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          Institute: MPI für molekulare Genetik     Collection: Department of Computational Molecular Biology     Display Documents

ID: 268509.0, MPI für molekulare Genetik / Department of Computational Molecular Biology
Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2
Authors:Seemann, Petra; Schwappacher, Raphaela; Kjaer, Klaus W.; Krakow, Deborah; Lehmann, Katarina; Dawson, Katherine; Stricker, Sigmar; Pohl, Jens; Ploeger, Frank; Staub, Eike; Nickel, Joachim; Sebald, Walter; Knaus, Petra; Mundlos, Stefan
Date of Publication (YYYY-MM-DD):2005-06-21
Title of Journal:Journal of Clinical Investigation
Journal Abbrev.:J. Clin. Invest
Issue / Number:9
Start Page:2373
End Page:2381
Copyright:© 2005 by the American Society for Clinical Investigation.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Martin Vingron
Affiliations:MPI für molekulare Genetik
External Affiliations:Institut für Medizinische Genetik, Charité, Universitätsmedizin Berlin, Berlin, Germany,
Institut für Chemie-Biochemie, Freie Universität Berlin, Berlin, Germany,
Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, Denmark,
Department of Obstetrics and Gynecology, Cedars-Sinai Research Institute, Los Angeles, California, USA,
Biopharm GmbH, Heidelberg, Germany.
7Institut für Physiologische Chemie II, Biozentrum, Universität Würzburg, Würzburg, Germany.
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