title: TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome.
abstract: The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral-facial-digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Lambacher
authors.affiliation: EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France.
authors.forename: Ange-Line
authors.initials: AL
authors.lastname: Bruel
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands.
authors.forename: Teunis J P
authors.initials: TJ
authors.lastname: van Dam
authors.affiliation: Section of Ophthalmology and Neurosciences, Leeds Institute of Biomolecular &Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymańska
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Gisela G
authors.initials: GG
authors.lastname: Slaats
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kuhns
authors.affiliation: School of Biochemistry and Immunology, Microscopy Facility, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: McManus
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, 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, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Karl
authors.initials: K
authors.lastname: Gaff
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Ka Man
authors.initials: KM
authors.lastname: Wu
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: van der Lee
authors.affiliation: Centre de référence des malformations et maladies congénitales du cervelet et Service de Génétique, APHP, Hôpital Trousseau, 75012 Paris, France.|INSERM U1141, 75019 Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.affiliation: Centre de référence des malformations et maladies congénitales du cervelet et Service de Génétique, APHP, Hôpital Trousseau, 75012 Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.affiliation: EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France.|FHU TRANSLAD, CHU Dijon, 21079 Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France.|FHU TRANSLAD, CHU Dijon, 21079 Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: INSERM UMR1163, Hôpital Necker-Enfants Malades, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.|Institut IMAGINE, 75015 Paris, France.|Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.affiliation: INSERM UMR1163, Hôpital Necker-Enfants Malades, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.|Institut IMAGINE, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Curd
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Michelle
authors.identifier: http://orcid.org/0000-0002-3754-2028
authors.initials: M
authors.lastname: Peckham
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Rachel H
authors.identifier: http://orcid.org/0000-0001-9133-2008
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Section of Ophthalmology and Neurosciences, Leeds Institute of Biomolecular &Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.affiliation: EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France.|FHU TRANSLAD, CHU Dijon, 21079 Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002531:Cerebellum / Q000002:abnormalities* / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000002:abnormalities* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; C575829:Tmem107 protein, mouse