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Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C.

Authors: Stange, Katja  Thieme, Tino  Hertel, Karen  Kuhfahl, Silke  Janecke, Andreas R  Piza-Katzer, Hildegunde  Penttinen, Maila  Hietala, Marja  Dathe, Katarina  Mundlos, Stefan  Schwarz, Elisabeth  Seemann, Petra 
Citation: Stange K, etal., J Mol Biol. 2014 Sep 23;426(19):3221-31. doi: 10.1016/j.jmb.2014.07.029. Epub 2014 Aug 1.
Pubmed: (View Article at PubMed) PMID:25092592
DOI: Full-text: DOI:10.1016/j.jmb.2014.07.029

Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. We identified two families with a heterozygosity for the novel missense mutations p.T201P or p.L263P located in the proregion of GDF5. The patients presented with dominant brachydactyly type C characterized by the shortening of skeletal elements in the distal extremities. Both mutations gave rise to decreased biological activity in in vitro analyses. The variants reduced the GDF5-induced activation of SMAD signaling by the GDF5 receptors BMPR1A and BMPR1B. Ectopic expression in micromass cultures yielded relatively low protein levels of the variants and showed diminished chondrogenic activity as compared to wild-type GDF5. Interestingly, stimulation of micromass cells with recombinant human proGDF5(T201P) and proGDF5(L263P) revealed their reduced chondrogenic potential compared to the wild-type protein. Limited proteolysis of the mutant recombinant proproteins resulted in a fragment pattern profoundly different from wild-type proGDF5. Modeling of a part of the GDF5 proregion into the known three-dimensional structure of TGFß1 latency-associated peptide revealed that the homologous positions of both mutations are conserved regions that may be important for the folding of the mature protein or the assembly of dimeric protein complexes. We hypothesize that the missense mutations p.T201P and p.L263P interfere with the protein structure and thereby reduce the amount of fully processed, biologically active GDF5, finally causing the clinical loss of function phenotype.


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RGD Object Information
RGD ID: 12738200
Created: 2017-01-30
Species: All species
Last Modified: 2017-01-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.