| Autor: |
Marquez, Jonathan, Mann, Nina, Arana, Kathya, Deniz, Engin, Ji, Weizhen, Konstantino, Monica, Mis, Emily K, Deshpande, Charu, Jeffries, Lauren, McGlynn, Julie, Hugo, Hannah, Widmeier, Eugen, Konrad, Martin, Tasic, Velibor, Morotti, Raffaella, Baptista, Julia, Ellard, Sian, Lakhani, Saquib Ali, Hildebrandt, Friedhelm, Khokha, Mustafa K |
| Zdroj: |
Journal of Medical Genetics (JMG); 2021, Vol. 58 Issue: 7 p453-464, 12p |
| Abstrakt: |
BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5(DLG5)that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5in Xenopus tropicalisfrog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5in Xenopusembryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5in frog embryos depleted of dlg5,introduction of DLG5patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopusshed light on how mutations in DLG5may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum. |
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