A GDF 5 Point Mutation Strikes Twice-Causing BDA 1 and SYNS 2

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 variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gainand 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. Citation: Degenkolbe E, König J, Zimmer J, Walther M, Reißner C, et al. (2013) A GDF5 Point Mutation Strikes Twice Causing BDA1 and SYNS2. PLoS Genet 9(10): e1003846. doi:10.1371/journal.pgen.1003846 Editor: Gregory S. Barsh, Stanford University School of Medicine, United States of America Received March 12, 2013; Accepted August 12, 2013; Published October 3, 2013 Copyright: 2013 Degenkolbe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Deutsche Forschungsgemeinschaft [SE 1778/1-1 to PS and SFB760-A2 to PS and SM] and the Bundesministerium für Bildung und Forschung [Biochance plus3; 0313851A/B to FP and SM]. Contributions were made possible by DFG funding through the Berlin-Brandenburg School for Regenerative Therapies GSC 203 [ED, JK, JZ] and by FCT-Fundação para a Ciência e a Tecnologia [JR]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Frank Plöger is an employee of the company Biopharm GmbH as indicated in the affiliation. Biopharm GmbH is a 100% privately owned company. All other authors have declared that no competing interests exist. * E-mail: petra.seemann@charite.de . These authors contributed equally to this work. ¤a Current address: Roche Diagnostics International AG, Rotkreuz, Switzerland. ¤b Current address: Section of Clinical Allergology, Paul-Ehrlich-Institut Federal Institute for Vaccines and Biomedicines, Langen, Germany.

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