Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2

Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12277-82. doi: 10.1073/pnas.2133476100. Epub 2003 Oct 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Bone Morphogenetic Protein Receptors, Type I
  • Cartilage / abnormalities
  • Chick Embryo
  • Chondrogenesis / genetics
  • Chromosome Mapping
  • Chromosomes, Human, Pair 4 / genetics
  • DNA, Complementary / genetics
  • Female
  • Genes, Dominant
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / metabolism
  • Limb Deformities, Congenital / pathology
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Growth Factor / genetics*
  • Receptors, Growth Factor / metabolism
  • Sequence Homology, Amino Acid


  • DNA, Complementary
  • Receptors, Growth Factor
  • Protein Serine-Threonine Kinases
  • BMPR1B protein, human
  • Bone Morphogenetic Protein Receptors, Type I