ARMC9 and TOGARAM1 define a Joubert syndrome-associated protein module that regulates axonemal post-translational modifications and cilium stability
Latour, B.; Van De Weghe, J. C.; Rusterholz, T.; Letteboer, S.; Gomez, A.; Shaheen, R.; Gesemann, M.; Grout, M.; van Reeuwijk, J.; van Beersum, S.; Miller, C.; Dempsey, J.; Morsy, H.; Bamshad, M.; Nickerson, D.; Neuhauss, S.; Boldt, K.; Ueffing, M.; Alkuraya, F.; Bachmann-Gagescu, R.; Roepman, R.; Doherty, D.
Show abstract
Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy, characterized by a pathognomonic hindbrain malformation. All known JBTS-genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we use the recently identified JBTS-associated protein ARMC9 in tandem-affinity purification and yeast two-hybrid screens to identify a novel ciliary module composed of ARMC9-TOGARAM1-CCDC66-CEP104- CSPP1. TOGARAM1-variants cause JBTS and disrupt its interaction with ARMC9. Using a combination of protein interaction analyses and characterization of patient-derived fibroblasts, CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrate that dysfunction of ARMC9 or TOGARAM1 results in short cilia with decreased axonemal acetylation and glutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in both ARMC9 and TOGARAM1 patient cells lines suggest a role for this new JBTS-associated protein complex in ciliary stability.
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