Alternative titles; symbols
HGNC Approved Gene Symbol: MMP13
SNOMEDCT: 254084008, 719171005;
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,942,995-102,955,732 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.2 | ?Spondyloepimetaphyseal dysplasia, Missouri type | 602111 | Autosomal dominant | 3 |
| Metaphyseal anadysplasia 1 | 602111 | Autosomal dominant | 3 | |
| Metaphyseal dysplasia, Spahr type | 250400 | Autosomal recessive | 3 |
Freije et al. (1994) cloned a cDNA coding for a novel human matrix metalloproteinase (MMP) from a cDNA library derived from a breast tumor. The isolated cDNA contains an open reading frame coding for a polypeptide of 471 amino acids. The predicted protein sequence displays extensive similarity to previously known MMPs and presented all the structural features characteristic of this protein family, including the well-conserved PRCGXPD motif. In addition, it contains in its amino acid sequence several residues specific to the collagenase subfamily (tyr214, asp235, and gly237) and lacks the 9-residue insertion present in the stromelysins. Because of the structural characteristics, Freije et al. (1994) called the new MMP collagenase-3 (CLG3), since it represented the third member of this family, composed of fibroblast (MMP1; 120353) and neutrophil (MMP8; 120355) collagenases. Northern blot analysis of RNA from normal and pathologic tissues demonstrated the existence in breast tumors of 3 different mRNA species, which seemed to be the result of utilization of different polyadenylation sites present in the 3-prime noncoding region of the gene. By contrast, no CLG3 mRNA was detected either by Northern blot or RNA polymerase chain reaction analysis with RNA from other human tissues, including normal breast, mammary fibroadenomas, liver, placenta, ovary, uterus, prostate, and parotid gland. A possible role for this metalloproteinase in the tumoral process was proposed.
Freije et al. (1994) expressed CLG3 cDNA in a vaccinia virus system and found that the recombinant protein was able to degrade fibrillar collagens, providing support to the idea that it codes for an authentic collagenase.
Mitchell et al. (1996) concluded that the expression of MMP13 in osteoarthritic cartilage and its activity against type II collagen indicates that the enzyme plays a significant role in cartilage collagen degradation and must, therefore, form part of a complex target for proposed therapeutic interventions based on collagenase inhibition. Reboul et al. (1996) likewise presented data on collagenase-3 expression and synthesis in human cartilage cells and suggested its involvement in human osteoarthritis cartilage pathophysiology.
Lausch et al. (2009) suggested that there is a functional link between MMP13 and MMP9 (120361) in the endochondral ossification, as impaired MMP9 protein function, caused by direct inactivation (in recessive disease due to MMP9 loss of function), impaired activation (in recessive disease due to MMP13 loss of function), or transcatalytic degradation (in dominant disease caused by MMP13 gain of function) appears to be a common downstream step in the pathogenesis of metaphyseal anadysplasia.
Pendas et al. (1997) reported that the MMP13 gene contains 10 exons and spans approximately 12.5 kb. The overall gene organization is similar to those of other MMP genes, including MMP1, MMP7 (178990), and MMP12 (601046).
By fluorescence in situ hybridization, Pendas et al. (1995) localized the CLG3 gene (also symbolized MMP13) to 11q22.3. Physical mapping of a YAC clone containing CLG3 revealed that this gene is tightly linked to those genes encoding other matrix metalloproteinases, including fibroblast collagenase (MMP1), stromelysin-1 (MMP3; 185250), and stromelysin-2 (MMP10; 185260). Further mapping of this region using pulsed field gel electrophoresis showed that the CLG3 gene is located on the telomeric side of the matrix metalloproteinase cluster. Pendas et al. (1995) found the relative order of the loci to be cen--STMY2--CLG1--STMY1--CLG3--tel. Pendas et al. (1996) isolated a 1.5-Mb YAC clone mapping to 11q22. Detailed analysis of this nonchimeric YAC clone ordered 7 MMP genes as follows: cen--MMP8--MMP10--MMP1--MMP3--MMP12--MMP7--MMP13--tel.
