A Human Chondrodysplasia Due to a Mutation in a TGF-beta Superfamily Member

Nat Genet. 1996 Mar;12(3):315-7. doi: 10.1038/ng0396-315.

Abstract

The TGF-beta superfamily comprises a number of functionally diverse growth factors/signalling molecules (1) which elicit their response upon binding to serine-threonine kinase receptors (2). We recently reported the isolation and characterization of two new members of the family, designated cartilage-derived morphogenetic protein (CDMP) 1 and 2 (ref. 3) which are closely related to the sub-family of bone morphogenetic proteins. CDMP-1 is predominantly expressed at sites of skeletal morphogenesis (3), and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type (4,5)). The disorder, characterized by skeletal abnormalities restricted to the limbs andlimb joints, is phenotypically similar to murine brachypodism (bp) which is due to mutations in growth/differentiation factor-5 (Gdf-5) (6), the mouse homologue of hCDMP-1. Affected individuals are homozygous for a 22-bp (tandem-duplication) frameshift mutation in the mature region of CDMP-1. The resulting phenotype provides direct evidence for the involvement of CDMP-1 in human skeletal development and represents the first human disorder attributable to a mutation in a TGF-beta superfamily member.

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Bone Morphogenetic Proteins*
  • DNA
  • Female
  • Frameshift Mutation*
  • Growth Differentiation Factor 5
  • Growth Substances / genetics*
  • Homozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Osteochondrodysplasias / genetics*
  • Transforming Growth Factor beta / genetics*

Substances

  • Bone Morphogenetic Proteins
  • Growth Differentiation Factor 5
  • Growth Substances
  • Transforming Growth Factor beta
  • DNA