Researchers at the University of California San Diego School of Medicine, Rady Children’s Institute for Genomic Medicine have discovered a previously unknown genetic condition that affects children. They also discovered a method to prevent the mutation by giving a drug during pregnancy.
The findings will be published in the September 30th, 2021 issue The New England Journal of Medicine.
Researchers from Egypt, India and the United Arab Emirates were involved in the project. Researchers from India, Egypt and the United Arab Emirates were involved in the.
Although the children were treated by different doctors, they all showed the same symptoms, and all had the same DNA mutations.
Joseph G. Gleeson MD, Senior Author, Rady Professor of Neuroscience at UC San Diego School of Medicine, and Director of Neuroscience at the Rady Children’s Institute for Genomic Medicine
Images illustrate the effects of Zaki syndrome and treatment with the drug CHIR99021. Left the skeleton of a normal mouse with tail and legs. In the center there is a mouse that has the gene mutation , with tail missing. Right, a mouse that has the mutation treated with a drug and showing regrown tail. Photo credit: Joseph Gleeson, UC San Diego
The condition was named “Zaki syndrome” by the research team in honor of Maha S. Zaki MD, PhD co-author of the National Research Center in Cairo. She was the first person to identify it. Zaki syndrome can affect the prenatal development of various organs in the body, including the brain, eyes hands, kidneys, hands and heart. Children suffer from lifelong impairments. While the condition is believed to be uncommon in children, future studies will be required to determine its prevalence.
“We have been awestruck by children with this condition for a long time,” said Gleeson. “We have observed children all over the world who had DNA mutations in the Wnt-less (WLS) gene however, we did not realize that they all had the same disease until doctors reviewed their clinical notes. We realized that we were dealing with a new syndrome that can be recognized by clinicians, and potentially prevented.”
Co-author Bruno Reversade, PhD, Director of research at the Agency for Science, Technology and Research (A*STAR) in Singapore helped identify several families that have members suffering from Zaki syndrome and investigate potential therapeutic intervention.
Reversade stated that while we have shown that it is possible to mimic WNT deficiency using dedicated drugs, the main challenge was to overcome and perhaps help treat this congenital disorder.
Researchers utilized whole genome sequencing to find mutations in WLS which regulates the signaling levels for Wnt (pronounced “wint”), a hormone-like protein. Wnt signaling is a highly conserved group of proteins involved in embryonic development.
The scientists developed stem cells and mouse models for Zaki syndrome, and treated the condition with a drug called CHIR99021 that boosts Wnt signaling. In each mouse model they observed CHIR99021 enhanced Wnt signaling and restored the development. The mouse embryos were able to grow the body parts that were missing and the normal growth of organs.
“The results were shocking since it was believed that structural defects like Zaki syndrome cannot be prevented with a medication,” stated Guoliang Chai (PhD) the lead author. He was a former postdoctoral fellow at UC San Diego School of Medicine and is now at Capital Medical University, Beijing, China. “We are seeing this drug, or other drugs like it, eventually being used to prevent birth defects when the babies are diagnosed at an early age.”
Chai, G., et al. (2021) A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. The New England Journal of Medicine. doi.org/10.1056/NEJMoa2033911.
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