MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO)
Ann M. Kennedy, … , Michael P. Whyte, Rajesh V. Thakker
Ann M. Kennedy, … , Michael P. Whyte, Rajesh V. Thakker
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2832-2842. https://doi.org/10.1172/JCI22900.
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Research Article Bone biology

MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO)

Abstract

MMPs, which degrade components of the ECM, have roles in embryonic development, tissue repair, cancer, arthritis, and cardiovascular disease. We show that a missense mutation of MMP13 causes the Missouri type of human spondyloepimetaphyseal dysplasia (SEMDMO), an autosomal dominant disorder characterized by defective growth and modeling of vertebrae and long bones. Genome-wide linkage analysis mapped SEMDMO to a 17-cM region on chromosome 11q14.3–23.2 that contains a cluster of 9 MMP genes. Among these, MMP13 represented the best candidate for SEMDMO, since it preferentially degrades collagen type II, abnormalities of which cause skeletal dysplasias that include Strudwick type SEMD. DNA sequence analysis revealed a missense mutation, F56S, that substituted an evolutionarily conserved phenylalanine residue for a serine in the proregion domain of MMP13. We predicted, by modeling MMP13 structure, that this F56S mutation would result in a hydrophobic cavity with misfolding, autoactivation, and degradation of mutant protein intracellularly. Expression of wild-type and mutant MMP13s in human embryonic kidney cells confirmed abnormal intracellular autoactivation and autodegradation of F56S MMP13 such that only enzymatically inactive, small fragments were secreted. Thus, the F56S mutation results in deficiency of MMP13, which leads to the human skeletal developmental anomaly of SEMDMO.

Authors

Ann M. Kennedy, Masaki Inada, Stephen M. Krane, Paul T. Christie, Brian Harding, Carlos López-Otín, Luis M. Sánchez, Anna A.J. Pannett, Andrew Dearlove, Claire Hartley, Michael H. Byrne, Anita A.C. Reed, M. Andrew Nesbit, Michael P. Whyte, Rajesh V. Thakker

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Schematic representation of chromosome 11 with Giemsa bands, showing the...
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 SEMDMO. (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 SEMDMO and the centromeric loci D11S4175 and D11S1358 and the telomeric loci D11S4206 and D11S908 (Figure 2 and Table 1) located SEMDMO to an approximate 17-cM (equivalent to a 20-Mbp) interval on chromosome 11q14.3–23.2. Within this interval, SEMDMO 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 SEMDMO 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 SEMDMO kindred likely represents a significant change.