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  Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN

Seemann, P., Brehm, A., König, J., Reissner, C., Stricker, S., Kuss, P., et al. (2009). Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN. PLoS Genetics, 5(11), e1000747-e1000747. doi:10.1371/journal.pgen.1000747.

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Seemann, Petra1, Autor           
Brehm, Anja2, Autor
König, Jana2, Autor
Reissner, Carsten, Autor
Stricker, Sigmar1, Autor           
Kuss, Pia1, Autor           
Haupt, Julia2, Autor
Renninger, Stephanie1, Autor           
Nickel, Joachim, Autor
Sebald, Walter, Autor
Groppe, Jay C., Autor
Plöger, Frank, Autor
Schmidt-von Kegler, Mareen2, Autor
Walther, Maria1, Autor           
Gassner, Ingmar, Autor
Rusu, Cristina, Autor
Janecke, Andreas R., Autor
Dathe, Katarina, Autor
Mundlos, Stefan1, Autor           
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Max Planck Society, ou_persistent13              

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 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2009-11-26
 Publikationsstatus: Erschienen
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 Ort, Verlag, Ausgabe: -
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Titel: PLoS Genetics
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 5 (11) Artikelnummer: - Start- / Endseite: e1000747 - e1000747 Identifikator: ISSN: 1553-7404