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Cited by 76Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesHereditary Neurological Disorders

Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome

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Latour, Brooke L., Van De Weghe, Julie C., Rusterholz, Tamara D.S., Letteboer, Stef J.F., Gomez, Arianna, Shaheen, Ranad, Gesemann, Matthias, Karamzade, Arezou +20 more·2020·Journal of Clinical Investigation
DOI 10.1172/jci131656PMC PMC7410078
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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.

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  • TOGARAM1 is associated with proper microtubule functions.

    “Among these proteins, TOGARAM1 and TRIM46 are associated with proper microtubule functions, 55 , 56 and MTFR1L is associated with mitochondrial fusion processes. 57”

    From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [55]

  • TRIM46 is associated with proper microtubule functions.

    “Among these proteins, TOGARAM1 and TRIM46 are associated with proper microtubule functions, 55 , 56 and MTFR1L is associated with mitochondrial fusion processes. 57”

    From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [55]

    The paper’s discussion of ciliary microtubules and tubulin modifications concerns ARMC9 and TOGARAM1, not TRIM46. A search of our full-text copy for “TRIM46” and “TRIM46 microtubule functions” found no passage addressing TRIM46’s role; page numbers were not available for the indexed passages. (LLM, conf=0.72)

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Authors
Latour, B. L., Van De Weghe, J. C., Rusterholz, T. D. S., Letteboer, S. J. F., Gomez, A., Shaheen, R., Gesemann, M., Karamzade, A., Asadollahi, M., Barroso-Gil, M., Chitre, M., Grout, M. E., van Reeuwijk, J., van Beersum, S. E. C., Miller, C. V., Dempsey, J. C., Morsy, H., Bamshad, M. J., Nickerson, D. A., Neuhauss, S. C. F., Boldt, K., Ueffing, M., Keramatipour, M., Sayer, J. A., Alkuraya, F. S., Bachmann-Gagescu, R., Roepman, R., & Doherty, D.
Affiliations
  • Radboud University Medical Center (NL)
  • University of Zurich (CH)
  • King Faisal Specialist Hospital & Research Centre (SA)
  • Tehran University of Medical Sciences (IR)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • University of Washington (US)
  • Alexandria University (EG)
  • University of Tübingen (DE)
  • Newcastle University (GB)
  • Alfaisal University (SA)
Corresponding author
  • Roepman, Ronald
  • Doherty, Dan
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2020-05-26
Volume
130
Issue
8
Pages
4423-4439
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci131656
PMC
PMC7410078
OpenAlex
W3028932329
Cited by
76
References
81
Citations by year
2026: 5 · 2025: 16 · 2024: 12 · 2023: 10 · 2022: 18 · 2021: 11 · 2020: 4
FWCI
6.30
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Netherlands Organisation for Scientific Research (NWO Vici-865.12.005)
  • Netherlands Organisation for Health Research and Development (ZonMW #91216051)
  • Foundation Fighting Blindness (PPA-0717-0719-RAD)
  • Swiss National Science Foundation SNF (PP00P3_170681, 31003A_173083)
  • NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091 Genetics Core and sub-project 6849, F32 HD095599)
  • NIH National Human Genome Research Institute (U54HG006493)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
Joubert syndrome, primary cilia, ciliopathies, protein-protein interaction, hindbrain malformation, neurodevelopmental disorders
MeSH terms
Abnormalities, Multiple, Acetylation, Animals, Cerebellum, Cilia, Disease Models, Animal, Eye Abnormalities, Humans, Peptides, Retina, Zebrafish, Zebrafish Proteins, Armadillo Domain Proteins, Kidney Diseases, Cystic, CRISPR-Cas Systems

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