2. Academic Validation
  3. Hypomorphic mutations of TRIP11 cause odontochondrodysplasia

Hypomorphic mutations of TRIP11 cause odontochondrodysplasia

  • JCI Insight. 2019 Feb 7;4(3):e124701. doi: 10.1172/jci.insight.124701.
Anika Wehrle 1,  Tomasz M Witkos 2,  Sheila Unger 3,  Judith Schneider 1,  John A Follit 4,  Johannes Hermann 1,  Tim Welting 5,  Virginia Fano 6,  Marja Hietala 7,  Nithiwat Vatanavicharn 8,  Katharina Schoner 9,  Jürgen Spranger 1,  Miriam Schmidts 1,  Bernhard Zabel 1,  Gregory J Pazour 4,  Agnes Bloch-Zupan 10 11 12 13,  Gen Nishimura 14,  Andrea Superti-Furga 3,  Martin Lowe 2,  Ekkehart Lausch 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 2 Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
  • 3 Division of Genetic Medicine, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • 4 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • 5 Laboratory for Experimental Orthopedics, Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands.
  • 6 Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina.
  • 7 Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
  • 8 Department of Paediatrics, Mahidol University, Bangkok, Thailand.
  • 9 Institute of Pathology, Philipps-University Marburg, Marburg, Germany.
  • 10 Centre de Référence des Manifestations Odontologiques des Maladies Rares, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France.
  • 11 Université de Strasbourg, Faculté de Chirurgie Dentaire, Institute of Advanced Studies, USIAS, Strasbourg, France.
  • 12 HUS, Pôle de Médecine et Chirurgie Bucco-dentaires Hôpital Civil, Centre de référence des maladies rares orales et dentaires, O-Rares, Filière Santé Maladies rares TETE COU, European Reference Network ERN CRANIO, Strasbourg, France.
  • 13 Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CERBM, INSERM U1258, CNRS- UMR7104, Illkirch, France.
  • 14 Department of Radiology and Medical Imaging, Tokyo Metropolitan Kiyose Children's Hospital, Kiyose, Japan.
PMID: 30728324 DOI: 10.1172/jci.insight.124701
Abstract

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

Keywords

Bone Biology; Bone development; Genetics; Molecular pathology; Protein traffic.

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