title: KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.
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.
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Anna A W M
authors.initials: AA
authors.lastname: Sanders
authors.affiliation: Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Vrieze
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Fatema
authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham Medical School, Birmingham, AL, 35294, USA.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Malarkey
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University of Mainz, 55122, Mainz, Germany.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Sorusch
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University of Mainz, 55122, Mainz, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tebbe
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kuhns
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Teunis J P
authors.initials: TJ
authors.lastname: van Dam
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Alhashem
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Brahim
authors.initials: B
authors.lastname: Tabarki
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69118, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, 69120, Heidelberg, Germany.
authors.forename: Qianhao
authors.initials: Q
authors.lastname: Lu
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Lambacher
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Kennedy
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Bowie
authors.affiliation: Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Hetterschijt
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: van Beersum
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.affiliation: Institute for Ophthalmic Research and Medical Proteome Center, Centre for Ophthalmology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.affiliation: Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.affiliation: Department of Genetics, University of Alabama at Birmingham Medical School, Birmingham, AL, 35294, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kesterson
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Huynen
authors.affiliation: Institute for Ophthalmic Research and Medical Proteome Center, Centre for Ophthalmology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: CellNetworks, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69118, Heidelberg, Germany.|Biochemie Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, 69120, Heidelberg, Germany.
authors.forename: Rob B
authors.initials: RB
authors.lastname: Russell
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University of Mainz, 55122, Mainz, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham Medical School, Birmingham, AL, 35294, USA.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Yoder
authors.affiliation: Department of Otorhinolaryngology, Radboud University Medical Center, PO Box 9101, 6500, HB, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.|Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands. Erwin.vanWyk@radboudumc.nl.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland. oliver.blacque@ucd.ie.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000818:Animals; D064652:Basal Bodies / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics / Q000473:pathology; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D000074201:Katanin; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D011485:Protein Binding; D012160:Retina / Q000002:abnormalities* / Q000473:pathology
chemical_list: C000608521:KATNIP protein, human; D008869:Microtubule-Associated Proteins; D000251:Adenosine Triphosphatases; D020727:ADP-Ribosylation Factors; C530391:ARL13B protein, human; D000074201:Katanin