Background: Cilia 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.
Methods: Among 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 dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.
Results: Patients with variants of DLG5 were 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 dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient 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.
Conclusion: These findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.JM is supported by the Yale MSTP NIH T32GM007205 Training Grant, the Yale Predoctoral Program in Cellular and Molecular Biology T32GM007223 Training Grant and the Paul and Daisy Soros Fellowship for New Americans. EKM is supported by a grant from the Hartwell Foundation and is a Hartwell Fellow. EW is supported by the Leopoldina Fellowship Program (LPDS 2015-07). MK is part of the NEOCYST consortium funded by the German Federal Ministry of Research and Education (BMBF, grant 01GM1903A). SE is a Wellcome Senior Investigator. This research was supported by grants from the National Institutes of Health to FH (DK076683, DK088767, DK068306). NM is supported by funding from the National Institutes of Health T32-DK007726-33 grant at Boston Children's Hospital. MKK is supported by NIH/NICHD (R01HD102186).published version, accepted version, submitted versio
