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Schlagwörter:
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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.