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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents

ID: 411663.0, MPI für molekulare Genetik / Research Group Development and Disease
Brachydactyly type A2 associated with a defect in proGDF5 processing
Authors:Plöger, Frank; Seemann, Petra; Schmidt-von Kegler, Mareen; Lehmann, Katarina; Seidel, Jörg; Kjaer, Klaus W.; Pohl, Jens; Mundlos, Stefan
Date of Publication (YYYY-MM-DD):2008-01-18
Title of Journal:Human Molecular Genetics
Journal Abbrev.:Hum Mol Genet
Issue / Number:9
Start Page:122
End Page:133
Copyright:© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email:
Review Status:not specified
Audience:Experts Only
Abstract / Description:We investigated a family with a brachydactyly type A2 and identified a heterozygous arginine to glutamine (R380Q) substitution in the growth/differentiation factor 5 (GDF5) in all affected individuals. The observed mutation is located at the processing site of the protein, at which the GDF5 precursor is thought to be cleaved releasing the mature molecule from the prodomain. In order to test the effect of the mutation, we generated the GDF5-R380Q mutant and a cleavage-resistant proGDF5 mutant (R380A/R381A) in vitro. Both mutants were secreted from chicken micromass cultures, but showed diminished biological activity. Western blot analyses showed that wt GDF5 was processed by the chicken micromass cells, whereas the mutants were not, indicating that the mutations interfere with processing and that this leads to a strong reduction of biological activity. To test the requirements for GDF5 processing in vitro we produced recombinant human (rh) proGDF5 wild-type protein in Escherichia coli. The results show that unprocessed (rh) proGDF5 is virtually inactive but can be proteolytically activated by different enzymes such as trypsin, furin, and MMP3. (rh) proGDF5 could thus be used as a locally administered depot form with retarded release of activity. In contrast to mature rhGDF5, (rh) proGDF5 shows a high solubility at physiological pH, a characteristic that might be useful for therapeutic applications.
Comment of the Author/Creator:To whom correspondence should be addressed at: Institut für Medizinische Genetik, Universitätsmedizin Berlin, Charité, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49 30 450 569 121; Fax: +49 30 450 569 915; Email:
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Biopharm GmbH, 69115 Heidelberg, Germany;
2.Institut für Medizinische Genetik, Universitätsmedizin Berlin, Charité, 13353 Berlin, Germany;
3.Klinik für Kinder-und Jugendmedizin, SRH Wald-Klinikum, 07548 Gera, Germany;
4.Wilhelm Johannsen Centre for Functional Genome Research, Institute of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;
5.Berlin Center for Regenerative Therapies (BCRT), 13353 Berlin, Germany.

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