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

Autor: Latour BL; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Van De Weghe JC; Department of Pediatrics, University of Washington, Seattle, Washington, USA., Rusterholz TD; Institute of Medical Genetics, and.; Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland., Letteboer SJ; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Gomez A; Department of Pediatrics, University of Washington, Seattle, Washington, USA., Shaheen R; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Gesemann M; Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland., Karamzade A; Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Asadollahi M; Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Barroso-Gil M; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom., Chitre M; Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom., Grout ME; Department of Pediatrics, University of Washington, Seattle, Washington, USA., van Reeuwijk J; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., van Beersum SE; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Miller CV; Department of Pediatrics, University of Washington, Seattle, Washington, USA., Dempsey JC; Department of Pediatrics, University of Washington, Seattle, Washington, USA., Morsy H; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt., Bamshad MJ; Department of Pediatrics, University of Washington, Seattle, Washington, USA.; The University of Washington Center for Mendelian Genomics is detailed in Supplemental Acknowledgments.; University of Washington Center for Mendelian Genomics, Seattle, Washington, USA.; Department of Genome Sciences, University of Washington, Seattle, Washington, USA., Nickerson DA; The University of Washington Center for Mendelian Genomics is detailed in Supplemental Acknowledgments.; University of Washington Center for Mendelian Genomics, Seattle, Washington, USA., Neuhauss SC; Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland., Boldt K; Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany., Ueffing M; Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany., Keramatipour M; Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Sayer JA; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Bachmann-Gagescu R; Institute of Medical Genetics, and.; Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland., Roepman R; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Doherty D; Department of Pediatrics, University of Washington, Seattle, Washington, USA.; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2020 Aug 03; Vol. 130 (8), pp. 4423-4439.
DOI: 10.1172/JCI131656
Abstrakt: 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.
Databáze: MEDLINE