title: Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe.
abstract: Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T>C, p.(C53R)) or nonsense (c.657G>A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G>A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A loss-of-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.
authors.affiliation: Ambulantes Gesundheitszentrum der Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Luitgard M
authors.initials: LM
authors.lastname: Graul-Neumann
authors.affiliation: 1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Deichsel
authors.affiliation: 1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille
authors.affiliation: 1] Institute of Human Genetics, University of Ulm, Ulm, Germany [2] Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan.
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Randi
authors.initials: R
authors.lastname: Koll
authors.affiliation: Pediatric Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bassir
authors.affiliation: Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan.
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.affiliation: Department of Genetics, Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hopital Necker-Enfants Malades, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: 1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Guntram
authors.identifier: 0000000322798052
authors.initials: G
authors.lastname: Borck
authors.affiliation: 1] Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Institute for Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.affiliation: Julius-von-Sachs Institute, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Mueller
authors.affiliation: Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Doelken
authors.affiliation: 1] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009139:Musculoskeletal Abnormalities / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I