A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans
2010 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 2, 126-137 p.Article in journal (Refereed) Published
Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.
Place, publisher, year, edition, pages
2010. Vol. 86, no 2, 126-137 p.
core protein; tenascin-r; spondyloepiphyseal dysplasia; identification; cartilage; gene; proteoglycans; versican; binding; dwarfism
Research subject Medicine
IdentifiersURN: urn:nbn:se:umu:diva-39245DOI: 10.1016/j.ajhg.2009.12.018PubMedID: 20137779OAI: oai:DiVA.org:umu-39245DiVA: diva2:389382