1. Defects in diffusion barrier function of ciliary transition zone caused by ciliopathy variations of TMEM218.
- Author
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Fujii T, Liang L, Nakayama K, and Katoh Y
- Subjects
- Humans, Cerebellum abnormalities, Cerebellum metabolism, Cerebellum pathology, Cerebellar Diseases genetics, Cerebellar Diseases metabolism, Cerebellar Diseases pathology, Animals, Cell Membrane metabolism, Mice, Ciliary Motility Disorders, Polycystic Kidney Diseases, Retinitis Pigmentosa, Cilia metabolism, Cilia genetics, Cilia pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Ciliopathies genetics, Ciliopathies metabolism, Ciliopathies pathology, Encephalocele genetics, Encephalocele metabolism, Encephalocele pathology, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic metabolism, Kidney Diseases, Cystic pathology, Abnormalities, Multiple genetics, Abnormalities, Multiple metabolism, Abnormalities, Multiple pathology, Eye Abnormalities genetics, Eye Abnormalities pathology, Eye Abnormalities metabolism, Mutation, Retina metabolism, Retina abnormalities, Retina pathology
- Abstract
Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP). Proteins constituting the TZ can be grouped into the MKS and NPHP modules. The MKS module is composed of several transmembrane proteins and three soluble proteins. TMEM218 was recently reported to be mutated in individuals diagnosed as MKS and JBTS. However, little is known about how TMEM218 mutations found in MKS and JBTS affect the functions of cilia. In this study, we found that ciliary membrane proteins were not localized to cilia in TMEM218-knockout cells, indicating impaired barrier function of the TZ. Furthermore, the exogenous expression of JBTS-associated TMEM218 variants but not MKS-associated variants in TMEM218-knockout cells restored the localization of ciliary membrane proteins. In particular, when expressed in TMEM218-knockout cells, the TMEM218(R115H) variant found in JBTS was able to restore the barrier function of cells, whereas the MKS variant TMEM218(R115C) could not. Thus, the severity of symptoms of MKS and JBTS individuals appears to correlate with the degree of their ciliary defects at the cellular level., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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