Defective Matrix Turnover Causes SEMD-Missouri
© 2006 Prime Health Consultants, Inc.
SEMD (spondyloepimetaphyseal dysplasia) refers the chondrodysplasias with radiographic manifestations affecting mainly the spine and long bone epiphyses and metaphyses. The best defined SEMDs include the Strudwick and Pakistani types and the recessive matrilin 3 deficiency type, all 3 of which are due to primary or secondary disturbances of extracellular matrix proteins in the cartilagenous growth plate. Such disturbances are also responsible for a broad spectrum of SEDs (spondyloepiphyseal dysplasias) including achondrogenesis type II, hypochondrogenesis, SED congenita and Kniest dysplasia. SEMD-Missouri (SEMDMO OMIM 602111) is an autosomal dominant disorder characterized by rhizomelic short stature accompanied by moderate to severe metaphyseal abnormalities, mild epiphyseal changes and pear-shaped verterbral anomalies detected on skeletal X-rays. Kennedy et al recently reported a mutation in the gene encoding MMP13 (matrix metalloprotein 13) also known as collagenase-3. What makes this report interesting is the mechanism by which the mutation acts to disturb endochondral bone growth.
The authors studied a large kindred in which SEMDMO was transmitted as an autosomal dominant trait through 5 generations. They first mapped this disorder to an interval of about 20 Mb on chromosome 11q22, which contains ~160 genes. The interval included a cluster of 9 genes coding for MMPs, which are zinc metalloendopeptidases that degrade components of extracellular matrix. They selected MMP13 for analysis because MMP13 degrades several components of growth plate cartilage extracellular matrix including types II and X collagen and aggrecan. Sequence analysis of genomic DNA revealed a missense mutation – Phe56Ser – in affected family members. Interestingly, this phenylalanine residue is conserved in MMP13s across many species and also in many other human MMPs. Of particular interest is that it maps to the proregion of the enzyme, which is normally secreted as a proenzyme to be activated outside the cell.
To delineate the functional significance of the mutation, they carried out a number of experiments, which in the aggregate revealed the mutant MMP13 enzyme is autoactivated prior to secretion from the cell, mostly likely in the endoplasmic reticulum or Golgo apparatus of the cell. In fact, their results suggested that the mutation adversely affects a molecular switch common to many secreted enzymes that is essential for keeping proenzymes inactive prior to release from the cell.
The authors noted that a knock-out mouse has been reported with an equivalent phenotype to that of human SEMDMO. Of note was that the skeletal defects in the mouse behave as a recessive trait with heterozygotes showing no evidence of disease, whereas they are inherited as a dominant trait in humans. One possible explanation is that the autoactivated mutant MMP13 not only destroys itself before it is secreted from the cell, but it also degrades the product of the normal copy of the MMP13 gene. Accordingly, they tested this possibility and observed it to be the case. Thus, the mutation behaves as in a dominant negative fashion in that the mutant gene product adversely affects the protein product of the normal MMP13 allele to produce a functional deficiency of MMP13.
Editor’s Comment: Convention wisdom of predicting inheritance patterns associated with different types of genetic defects can only go so far. In this case, the dominant inheritance pattern and clinical similarities of SEMDMO to the SED group of chondrodysplasias would have correctly suggested that this disorder would be due to a disturbance in cartilage matrix. The unexpected finding was dominant negative effect of the mutant enzyme, ie, mutated MMP13 degrading normal as well as mutant enzyme during biosynthesis.
William A. Horton. MD