A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans.
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.
Stattin
Eva-Lena
EL
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University Hospital, Umeå, Sweden.
Wiklund
Fredrik
F
Lindblom
Karin
K
Onnerfjord
Patrik
P
Jonsson
Björn-Anders
BA
Tegner
Yelverton
Y
Sasaki
Takako
T
Struglics
André
A
Lohmander
Stefan
S
Dahl
Niklas
N
Heinegård
Dick
D
Aspberg
Anders
A
D000293:Adolescent; D053674:Aggrecans / Q000737:chemistry* / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004252:DNA Mutational Analysis; D005109:Extracellular Matrix / Q000378:metabolism*; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry*; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010008:Osteochondritis Dissecans / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011859:Radiography
C508319:ACAN protein, human; D053674:Aggrecans; D037181:Lectins, C-Type; D008024:Ligands