| http://purl.uniprot.org/citations/30685387 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/30685387 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundMutations in the SLC26A2 gene cause a spectrum of currently incurable human chondrodysplasias. However, genotype-phenotype relationships of SLC26A2-deficient chondrodysplasias are still perplexing and thus stunt therapeutic development.MethodsTo investigate the causative role of SLC26A2 deficiency in chondrodysplasias and confirm its skeleton-specific pathology, we generated and analyzed slc26a2-/- and Col2a1-Cre; slc26a2fl/fl mice. The therapeutic effect of NVP-BGJ398, an FGFR inhibitor, was tested with both explant cultures and timed pregnant females.FindingsTwo lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2-/- mice. Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2-/- chondrocytes. Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2-/- cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2-/- newborns. Finally, we confirm the skeleton-specific lethality and pathology of global SLC26A2 deletion through analyzing the Col2a1-Cre; slc26a2fl/fl mouse line.InterpretationOur study unveils a previously unrecognized pathogenic mechanism underlying ACG1B and AO2, and supports suppression of FGFR3 signaling as a promising therapeutic approach for SLC26A2-related chondrodysplasias. FUND: This work was supported by National Natural Science Foundation of China (81871743, 81730065 and 81772377)."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.ebiom.2019.01.010"xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Fan J."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Hu Y."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Lu W."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Gao B."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Lin X."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Luo Z."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Wang C."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Zhou J."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Xu X."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Yang L."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Zheng C."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/author | "Jie Q."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/date | "2019"xsd:gYear |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/name | "EBioMedicine"xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/pages | "695-709"xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/title | "Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias."xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://purl.uniprot.org/core/volume | "40"xsd:string |
| http://purl.uniprot.org/citations/30685387 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/30685387 |
| http://purl.uniprot.org/citations/30685387 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/30685387 |
| http://purl.uniprot.org/uniprot/#_A0A0A6YVW7-mappedCitation-30685387 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/30685387 |
| http://purl.uniprot.org/uniprot/#_A0A0A6YVX7-mappedCitation-30685387 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/30685387 |
| http://purl.uniprot.org/uniprot/#_A0A0A6YWC4-mappedCitation-30685387 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/30685387 |