Schematic representation of chromosome 11 with Giemsa bands, showing the positions of 8 polymorphic loci from 11q14.3–23.2 that helped define the location of SEMD_MO. (A) The locus order was derived from consensus maps (http://www.ensembl.org/Homo_sapiens/mapview?chr=11; http://www.broad.mit.edu/tools/data/data-human.html). Recombinants between SEMD_MO and the centromeric loci D11S4175 and D11S1358 and the telomeric loci D11S4206 and D11S908 (Figure 2 and Table 1) located SEMD_MO to an approximate 17-cM (equivalent to a 20-Mbp) interval on chromosome 11q14.3–23.2. Within this interval, SEMD_MO cosegregated with 6 loci (Table 1), and 4 of these (D11S1333, D11S898, D11S1339, and D11S927) revealed peak LOD scores greater than +3 at 0% recombination. This 20-Mbp interval contains 160 genes (http://www.ensembl.org/Homo_sapiens/mapview?chr=11) that include a cluster of 9 genes encoding MMPs, located at 11q22.3. These are MMP1, -3, -7, -8, -10, -12, -13, -20, and -27. The MMP13 gene, which is also referred to as collagenase 3, harbored a missense mutation, F56S (Figure 4), in the SEMD_MO kindred (Figure 2). PTH, parathyroid hormone; MEN1, multiple endocrine neoplasia type 1. (B) The human F56 residue (asterisk) is evolutionarily conserved in the MMP13 of mammals, amphibia, and teleost fish (http://www.broad.mit.edu/tools/data/data-human.html). (C) The MMP13 F56 residue (asterisk) is also conserved in other members of the MMP family (e.g., MMP-1, -3, -7, -8, -10, -12, -13, -20, and -27) in humans and similarly in mouse, rat, horse, rabbit, and cow (data not shown) (http://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi?term=mmp13). Thus, the F56S mutation in the SEMD_MO kindred likely represents a significant change.