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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.
Kennedy
AM, Inada M, Krane SM, et al. MMP13 mutation causes spondyloepimetaphyseal
dysplasia, Missouri type (SEMDMO). J Clin Invest. 2005;115:2832 - 2842.
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
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Current GGH - Vol. 24 No. 1
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