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Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2
Petra Seemann, … , Petra Knaus, Stefan Mundlos
Petra Seemann, … , Petra Knaus, Stefan Mundlos
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2373-2381. https://doi.org/10.1172/JCI25118.
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Research Article Genetics

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2

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Abstract

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.

Authors

Petra Seemann, Raphaela Schwappacher, Klaus W. Kjaer, Deborah Krakow, Katarina Lehmann, Katherine Dawson, Sigmar Stricker, Jens Pohl, Frank Plöger, Eike Staub, Joachim Nickel, Walter Sebald, Petra Knaus, Stefan Mundlos

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Figure 2

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Protein sequence alignment of GDF5 homologs and 3D models for GDF5 recep...
Protein sequence alignment of GDF5 homologs and 3D models for GDF5 receptor binding. (A) Primary sequence alignment of GDF5, BMP2, and BMP4 from different species, including drosophila DPP. The positions of R438L and L441P mutations in GDF5 are indicated by arrows. Note the widespread conservation of residue L441 in BMPs and the specificity of R438 conservation for the GDF5 subfamily (replaced by A in the BMPs). (B) 3D model of a BMP2 dimer (yellow and gold) linked via a disulfide bridge and bound to the ectodomain of BMPR1A (BMPR1Aec). The amino acids mutated in GDF5 are indicated in red (L441) and green (R438). Note their position within the receptor interaction site. (C) Predicted structure of a GDF5 monomer. The positions of the mutated amino acids are indicated in red (L441) and green (R438).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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