title: A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia.
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.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Stange
authors.affiliation: Institut de Pathologie et de Génétique, 6041, Gosselies, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Désir
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081, Ulm, Germany.
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.affiliation: Julius-von-Sachs Institute, University of Würzburg, 97082, Würzburg, Germany.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Mueller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Budde
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris, 75015, France.|Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, 75015, France.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.affiliation: Institute of Human Genetics, University of Ulm, 89081, Ulm, Germany. guntram.borck@uni-ulm.de.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D004392:Dwarfism / Q000209:etiology / Q000235:genetics*; D005260:Female; D055428:Growth Differentiation Factor 5 / Q000235:genetics; D006801:Humans; D009154:Mutation; D010009:Osteochondrodysplasias / Q000209:etiology / Q000235:genetics*; D010641:Phenotype
chemical_list: C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I