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GDF5 point mutation strikes twice--causing BDA1 and SYNS2

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dc.contributor.author Degenkolbe, Elisa
dc.contributor.author König, Jana
dc.contributor.author Zimmer, Julia
dc.contributor.author Walther, Maria
dc.contributor.author Reißner, Carsten
dc.contributor.author Nickel, Joachim
dc.contributor.author Plöger, Frank
dc.contributor.author Raspopovic, Jelena, 1984-
dc.contributor.author Sharpe, James
dc.contributor.author Dathe, Katarina
dc.contributor.author Hecht, Jacqueline T.
dc.contributor.author Mundlos, Stefan
dc.contributor.author Doelken, Sandra C.
dc.contributor.author Seemann, Petra
dc.date.accessioned 2015-03-17T08:23:59Z
dc.date.available 2015-03-17T08:23:59Z
dc.date.issued 2013
dc.identifier.citation Degenkolbe E, König J, Zimmer J, Walther M, Reißner C, Nickel J et al. GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PLoS Genet. 2013;9(10):e1003846. DOI: 10.1371/journal.pgen.1003846
dc.identifier.issn 1553-7390
dc.identifier.uri http://hdl.handle.net/10230/23204
dc.description.abstract Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5(W414R) variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS Genet. 2013;9(10):e1003846
dc.rights © 2013 Elisa Degenkolbe et al. This is an open-access article distributed under the terms of a Creative Commons Attribution License, which permits/nunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.uri http://creativecommons.org/licenses/by/2.5/
dc.subject.other Artrosi
dc.subject.other Genètica
dc.title GDF5 point mutation strikes twice--causing BDA1 and SYNS2
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1003846
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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