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Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome Publisher Pubmed



Latour BL1 ; Van De Weghe JC2 ; Rusterholz TDS3, 4 ; Letteboer SJF1 ; Gomez A2 ; Shaheen R5 ; Gesemann M4 ; Karamzade A6 ; Asadollahi M6 ; Barrosogil M7 ; Chitre M8 ; Grout ME2 ; Van Reeuwijk J1 ; Van Beersum SEC1 Show All Authors
Authors
  1. Latour BL1
  2. Van De Weghe JC2
  3. Rusterholz TDS3, 4
  4. Letteboer SJF1
  5. Gomez A2
  6. Shaheen R5
  7. Gesemann M4
  8. Karamzade A6
  9. Asadollahi M6
  10. Barrosogil M7
  11. Chitre M8
  12. Grout ME2
  13. Van Reeuwijk J1
  14. Van Beersum SEC1
  15. Miller CV2
  16. Dempsey JC2
  17. Morsy H9
  18. Bamshad MJ2, 10, 11
  19. Nickerson DA10
  20. Neuhauss SCF4
  21. Boldt K12
  22. Ueffing M12
  23. Keramatipour M6
  24. Sayer JA7
  25. Alkuraya FS5, 13
  26. Bachmanngagescu R3, 4
  27. Roepman R1
  28. Doherty D2, 14

Source: Journal of Clinical Investigation Published:2020


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. Copyright: © 2020, American Society for Clinical Investigation.