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Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion
Guoliang Chai1, Emmanuelle Szenker-Ravi1, Changuk Chung1
1From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.).
Genetic mutations in WLS cause Zaki syndrome, a condition involving structural birth defects and microcephaly. Wnt signaling pathway modulation in mouse models suggests this syndrome may be preventable with targeted therapies.
Area of Science:
- Genetics
- Developmental Biology
- Medical Research
Background:
- Structural birth defects affect ~3% of newborns, often with unknown causes.
- Current treatments focus on surgery, with limited pharmacologic prevention options.
Purpose of the Study:
- To identify genetic causes of structural birth defects and neurodevelopmental disorders.
- To investigate the role of Wnt signaling in embryogenesis and birth defects.
- To explore potential therapeutic strategies for these conditions.
Main Methods:
- Sequenced exomes/genomes from 20,248 families with neurodevelopmental disorders.
- Identified biallelic mutations in candidate genes across multiple families.
- Generated mouse models with pathogenic variants to study disease mechanisms.
- Administered Wnt agonists to pregnant mice to assess treatment efficacy.
Main Results:
- Identified homozygous mutations in WLS (Wnt ligand secretion mediator) in 10 individuals from 5 families.
- Patients exhibited multiorgan defects including microcephaly, facial dysmorphism, and heart defects.
- WLS mutations impaired protein stability and Wnt signaling; mouse models confirmed Wnt pathway involvement in embryogenesis.
- Wnt agonist treatment partially rescued developmental defects in mouse models.
Conclusions:
- Genetic variations in WLS cause syndromic structural birth defects, termed Zaki syndrome.
- Mouse model data suggest Zaki syndrome is a potentially preventable disorder.
- Targeting Wnt signaling represents a promising therapeutic avenue for these birth defects.
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