2. Academic Validation
  3. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome

  • Nat Cell Biol. 2016 Jan;18(1):122-31. doi: 10.1038/ncb3273.
Nils J Lambacher 1,  Ange-Line Bruel 2,  Teunis J P van Dam 3,  Katarzyna Szymańska 4,  Gisela G Slaats 5,  Stefanie Kuhns 1,  Gavin J McManus 6,  Julie E Kennedy 1,  Karl Gaff 1,  Ka Man Wu 5,  Robin van der Lee 3,  Lydie Burglen 7 8,  Diane Doummar 7,  Jean-Baptiste Rivière 2 9,  Laurence Faivre 2 9,  Tania Attié-Bitach 10 11 12 13,  Sophie Saunier 10 11 12,  Alistair Curd 14,  Michelle Peckham 14,  Rachel H Giles 5,  Colin A Johnson 4,  Martijn A Huynen 3,  Christel Thauvin-Robinet 2 9,  Oliver E Blacque 1
Affiliations

Affiliations

  • 1 School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
  • 2 EA4271 GAD, Genetics of Development Abnormalities, Burgundy University, 21078 Dijon, France.
  • 3 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands.
  • 4 Section of Ophthalmology and Neurosciences, Leeds Institute of Biomolecular &Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
  • 5 Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
  • 6 School of Biochemistry and Immunology, Microscopy Facility, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
  • 7 Centre de référence des malformations et maladies congénitales du cervelet et Service de Génétique, APHP, Hôpital Trousseau, 75012 Paris, France.
  • 8 INSERM U1141, 75019 Paris, France.
  • 9 FHU TRANSLAD, CHU Dijon, 21079 Dijon, France.
  • 10 INSERM UMR1163, Hôpital Necker-Enfants Malades, 75015 Paris, France.
  • 11 Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
  • 12 Institut IMAGINE, 75015 Paris, France.
  • 13 Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
  • 14 School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
PMID: 26595381 DOI: 10.1038/ncb3273
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.

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