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
J Clin Invest.
2005;
115(10):2832–2842
doi:10.1172/JCI22900
This article Copyright © 2005, The American Society for Clinical Investigation
Abstract
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MPs, 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.
Figure 2
Pedigree of family segregating for SEMDMO and chromosome 11q loci. SEMDMO is segregating in the affected individuals II.7 and III.14 with the haplotype [6,3,6,8,5,5,12,2], defined by the loci: 11cen — D11S314 — D11S937 — D11S901 — D11S4175 — D11S898 — D11S908 — D11S925 — D11S4151 — 11qter. However, recombinants between SEMDMO and the centromeric loci D11S314, D11S937, D11S901, and D11S4175 are observed in individuals II.1, II.3, III.4, III.9, IV.4, IV.5, and IV.8, thereby locating SEMDMO telomeric to D11S4175. The recombinants observed between SEMDMO and the telomeric loci D11S4151, D11S925, and D11S908 in the affected individuals II.4, III.7, III.9, IV.6, IV.7, and IV.8, locate SEMDMO centromeric to D11S908. These combined observations locate SEMDMO in the vicinity of D11S898. The location of MMP13, 1.69 Mb telomeric to D11S898 (Figure 3), is indicated by the arrow. The presence, in each individual, of the wild-type F56 or the mutant S56 is represented by + and –, respectively. The pedigree has been revised from the original description (5, 11) to indicate those family members who yielded information for the localization of SEMDMO. Squares, males; circles, females; open symbols, unaffected individuals; filled symbols, affected individuals; (?), uncertain SEMDMO phenotype; black bars, affected haplotypes; white bars, unaffected haplotypes. The paternal haplotypes are on the left, and the maternal haplotypes are on the right. Deduced haplotypes are within brackets.
