Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3

Abstract

Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene, MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor-like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.

Figure  1

Framework genomewide scan for 329 families with 1,143 individuals with idiopathic hand OA, using a 1,000-marker screening set. The allele-sharing LOD score is given on the Y-axis, and the genetic location (in Kosambi cM) is given on the X-axis.

Figure  2

Fine-mapping results for chromosomes 2, 3, and 4 for the cohorts with idiopathic hand OA and the DIP, CMC1, and DIP/CMC1 phenotypes. The allele-sharing LOD score is given on the Y-axis, and the genetic location (in Kosambi cM) is given on the X-axis.

Figure  3

Allelic variation in MATN3. The top chromatogram shows the nucleotide sequence for an individual homozygous for the allele for the predicted missense mutation resulting in methionine residue (ATG codon). The center chromatograph depicts the sequence for an individual heterozygous for the allele, and the bottom chromatograph shows the sequence for an individual homozygous for the threonine residue (ACG codon). The nucleotide highlighted in red depicts the polymorphic allele.

Figure  4

Alignment of amino acid residues for all four EGF domains of matrilin-3 from human (HuEGF1–4), mouse (MouEGF1–4), and chicken (ChEGF1–4). Residues conserved in all EGF domains are highlighted in green. The predicted missense mutation at position 303 in MATN3 from human protein sequence changes the threonine residue (boldface) to methionine.