Researchers discover unknown childhood genetic condition and its
potential cure
Findings point to the possibility of treating and preventing birth
defects before birth

Date:
September 29, 2021
Source:
University of California - San Diego
Summary:
International group of researchers identify new childhood genetic
condition and a potential cure that can be delivered during
pregnancy.



FULL STORY ========================================================================== Describing a previously unknown genetic condition that affects children, researchers at University of California San Diego School of Medicine
and Rady Children's Institute for Genomic Medicine say they also found
a potential method to prevent the gene mutation by administering a drug
during pregnancy.


==========================================================================
The findings publish in the September 30, 2021 issue of The New England
Journal of Medicine.

The work involved researchers in Egypt, India, the United Arab Emirates,
Brazil and the United States. "Although different doctors were caring for
these children, all of the children showed the same symptoms and all had
DNA mutations in the same gene," said senior author Joseph G. Gleeson,
MD, Rady Professor of Neuroscience at UC San Diego School of Medicine
and director of neuroscience at the Rady Children's Institute for
Genomic Medicine.

The research team dubbed the condition "Zaki syndrome" after co-author
Maha S.

Zaki, MD, PhD, of the National Research Center in Cairo, Egypt, who
first spotted the condition. Zaki syndrome affects prenatal development
of several organs of the body, including eyes, brain, hands, kidneys and
heart. Children suffer from lifelong disabilities. The condition appears
to be rare, but future studies are required to determine prevalence.

"We have been perplexed by children with this condition for many years,"
said Gleeson. "We had observed children around the world with DNA
mutations in the Wnt-less (WLS) gene, but did not recognize that they all
had the same disease until doctors compared clinical notes. We realized
we were dealing with a new syndrome that can be recognized by clinicians,
and potentially prevented." Co-author Bruno Reversade, PhD, a research director at the Agency for Science, Technology and Research (A*STAR)
in Singapore, helped identify several families with members suffering
from Zaki syndrome and investigate potential therapeutic intervention.

"While we have shown that it's possible to mimic WNT-deficiency with
dedicated drugs, the real challenge was to overcome, and possibly rescue,
this congenital disease," Reversade said.

Using whole genome sequencing, researchers documented mutations in the
WLS gene, which controls signaling levels for a hormone-like protein
known as Wnt (pronounced wint). Wnt signaling is a highly conserved
group of protein pathways involved in embryonic development.

The scientists generated stem cells and mouse models for Zaki syndrome,
and treated the condition with a drug called CHIR99021, which boosts
Wnt signaling.

In each mouse model, they found CHIR99021 boosted Wnt signals, and
restored development. Mouse embryos grew body parts that had been missing
and organs resumed normal growth.

"The results were very surprising because it was assumed that structural
birth defects like Zaki syndrome could not be prevented with a drug," said first author Guoliang Chai, PhD, a former postdoctoral fellow at UC San
Diego School of Medicine now at Capital Medical University in Beijing,
China. "We can see this drug, or drugs like it, eventually being used
to prevent birth defects, if the babies can be diagnosed early enough." Co-authors include: Changuk Chung, Zhen Li, Lu Wang, Trevor Marshall,
Nan Jiang, Xiaoxu Yang, Jennifer McEvoy-Venneri, Valentina Stanley,
Paula Anzenberg and Nhi Lang, all at Rady Children's and UC San Diego;
Karl Willert, UC San Diego; Emmanuelle Szenker-Ravi, Muznah Khatoo and
Vanessa Wazny, Genome Institute of Singapore; Jia Yu and David M. Virshup, National University of Sinapore; Rie Nygaard, Filippo Mancia, Rebecca
Hernan and Wendy K. Chung, Columbia University; Rijad Merdzanic and Aida
M. Bertoli-Avella, Centogene, Germany; Maria B.P. Toralles and Paula
M.L. Pitanga, Laboratorio e Genetica Medica, Brazil; Ratna D. Puri,
Sir Ganga Ram Hospital; and Nouriya Al-Sannaa, Dhahran Health Center,
Saudi Arabia.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Scott
LaFee. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Guoliang Chai, Emmanuelle Szenker-Ravi, Changuk Chung, Zhen Li,
Lu Wang,
Muznah Khatoo, Trevor Marshall, Nan Jiang, Xiaoxu Yang,
Jennifer McEvoy- Venneri, Valentina Stanley, Paula Anzenberg,
Nhi Lang, Vanessa Wazny, Jia Yu, David M. Virshup, Rie Nygaard,
Filippo Mancia, Rijad Merdzanic, Maria B.P. Toralles, Paula
M.L. Pitanga, Ratna D. Puri, Rebecca Hernan, Wendy K. Chung, Aida
M. Bertoli-Avella, Nouriya Al-Sannaa, Maha S. Zaki, Karl Willert,
Bruno Reversade, Joseph G. Gleeson. A Human Pleiotropic Multiorgan
Condition Caused by Deficient Wnt Secretion. New England Journal
of Medicine, 2021; 385 (14): 1292 DOI: 10.1056/NEJMoa2033911 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210929212207.htm

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