{"doi":"10.1172/jci131656","title":"Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome","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 used the recently identified JBTS-associated protein armadillo repeat motif-containing 9 (ARMC9) in tandem-affinity purification and yeast 2-hybrid screens to identify a ciliary module whose dysfunction underlies JBTS. In addition to the known JBTS-associated proteins CEP104 and CSPP1, we identified coiled-coil domain containing 66 (CCDC66) and TOG array regulator of axonemal microtubules 1 (TOGARAM1) as ARMC9 interaction partners. We found that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses, characterization of patient-derived fibroblasts, and analysis of CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrated that dysfunction of ARMC9 or TOGARAM1 resulted in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability.","journal":"Journal of Clinical Investigation","year":2020,"id":56056,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":88,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":291066,"name":"Julie C. Van De Weghe","orcid":"0000-0002-4492-6089","position":1,"is_corresponding":false},{"id":293352,"name":"Tamara D. S. Rusterholz","orcid":null,"position":2,"is_corresponding":false},{"id":283717,"name":"Stef J.F. Letteboer","orcid":null,"position":3,"is_corresponding":false},{"id":291067,"name":"Arianna Gómez","orcid":"0000-0002-9334-4130","position":4,"is_corresponding":false},{"id":291068,"name":"Ranad Shaheen","orcid":"0000-0002-2590-1759","position":5,"is_corresponding":false},{"id":291069,"name":"Matthias Gesemann","orcid":"0000-0001-7635-1235","position":6,"is_corresponding":false},{"id":291070,"name":"Arezou Karamzade","orcid":"0000-0001-8209-8504","position":7,"is_corresponding":false},{"id":291071,"name":"Mostafa Asadollahi","orcid":"0000-0003-3728-189X","position":8,"is_corresponding":false},{"id":291072,"name":"Miguel Barroso‐Gil","orcid":"0000-0001-8245-1929","position":9,"is_corresponding":false},{"id":293353,"name":"Manali Chitre","orcid":null,"position":10,"is_corresponding":false},{"id":291073,"name":"Megan E. Grout","orcid":"0000-0001-7704-2100","position":11,"is_corresponding":false},{"id":291074,"name":"Jeroen van Reeuwijk","orcid":"0000-0002-0658-4399","position":12,"is_corresponding":false},{"id":291075,"name":"Sylvia E. C. van Beersum","orcid":"0000-0002-4552-2908","position":13,"is_corresponding":false},{"id":291076,"name":"Caitlin V. Miller","orcid":"0000-0003-0850-1486","position":14,"is_corresponding":false},{"id":291077,"name":"Jennifer C. Dempsey","orcid":"0000-0002-5937-5830","position":15,"is_corresponding":false},{"id":291078,"name":"Heba Morsy","orcid":"0000-0002-9047-0959","position":16,"is_corresponding":false},{"id":36514,"name":"Michael J. Bamshad","orcid":"0000-0002-9647-0861","position":17,"is_corresponding":false},{"id":24999,"name":"Deborah A. Nickerson","orcid":"0000-0002-9954-4897","position":18,"is_corresponding":false},{"id":291079,"name":"Stephan C. F. Neuhauss","orcid":"0000-0002-9615-480X","position":19,"is_corresponding":false},{"id":34883,"name":"Karsten Boldt","orcid":"0000-0002-2693-689X","position":20,"is_corresponding":false},{"id":34885,"name":"Marius Ueffing","orcid":"0000-0003-2209-2113","position":21,"is_corresponding":false},{"id":291080,"name":"Mohammad Keramatipour","orcid":"0000-0002-5803-4209","position":22,"is_corresponding":false},{"id":259785,"name":"John A. Sayer","orcid":"0000-0003-1881-3782","position":23,"is_corresponding":false},{"id":291081,"name":"Fowzan S. 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