UMMS Affiliation

Program in Molecular Medicine

Publication Date

2019-02-07

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Cells | Developmental Biology | Genetic Phenomena | Genetics and Genomics | Molecular Biology | Musculoskeletal Diseases | Musculoskeletal System

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

Rights and Permissions

Copyright © 2019 Wehrle et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1172/jci.insight.124701

Source

JCI Insight. 2019 Feb 7;4(3). pii: 124701. doi: 10.1172/jci.insight.124701. [Epub ahead of print] Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

30728324

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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