DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes.
J Med Genet
; 58(7): 453-464, 2021 07.
Article
en En
| MEDLINE
| ID: mdl-32631816
ABSTRACT
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Anomalías Congénitas
/
Proteínas Supresoras de Tumor
/
Ciliopatías
/
Proteínas de la Membrana
/
Mutación
Tipo de estudio:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Child
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos