Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish

Am J Hum Genet. 2012 Apr 6;90(4):661-74. doi: 10.1016/j.ajhg.2012.02.026.


Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Density Conservation Agents / therapeutic use
  • Bone Morphogenetic Protein 1 / genetics
  • Bone Morphogenetic Protein 1 / metabolism
  • Bone Morphogenetic Protein 1 / physiology*
  • Bone and Bones / metabolism
  • Cell Differentiation
  • Child, Preschool
  • Collagen / biosynthesis
  • Diphosphonates / therapeutic use
  • Exome
  • Female
  • Fractures, Bone / drug therapy
  • Fractures, Bone / prevention & control
  • Genetic Loci
  • Heat-Shock Proteins
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Osteoblasts / drug effects
  • Osteoblasts / physiology
  • Osteogenesis / drug effects
  • Osteogenesis / genetics*
  • Osteogenesis / physiology*
  • Peptide Fragments
  • Protein Processing, Post-Translational
  • Zebrafish / genetics
  • Zebrafish / metabolism


  • Bone Density Conservation Agents
  • Diphosphonates
  • Heat-Shock Proteins
  • Peptide Fragments
  • SNP nonapeptide
  • Collagen
  • BMP1 protein, human
  • Bone Morphogenetic Protein 1