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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Figure 4

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Schematic representation of the genomic structure of the MMP13 gene illu...
Schematic representation of the genomic structure of the MMP13 gene illustrating locations of the SEMDMO mutation and protein domains. The 1,413-bp MMP13 coding region yields a 471–amino acid preproenzyme. The signal sequence consists of 19 amino acids that are removed on processing and are not present in the secreted proenzyme (15, 16). The pro- and catalytic domains comprise 84 and 166 amino acids, respectively. The catalytic domain has a zinc-binding motif (HEXXHXXGXXH) that contains 3 histidine residues that bind the catalytic zinc ion at the active site (15, 16, 19, 36). The proregion contains a cysteine residue (Cys77) that ligates this catalytic zinc ion to maintain the latency of proMMP13. An 11–amino acid proline-rich linker peptide (hinge domain) connects the catalytic domain and hemopexin domain, which consists of 191 amino acids. The position of the T→C transition at nucleotide 252 of exon 2, detected in the SEMDMO kindred (Figure 2) and found to result in the F56S mutation (Figure 5) in the proregion, is shown. The shading or hatching of each protein domain indicates its exonic origins.