KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome

Genome Biol. 2015 Dec 29;16:293. doi: 10.1186/s13059-015-0858-z.

Anna A W M Sanders ¹, Erik de Vrieze ² ³, Anas M Alazami ⁴, Fatema Alzahrani ⁴, Erik B Malarkey ⁵, Nasrin Sorusch ⁶, Lars Tebbe ⁶, Stefanie Kuhns ¹, Teunis J P van Dam ⁷, Amal Alhashem ⁸, Brahim Tabarki ⁸, Qianhao Lu ⁹ ¹⁰, Nils J Lambacher ¹, Julie E Kennedy ¹, Rachel V Bowie ¹, Lisette Hetterschijt ² ³, Sylvia van Beersum ³ ¹¹, Jeroen van Reeuwijk ³ ¹¹, Karsten Boldt ¹², Hannie Kremer ² ³ ¹¹, Robert A Kesterson ¹³, Dorota Monies ⁴, Mohamed Abouelhoda ⁴, Ronald Roepman ³ ¹¹, Martijn H Huynen ⁷, Marius Ueffing ¹², Rob B Russell ⁹ ¹⁰, Uwe Wolfrum ⁶, Bradley K Yoder ⁵, Erwin van Wijk ¹⁴ ¹⁵, Fowzan S Alkuraya ¹⁶ ¹⁷, Oliver E Blacque ¹⁸

Affiliations

1 School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
2 Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
3 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
4 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
5 Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham Medical School, Birmingham, AL, 35294, USA.
6 Cell and Matrix Biology, Institute of Zoology, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University of Mainz, 55122, Mainz, Germany.
7 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
8 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
9 CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69118, Heidelberg, Germany.
10 Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, 69120, Heidelberg, Germany.
11 Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
12 Institute for Ophthalmic Research and Medical Proteome Center, Centre for Ophthalmology, Eberhard Karls University, Tuebingen, Germany.
13 Department of Genetics, University of Alabama at Birmingham Medical School, Birmingham, AL, 35294, USA.
14 Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.
15 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.
16 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
17 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
18 School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland. oliver.blacque@ucd.ie.

PMID: 26714646 DOI: 10.1186/s13059-015-0858-z

Abstract

Background: Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures.

Results: Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing Enzyme complex that regulates microtubule dynamics as well as ciliary functions.

Conclusions: We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation.

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