Abstract
Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.
MeSH terms
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Abnormalities, Multiple / genetics
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Abnormalities, Multiple / metabolism
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Abnormalities, Multiple / pathology*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adolescent
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Adult
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cerebellum / abnormalities*
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Cerebellum / metabolism
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Cerebellum / pathology
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Child
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Cilia / metabolism
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Cilia / pathology*
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Ciliopathies / genetics
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Ciliopathies / metabolism
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Ciliopathies / pathology*
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Cytoskeletal Proteins
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Eye Abnormalities / genetics
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Eye Abnormalities / metabolism
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Eye Abnormalities / pathology*
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Female
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Genetic Predisposition to Disease
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Humans
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Image Processing, Computer-Assisted
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Kidney Diseases, Cystic / genetics
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Kidney Diseases, Cystic / metabolism
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Kidney Diseases, Cystic / pathology*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice, Inbred C57BL
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Microscopy, Fluorescence / methods*
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Mutation
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Patched-1 Receptor / genetics
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Patched-1 Receptor / metabolism
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Phenotype
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Retina / abnormalities*
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Retina / metabolism
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Retina / pathology
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Signal Transduction
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Smoothened Receptor / genetics
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Smoothened Receptor / metabolism
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Stochastic Processes
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Young Adult
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cytoskeletal Proteins
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Ftm protein, mouse
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Membrane Proteins
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NPHP1 protein, human
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Nphp1 protein, mouse
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Patched-1 Receptor
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Ptch1 protein, mouse
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RPGRIP1L protein, human
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Smo protein, mouse
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Smoothened Receptor
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TCTN2 protein, human
Supplementary concepts
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Agenesis of Cerebellar Vermis