title: Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN.
abstract: 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.
authors: Research Group Development and Disease, Max-Planck-Institut für Molekulare Genetik, Berlin, Germany. petra.seemann@charite.de
authors: Petra
authors: P
authors: Seemann
authors: Anja
authors: A
authors: Brehm
authors: Jana
authors: J
authors: König
authors: Carsten
authors: C
authors: Reissner
authors: Sigmar
authors: S
authors: Stricker
authors: Pia
authors: P
authors: Kuss
authors: Julia
authors: J
authors: Haupt
authors: Stephanie
authors: S
authors: Renninger
authors: Joachim
authors: J
authors: Nickel
authors: Walter
authors: W
authors: Sebald
authors: Jay C
authors: JC
authors: Groppe
authors: Frank
authors: F
authors: Plöger
authors: Jens
authors: J
authors: Pohl
authors: Mareen
authors: M
authors: Schmidt-von Kegler
authors: Maria
authors: M
authors: Walther
authors: Ingmar
authors: I
authors: Gassner
authors: Cristina
authors: C
authors: Rusu
authors: Andreas R
authors: AR
authors: Janecke
authors: Katarina
authors: K
authors: Dathe
authors: Stefan
authors: S
authors: Mundlos
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000502:physiology*; D002356:Cartilage; D002478:Cells, Cultured; D002645:Chickens; D025461:Feedback, Physiological; D055428:Growth Differentiation Factor 5 / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation; D013580:Synostosis / Q000235:genetics; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D055428:Growth Differentiation Factor 5; D000099176:Noggin Protein; C525893:GDF5 protein, human