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Title: Hypomorphic mutations of TRIP11 cause odontochondrodysplasia
Authors: Anika Wehrle
Tomasz M. Witkos
Sheila Unger
Judith Schneider
John A. Follit
Johannes Hermann
Tim Welting
Virginia Fano
Marja Hietala
Nithiwat Vatanavicharn
Katharina Schoner
Jürgen Spranger
Miriam Schmidts
Bernhard Zabel
Gregory J. Pazour
Agnes Bloch-Zupan
Gen Nishimura
Andrea Superti-Furga
Martin Lowe
Ekkehart Lausch
Université de Strasbourg
Universität Freiburg im Breisgau
Centre Hospitalier Universitaire Vaudois
Maastricht University
Hopital Civil
Mahidol University
Philipps-Universität Marburg
CHU Strasbourg
Turun yliopisto
University of Manchester
Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan
University of Massachusetts Medical School
Tokyo Metropolitan Kiyose Children’s Hospital
Keywords: Medicine
Issue Date: 7-Feb-2019
Citation: JCI Insight. Vol.4, No.3 (2019)
Abstract: © Copyright 2019, American Society for Clinical Investigation. 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.
ISSN: 23793708
Appears in Collections:Scopus 2019

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