Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome
Open Access
- 3 August 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (8), 4423-4439
- https://doi.org/10.1172/jci131656
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 whose dysfunction underlies JBTS. In addition to known JBTS-associated proteins CEP104 and CSPP1, we identify CCDC66 and TOGARAM1 as ARMC9 interaction partners. We show that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 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 polyglutamylation, but relatively intact transition zone function. Aberrant cold- and serum-induced ciliary loss in both ARMC9 and TOGARAM1 patient cell lines suggests a role for this new JBTS-associated protein module in ciliary stability.Funding Information
- 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)
- Swiss National Science Foundation SNF (31003A_173083)
- NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091 Genetics Core and sub-project 6849)
- NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32 HD095599)
- NIH National Human Genome Research Institute (U54HG006493)
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