Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia

Am J Hum Genet. 2009 Jun;84(6):760-70. doi: 10.1016/j.ajhg.2009.05.002. Epub 2009 May 28.


Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Animals
  • Child, Preschool
  • Chondrocytes / metabolism*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 13 / genetics
  • Comparative Genomic Hybridization
  • Dwarfism / genetics*
  • Female
  • Fluorescent Antibody Technique
  • Genes, Recessive / genetics*
  • Glypicans / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mice
  • Mutation / genetics*
  • Osteogenesis / physiology*


  • GPC6 protein, human
  • Glypicans