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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)

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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 1

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Radiographic abnormalities of SEMDMO. The thoracolumbar spine and left k...
Radiographic abnormalities of SEMDMO. The thoracolumbar spine and left knee of patients IV.7 and IV.8 (Figure 2) at age 3.8 years are shown. (A) Pear-shaped vertebrae, with greatest vertical height anteriorly as well as bulbous anterior superior-inferior contours that are more pronounced in the lumbar region in patient IV.7. Disc spaces are increased posteriorly in both patients. These pear-shaped vertebrae in early childhood evolve to mild platyspondyly with irregular superior and inferior margins in adults. (B) The left knees of patients IV.7 and IV.8 show femoral bowing, metaphyseal flaring and irregularity, and widened growth plates. The epiphyses are small and flat, and those of patient IV.7 have slightly irregular margins. There is rhizomelic shortening in patient IV.8. These findings of rhizomelic shortening, femoral bowing, and metaphyseal flaring and irregularity, with widened growth plates (physes), are consistent with those in SEMD.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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