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Presenting Author(s) Petra Seemann
Abstract Title Functional analysis of brachydactyly-causing mutations in GDF5 and BMPR1b.
Full author List Petra Seemann 1 , Katarina Lehmann 2 , Gundula Leschik 2 , Georg Schwabe 1 , Sigmar Stricker 1 , & Stefan Mundlos 1,2
Text of abstract

Growth and Differentiation Factor-5 (GDF-5) is a member of the TGF- ß superfamily and plays a key role in early limb development. GDF-5 is expressed during chondrogenesis in the condensing mesenchyme and later, its expression is restricted to the future joint regions. Previous studies showed that GDF-5 is translated as a large precursor protein. The active form of GDF-5 is released proteolytically after specific cleavage at a dibasic consensus site (RXXR). Mature GDF-5 then binds to the Bone Morphogenic Protein Receptor 1B ( BMPR1B ) and thereby activates the SMAD-pathway. In humans, heterozygous mutations in GDF5 and in BMPR1B are known to cause brachydactyly, and homozygous mutations cause more severe disturbances of limb morphogenesis resulting in acromesomelic chondrodysplasias.

We used micromass cultures to perform functional characterisation of mutations in BmpR1b and GDF-5. Our studies revealed that mutations in BMPR1B (I200K; R486W), causing brachydactyly type A2, have a dominant negative effect on early chondrocyte differentiation. This was demonstrated by a drastic reduction of Alcian Blue staining in the micromass culture system. Currently, we are investigating mutations in the prodomain of GDF-5 that we and others recently identified in patients with brachydactyly type C. Our first results show that these GDF5 mutations (M173V, S204R), in contrast to the mutations investigated in BMPR1B, do not have an inhibitory effect on chondrogenesis in the micromass culture system. The N-terminal prodomain of GDF5 is presumed not to be directly involved in GDF-5 signalling. Therefore analysis of these mutations is of particular interest as they lead to the same phenotype in man as do mutations in the signalling domain.
Which session is your work most relevant to: Human limb abnormalities