A human chondrodysplasia due to a mutation in a TGF- superfamily member

The TGF- superfamily comprises a number of functionally diverse growth factors/signalling molecules¹ which elicit their response upon binding to serine-threonine kinase receptors². 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 morphogenesis³, 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 and limb 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- superfamily member.

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