Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.

Details

Serval ID
serval:BIB_FFBC7D52BB3D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.
Journal
JCI insight
Author(s)
Wehrle A., Witkos T.M., Unger S., Schneider J., Follit J.A., Hermann J., Welting T., Fano V., Hietala M., Vatanavicharn N., Schoner K., Spranger J., Schmidts M., Zabel B., Pazour G.J., Bloch-Zupan A., Nishimura G., Superti-Furga A., Lowe M., Lausch E.
ISSN
2379-3708 (Electronic)
ISSN-L
2379-3708
Publication state
Published
Issued date
07/02/2019
Peer-reviewed
Oui
Volume
4
Number
3
Pages
e124701
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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
Pubmed
Web of science
Open Access
Yes
Create date
25/02/2019 18:10
Last modification date
20/12/2019 7:21
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