorders that have a loss of many genes, a single deleted gene is sufficient to cause symptoms for the patients".

The gene Thousand and one amino-acid kinase 2 (TAOK2) has been found to play a vital role in these kinds of disorders. This research was conducted on mice and human cells, where behavior analysis using TAOK2 heterozygous (Het) and knockout (KO) mice. Finding that "three de novo mutations in TAOK2 all hindered protein stability, but

but they differentially impact kinase activity, dendrite growth, and spine/synapse development."

Data that was gathered showed evidence that the neurodevelopmental disorder risk gene was "TAOK2 and that a signaling RhoA as the mediator of TAOK2 dependent synaptic development." Singh stated that the next step was to figure out drugs that corrected cognitive brain deficits that was caused by TAOK2 and finding people for clinical trials.

For more in depth click LINK 1 and LINK2. (references)