Spondyloepimetaphyseal Dysplasia, Missouri Type
The spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of skeletal disorders featuring defective growth and modeling of the spine and long bones. In affected members of a family segregating the Missouri type of SEMD (SEMDM; 602111) originally described by Patel et al. (1993), Kennedy et al. (2005) identified heterozygosity for a missense mutation (F56S; 600108.0001) in the MMP13 gene. Kennedy et al. (2005) predicted, by modeling MMP13 structure, that the F56S mutation would result in a hydrophobic cavity with misfolding, autoactivation, and degradation of mutant protein intracellularly. Expression of wildtype 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 seen in the Missouri form of SEMD.
Metaphyseal Anadysplasia 1
Lausch et al. (2009) investigated the molecular basis of metaphyseal anadysplasia in 5 families and identified heterozygous mutations in the MMP13 gene (600108.0002-600108.0003) in 3; see MANDP1 (602111). In the fourth family, they identified a mutation in the MMP9 gene (120361.0001); see MANDP2 (613073). Lausch et al. (2009) found that recessive metaphyseal anadysplasia (MANDP2) is caused by homozygous loss of function of MMP9, whereas dominant metaphyseal anadysplasia (MANDP1) is caused by missense mutations in the prodomain of MMP13; these mutations determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. In the fifth family studied by Lausch et al. (2009), the proband was homozygous for a missense mutation in the MMP13 gene (H213N; 600108.0004). Although this patient was initially diagnosed as having a recessive form of MANDP1, Bonafe et al. (2014) stated that he could be retrospectively diagnosed with the Spahr type of metaphyseal dysplasia (MDST; 250400).
In a Chinese boy with MANDP1, Song et al. (2019) identified a de novo heterozygous missense mutation in the MMP13 gene (M71T; 600108.0003) that had previously been identified by Lausch et al. (2009). The variant, which was identified by targeted next-generation sequencing and confirmed by Sanger sequencing, was not present in large population databases, including gnomAD.
Metaphyseal Dysplasia, Spahr Type
In affected members of the Swiss family with metaphyseal dysplasia originally described by Spahr and Spahr-Hartmann (1961), Bonafe et al. (2014) identified homozygosity for a missense mutation in the MMP13 gene (W207G; 600108.0005).
In 2 Albanian brothers with short stature and mixed epiphyseal and metaphyseal dysplasia, Li et al. (2015) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the MMP13 gene (R109X; 600108.0006).
By gene targeting, Inada et al. (2004) created Mmp13-null mice. Homozygous null mice were born at predicted mendelian ratios and appeared healthy at birth. However, mutant mice showed profound defects in growth plate cartilage, with markedly increased hypertrophic domains, as well as delay in endochondral ossification and in formation and vascularization of primary ossification centers. Absence of Mmp13 resulted in significant interstitial collagen accumulation due, in part, to lack of collagenase-mediated cleavage that normally occurs in growth plates and primary ossification centers. Cartilaginous growth plate abnormalities persisted in adult mice and phenocopied defects observed in human hereditary chondrodysplasias.
In the Missouri family with spondyloepimetaphyseal dysplasia (SEMDM; 602111) originally described by Patel et al. (1993), Kennedy et al. (2005) demonstrated that the disorder was caused by a heterozygous 252T-C transition in codon 56 of the MMP13 gene that resulted in substitution of serine for an evolutionarily conserved phenylalanine residue (F56S) in the proregion domain of the protein.
In 3 affected members of a German family segregating a dominant form of metaphyseal anadysplasia (see 602111), Lausch et al. (2009) identified heterozygosity for a 249-C transition in the MMP13 gene, resulting in a phe55-to-ser (F55S) substitution in the prodomain. The mutation was not found among 228 alleles of ancestry-matched unaffected individuals.
In 7 patients from 2 families, one German and the other Japanese, segregating a dominant form of metaphyseal anadysplasia (see 602111), Lausch et al. (2009) identified heterozygosity for a 300T-C transition in exon 2 of the MMP3 gene, resulting in an met72-to-thr (M72T) substitution in the prodomain. The mutation was not present among 228 alleles of ancestry-matched unaffected individuals.
In a Chinese boy with MANDP1, Song et al. (2019) identified a de novo heterozygous T-C transition (c.212T-C, NM_002427.3) in exon 2 of the MMP13 gene, resulting in a met71-to-thr (M71T) substitution at a highly conserved residue in the prodomain of the protein. The variant was identified by targeted next-generation sequencing and confirmed by Sanger sequencing; the variant was not present in either of the unaffected parents or in large population databases. The numbering of the variant is based on a different sequence and numbering system from that used by Lausch et al. (2009).
