Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia

Am J Hum Genet. 1994 Dec;55(6):1128-36.


Kniest dysplasia is a heritable chondrodysplasia that severely affects skeletal growth. Recent evidence suggests that the etiology is based on mutations in COL2A1, the gene for collagen type II. We report the detection and partial characterization of an identical defect in type II collagen in two unrelated patients with Kniest dysplasia. Analysis of cyanogen bromide (CB)-digested cartilage samples from both probands by SDS-PAGE revealed an abnormal band for peptide alpha 1(II)CB12. The peptide was purified and digested with endoproteinase Asp-N. Fragments unique to the Kniest tissues were identified by reverse-phase high-pressure liquid chromatography and by sequence analysis. The results established a deletion of amino acids 102-108 of the alpha 1(II) triple-helical domain, which disrupted the (gly-X-Y)n repeat needed for helix formation. This was confirmed by sequence analysis of DNA amplified from both probands, revealing the molecular basis to be a single nucleotide mutation at a CpG dinucleotide (GCG-->GTG) in the codon for alanine 102. The mutation created a new splice donor site, which would account for the absence of the last seven amino acids from the 3' end of exon 12 in alpha 1(II)CB12. Light and electron micrographs of the probands' cartilage showed the perilacunar foamy matrix ("Swiss cheese") characteristic of Kniest dysplasia and chondrocytes containing dilated rough endoplasmic reticulum, which earlier studies had shown were filled with type II procollagen. These two cases strengthen the concept that Kniest dysplasia is based on mutations of COL2A1 and belongs within the broad spectrum of chondrodysplasias caused by type II collagenopathies.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / pathology
  • Cartilage / anatomy & histology
  • Cartilage / chemistry*
  • Child
  • Collagen / chemistry
  • Collagen / genetics*
  • Exons / genetics
  • Female
  • Genome, Human
  • Heterozygote
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Osteochondrodysplasias / genetics*
  • Polymorphism, Restriction Fragment Length
  • RNA Splicing / genetics
  • Radiography


  • Collagen