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

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

Latour BL¹ ; Van De Weghe JC² ; Rusterholz TDS^{3, 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

Latour BL¹
Van De Weghe JC²
Rusterholz TDS^{3, 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
Miller CV²
Dempsey JC²
Morsy H⁹
Bamshad MJ^{2, 10, 11}
Nickerson DA¹⁰
Neuhauss SCF⁴
Boldt K¹²
Ueffing M¹²
Keramatipour M⁶
Sayer JA⁷
Alkuraya FS^{5, 13}
Bachmanngagescu R^{3, 4}
Roepman R¹
Doherty D^{2, 14}

Show Affiliations

1. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
2. Department of Pediatrics, University of Washington, Seattle, WA, United States
3. Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
4. Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
5. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
6. Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
7. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
8. Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
9. Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
10. University of Washington Center for Mendelian Genomics, Seattle, WA, United States
11. Department of Genome Sciences, University of Washington, Seattle, WA, United States
12. Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany
13. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
14. Center for Integrative Brain Research, Seattle Childrenâ€™s Research Institute, Seattle, WA, United States

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.

2. Identification of a Novel Truncating Variant in Ahi1 Gene and a Brief Review on Mutations Spectrum, Molecular Biology Reports (2021)

3. Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia, American Journal of Human Genetics (2024)

4. Whole-Genome Sequencing Reveals Host Factors Underlying Critical Covid-19, Nature (2022)

5. Novel Variants Broaden the Phenotypic Spectrum of Plekhg5-Associated Neuropathies, European Journal of Neurology (2021)

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Style	Citing Format
MLA	Latour BL, et al.. "Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome." Journal of Clinical Investigation, vol. 140, no. 8, 2020, pp. 4423-4439.
APA	Latour BL, Van De Weghe JC, Rusterholz TDS, Letteboer SJF, Gomez A, Shaheen R, Gesemann M, Karamzade A, Asadollahi M, Barrosogil M, Chitre M, Grout ME, Van Reeuwijk J, Van Beersum SEC, Miller CV, Dempsey JC, Morsy H, Bamshad MJ, Nickerson DA, ... Doherty D (2020). Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome. Journal of Clinical Investigation, 140(8), 4423-4439.
Chicago	Latour BL, Van De Weghe JC, Rusterholz TDS, Letteboer SJF, Gomez A, Shaheen R, Gesemann M, et al.. "Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome." Journal of Clinical Investigation 140, no. 8 (2020): 4423-4439.
Harvard	Latour BL et al. (2020) 'Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome', Journal of Clinical Investigation, 140(8), pp. 4423-4439.
Vancouver	Latour BL, Van De Weghe JC, Rusterholz TDS, Letteboer SJF, Gomez A, Shaheen R, et al.. Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome. Journal of Clinical Investigation. 2020;140(8):4423-4439.
BibTex	@article{ author = {Latour BL and Van De Weghe JC and Rusterholz TDS and Letteboer SJF and Gomez A and Shaheen R and Gesemann M and Karamzade A and Asadollahi M and Barrosogil M and Chitre M and Grout ME and Van Reeuwijk J and Van Beersum SEC and Miller CV and Dempsey JC and Morsy H and Bamshad MJ and Nickerson DA and Neuhauss SCF and Boldt K and Ueffing M and Keramatipour M and Sayer JA and Alkuraya FS and Bachmanngagescu R and Roepman R and Doherty D}, title = {Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome}, journal = {Journal of Clinical Investigation}, volume = {140}, number = {8}, pages = {4423-4439}, year = {2020} }
RIS	TY - JOUR AU - Latour BL AU - Van De Weghe JC AU - Rusterholz TDS AU - Letteboer SJF AU - Gomez A AU - Shaheen R AU - Gesemann M AU - Karamzade A AU - Asadollahi M AU - Barrosogil M AU - Chitre M AU - Grout ME AU - Van Reeuwijk J AU - Van Beersum SEC AU - Miller CV AU - Dempsey JC AU - Morsy H AU - Bamshad MJ AU - Nickerson DA AU - Neuhauss SCF AU - Boldt K AU - Ueffing M AU - Keramatipour M AU - Sayer JA AU - Alkuraya FS AU - Bachmanngagescu R AU - Roepman R AU - Doherty D TI - Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome JO - Journal of Clinical Investigation VL - 140 IS - 8 SP - 4423 EP - 4439 PY - 2020 ER -

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