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Lookup NU author(s): Silvia Lecci, Dr Beth Gibson, Dr Katarzyna PirogORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.
Author(s): Paganini C, Monti L, Costantini R, Besio R, Lecci S, Biggiogera M, Tian K, Schwartz JM, Huber C, Cormier-Daire V, Gibson BG, Pirog KA, Forlino A, Rossi A
Publication type: Article
Publication status: Published
Journal: Matrix Biology
Year: 2019
Volume: 81
Pages: 70-90
Print publication date: 01/08/2019
Online publication date: 12/11/2018
Acceptance date: 05/11/2018
Date deposited: 20/11/2018
ISSN (print): 0945-053X
ISSN (electronic): 1569-1802
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.matbio.2018.11.002
DOI: 10.1016/j.matbio.2018.11.002
PubMed id: 30439444
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