title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
abstract: Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.
authors.affiliation: Institut für Medizinische Genetik, Humboldt-Universität, Charité, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lehmann
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Marai
authors.initials: M
authors.lastname: Sammar
authors.forename: Birgit
authors.initials: B
authors.lastname: Meyer
authors.forename: Katrin
authors.initials: K
authors.lastname: Süring
authors.forename: Frank
authors.initials: F
authors.lastname: Majewski
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
authors.forename: Dietmar
authors.initials: D
authors.lastname: Müller
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D052005:Bone Morphogenetic Protein Receptors, Type I; D002356:Cartilage / Q000002:abnormalities; D002642:Chick Embryo; D020219:Chondrogenesis / Q000235:genetics; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D018076:DNA, Complementary; D017978:Receptors, Growth Factor; D017346:Protein Serine-Threonine Kinases; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I