A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis

Am J Hum Genet. 2005 Sep;77(3):484-90. doi: 10.1086/444401. Epub 2005 Jul 22.


Spondyloepiphyseal dysplasia (SED) encompasses a heterogeneous group of disorders characterized by shortening of the trunk and limbs. The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1. This locus contains the gene AGC1, which encodes aggrecan, the core protein of the most abundant proteoglycan of cartilage. We screened AGC1 for mutations and identified a single-base-pair insertion, within the variable repeat region of exon 12 in affected individuals from the family with SEDK, that introduces a frameshift of 212 amino acids, including 22 cysteine residues, followed by a premature stop codon. This is the first identification of an AGC1 mutation causing a human disorder. This finding extends the spectrum of mutated genes that may cause SED and thus will aid in the molecular delineation of this complex group of conditions.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans
  • Amino Acid Sequence
  • Base Sequence
  • Frameshift Mutation / genetics*
  • Gene Components
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Humans
  • Minisatellite Repeats / genetics
  • Molecular Sequence Data
  • Osteoarthritis / genetics*
  • Osteochondrodysplasias / genetics*
  • Pedigree
  • Proteoglycans / genetics*
  • Sequence Analysis, DNA


  • ACAN protein, human
  • Aggrecans
  • Proteoglycans