A Missense Mutation in the Aggrecan C-type Lectin Domain Disrupts Extracellular Matrix Interactions and Causes Dominant Familial Osteochondritis Dissecans

• Published in: American journal of human genetics Vol. 86; no. 2; pp. 126 - 137
• Main Authors: Stattin, Eva-Lena, Wiklund, Fredrik, Lindblom, Karin, Önnerfjord, Patrik, Jonsson, Björn-Anders, Tegner, Yelverton, Sasaki, Takako, Struglics, André, Lohmander, Stefan, Dahl, Niklas, Heinegård, Dick, Aspberg, Anders
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 12-02-2010; Cell Press; Elsevier
• Subjects: Adolescent; Aggrecans - chemistry; Aggrecans - genetics; Amino Acid Sequence; Amino acids; Base Sequence; Basic Medicine; Binding sites; Biological and medical sciences; Cartilage; Cells; Chromosomes, Human, Pair 15 - genetics; Diseases of the osteoarticular system; DNA Mutational Analysis; Extracellular Matrix - metabolism; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genes, Dominant - genetics; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Health Science; Humans; Hälsovetenskap; Lectins, C-Type - chemistry; Ligands; Male; Mass Spectrometry; Medical and Health Sciences; Medical Genetics; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Musculoskeletal diseases; Mutation; Mutation, Missense - genetics; Osteochondritis Dissecans - diagnostic imaging; Osteochondritis Dissecans - genetics; Phenotype; Protein Binding; Protein Structure, Tertiary; Proteins; Radiography; Vascular bone diseases; Human; Lectin; Missense mutation; Family study; Osteochondritis dissecans; Interaction; Diseases of the osteoarticular system; Genetics; Extracellular matrix; Dominant character; proteoglycans; identification; gene; dwarfism; cartilage; tenascin-r; core protein; versican; binding; spondyloepiphyseal dysplasia
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2009.12.018

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.