@article{DegenkolbeKoenigZimmeretal.2013,
  author    = {Degenkolbe, Elisa and K{\"o}nig, Jana and Zimmer, Julia and Walther, Maria and Reißner, Carsten and Nickel, Joachim and Pl{\"o}ger, Frank and Raspopovic, Jelena and Sharpe, James and Dathe, Katharina and Hecht, Jacqueline T. and Mundlos, Stefan and Doelken, Sandra C. and Seemann, Petra},
  title     = {A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2},
  series = {PLOS Genetics},
  volume    = {9},
  journal   = {PLOS Genetics},
  number    = {10},
  issn      = {1553-7404},
  doi       = {10.1371/journal.pgen.1003846},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127556},
  pages     = {e1003846},
  year      = {2013},
  abstract  = {Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5 W-414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain-and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.},
  language  = {en}
}
@article{StangeDesirKakaretal.2015,
  author    = {Stange, Katja and D{\´e}sir, Julie and Kakar, Naseebullah and Mueller, Thomas D. and Budde, Birgit S. and Gordon, Christopher T. and Horn, Denise and Seemann, Petra and Borck, Guntram},
  title     = {A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {10},
  journal   = {Orphanet Journal of Rare Diseases},
  number    = {84},
  doi       = {10.1186/s13023-015-0299-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151650},
  year      = {2015},
  abstract  = {Background: Grebe dysplasia, Hunter-Thompson dysplasia, and du Pan dysplasia constitute a spectrum of skeletal dysplasias inherited as an autosomal recessive trait characterized by short stature, severe acromesomelic shortening of the limbs, and normal axial skeleton. The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5. In single instances, Grebe dysplasia and a Grebe dysplasia-like phenotype with genital anomalies have been shown to be caused by mutations in BMPR1B, encoding a GDF5 receptor. Methods: We clinically and radiologically characterised an acromesomelic chondrodysplasia in an adult woman born to consanguineous parents. We sequenced GDF5 and BMPR1B on DNA of the proposita. We performed 3D structural analysis and luciferase reporter assays to functionally investigate the identified BMPR1B mutation. Results: We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation. We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia. Conclusions: The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B.},
  language  = {en}
}