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



  history
ID: 456439.0, MPI für molekulare Genetik / Research Group Development and Disease
Mutations in GDF5 reveal a key residue mediating BMP
inhibition by NOGGIN
Authors:Seemann, Petra; Brehm, Anja; König, Jana; Reissner, Carsten; Stricker, Sigmar; Kuss, Pia; Haupt, Julia; Renninger, Stephanie; Nickel, Joachim; Sebald, Walter; Groppe, Jay C.; Plöger, Frank; Schmidt-von Kegler, Mareen; Walther, Maria; Gassner, Ingmar; Rusu, Cristina; Janecke, Andreas R.; Dathe, Katarina; Mundlos, Stefan
Language:English
Date of Publication (YYYY-MM-DD):2009-11-26
Title of Journal:PLoS Genetics
Volume:5
Issue / Number:11
Start Page:e1000747
End Page:e1000747
Copyright:© 2009 Seemann et al
Review Status:not specified
Audience:Experts Only
Abstract / Description:Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with
heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We
identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5.
Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to
the BMP–inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and
antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is
substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity.
Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model
presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site
alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions
imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal
joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.
Comment of the Author/Creator:Email: petra.seemann@charite.de
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Berlin-Brandenburg Center for Regenerative Therapies,
Charité – Universitätsmedizin Berlin, Berlin, Germany
Institut für Medizinische Genetik, Charité – Universitätsmedizin Berlin, Berlin, Germany
Freie Universität Berlin, Berlin, Germany
Institute of Anatomy, Department of Anatomy and Molecular Neurobiology, Universitätsklinikum Münster, Münster, Germany
Lehrstuhl für Physiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, Würzburg, Germany
Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M University System Health Science Center, Dallas, Texas, United States of America
Biopharm GmbH, Heidelberg, Germany
Department für Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck, Innsbruck, Austria
Medical Genetics Department, University of Medicine
and Pharmacy, Ias¸i, Romania
Sektion für Klinische Genetik, Medizinische Universität Innsbruck, Innsbruck, Austria
Identifiers:DOI:10.1371/journal.pgen.1000747
ISSN:1553-7404
URL:http://www.plosgenetics.org/article/fetchObjectAtt...
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