| Project 12 |
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Analysis of genetic mutations in the BMP signaling pathway and translation of BMP variants into therapeutic applicationsProf. Seemann (first supervisor), Prof. Mundlos (secon supervisor); Charité and Max Planck Institute for molecular Genetics This project aims to characterize specific point mutations within the genes of the Bone Morphogenetic Protein (BMP) pathway associated with distinct skeletal malformations. The genotype-phenotype correlations in combination with functional analyses yield important information on the inherited disease and the function of the proteins. In the past we could identify several distinct point mutations in the Growth and Differentiation Factor 5 (GDF5), its receptor (BMPR1B) and its antagonist (NOGGIN) that are associated with different hand malformations. Functional studies revealed that certain GDF5 variants have profoundly different biological activities. For example, by the alteration of just one amino acid of GDF5 (R380Q, R438L, L441P, N445T) it is possible to generate growth factors with distinct activity profiles on various biological readouts when compared to wild-type GDF5. The treatment of pre-myoblastic cells (C2C12) with wild-type GDF5 leads to an inhibition of myogenesis, whereas e.g. the L441P mutant leads to enhanced muscle cell differentiation. In contrast, the R438L mutant showed an enhanced osteoblastic differentiation potential in comparison to wild-type GDF5. We will take advantage of the new characteristics of these GDF5 variants and make use of them for potential clinical applications in the field of regenerative medicine. Dathe K, Kjaer KW, Brehm A, Meinecke P, Nürnberg P, Neto JC, Brunoni D, Tommerup N, Ott CE, Klopocki E, Seemann P, Mundlos S. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet. 2009 Apr;84(4):483-92. Plöger F, Seemann P, Schmidt-von Kegler M, Lehmann K, Seidel J, Kjaer KW, Pohl J, Mundlos S. Brachydactyly type A2 associated with a defect in proGDF5 processing. Hum Mol Genet. 2008 May 1;17(9):1222-33. Lehmann K, Seemann P, Silan F, Goecke TO, Irgang S, Kjaer KW, Kjaergaard S, Mahoney MJ, Morlot S, Reissner C, Kerr B, Wilkie AO, Mundlos S. A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic |
