| http://purl.uniprot.org/citations/21976273 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/21976273 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/21976273 | http://www.w3.org/2000/01/rdf-schema#comment | "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism. Here we present a novel molecular mechanism of a GDF5 mutation affecting chondrogenesis and osteogenesis. GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells. Surprisingly, chondrogenesis in mouse micromass cultures was strongly enhanced by GDF5-S94N. By using quantitative techniques (SPR, reporter gene assay, ALP assay, qPCR), we uncovered that this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition. Thus, since noggin is upregulated during chondrogenic differentiation, GDF5-S94N exceeds the GDF5 action, which results in the phenotypic outcome of SYNS. The detailed molecular characterization of GDF5-S94N as a noggin-resistant growth factor illustrates the potential of GDF5 mutants in applications with defined therapeutical needs."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.org/dc/terms/identifier | "doi:10.1002/jbmr.532"xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.org/dc/terms/identifier | "doi:10.1002/jbmr.532"xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Mueller T."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Mueller T."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Sebald W."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Sebald W."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Schrewe H."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Schrewe H."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Knaus P."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Knaus P."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Nickel J."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Nickel J."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Hiepen C."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Hiepen C."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Ploeger F."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Ploeger F."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Schwaerzer G.K."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/author | "Schwaerzer G.K."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/date | "2012"xsd:gYear |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/date | "2012"xsd:gYear |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/name | "J. Bone Miner. Res."xsd:string |
| http://purl.uniprot.org/citations/21976273 | http://purl.uniprot.org/core/name | "J. Bone Miner. Res."xsd:string |