In a Moroccan patient with metaphyseal dysplasia (patient 11), born of consanguineous parents, Lausch et al. (2009) identified homozygosity for a 722C-A transition in exon 5 of the MMP13 gene, which changed the highly conserved histidine 213 of the catalytic domain to asparagine (H213N) in the predicted open reading frame of proMMP13. The parents were heterozygous for the mutation and unaffected sibs were either heterozygous or homozygous wildtype. The mutation was not found among 228 alleles of unaffected controls. Although Lausch et al. (2009) diagnosed the boy's condition as metaphyseal anadysplasia, Bonafe et al. (2014) stated that he could be retrospectively diagnosed with the Spahr type of metaphyseal dysplasia (MDST; 250400).
In 2 affected members of the Swiss family with Spahr type metaphyseal dysplasia (MDST; 250400), originally described by Spahr and Spahr-Hartmann (1961), Bonafe et al. (2014) identified homozygosity for a c.619T-G transversion in the MMP13 gene, resulting in a trp207-to-gly (W207G) substitution at a highly conserved residue in the core of the catalytic domain. The mutation, which was present in heterozygosity in all obligate carriers in the family, was not found in 100 local controls; however, it was detected in 2 of approximately 13,000 unselected alleles in the Exome Variant Server database, for an allelic frequency of approximately 0.00015, which the authors stated was in the range of a very rare recessive allele.
In 2 Albanian brothers with short stature and mixed epiphyseal and metaphyseal dysplasia (MDST; 250400), Li et al. (2015) identified homozygosity for a c.325C-T transition in exon 2 of the MMP13 gene, resulting in an arg109-to-ter (R109X) substitution that was predicted to result in a markedly truncated, nonfunctional protein. The mutation was present in heterozygosity in the unaffected parents; SNP analysis indicated that the mutation arose in a common founder and that the 2 mutant alleles were identical by descent. The variant was detected in the ESP6500SI dataset with a minor allele frequency of 0.000077 and was reported in dbSNP (build 138) (rs369083541) without any clinical significance; however, it was not found in the 1000 Genomes Project or COSMIC v.67 databases or in the authors' 1,200 whole-exome sequencing samples.
Bonafe, L., Liang, J., Gorna, M. W., Zhang, Q., Ha-Vinh, R., Campos-Xavier, A. B., Unger, S., Beckmann, J. S., Le Bechec, A., Stevenson, B., Giedion, A., Liu, X., Superti-Furga, G., Wang, W., Spahr, A., Superti-Furga, A. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am. J. Med. Genet. 164A: 1175-1179, 2014. [PubMed: 24648384] [Full Text: https://doi.org/10.1002/ajmg.a.36431]
Freije, J. M. P., Diez-Itza, I., Balbin, M., Sanchez, L. M., Blasco, R., Tolivia, J., Lopez-Otin, C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269: 16766-16773, 1994. [PubMed: 8207000]
Inada, M., Wang, Y., Byrne, M. H., Rahman, M. U., Miyaura, C., Lopez-Otin, C., Krane, S. M. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc. Nat. Acad. Sci. 101: 17192-17197, 2004. [PubMed: 15563592] [Full Text: https://doi.org/10.1073/pnas.0407788101]
Kennedy, A. M., Inada, M., Krane, S. M., Christie, P. T., Harding, B., Lopez-Otin, C., Sanchez, L. M., Pannett, A. A. J., Dearlove, A., Hartley, C., Byrne, M. H., Reed, A. A. C., Nesbit, M. A., Whyte, M. P., Thakker, R. V. MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO)). J. Clin. Invest. 115: 2832-2842, 2005. [PubMed: 16167086] [Full Text: https://doi.org/10.1172/JCI22900]
Lausch, E., Keppler, R., Hilbert, K., Cormier-Daire, V., Nikkel, S., Nishimura, G., Unger, S., Spranger, J., Superti-Furga, A., Zabel, B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet. 85: 168-178, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 420 only, 2009. [PubMed: 19615667] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.014]
Li, D., Weber, D. R., Deardorff, M. A., Hakonarson, H., Levine, M. A. Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia. Europ. J. Hum. Genet. 23: 264-266, 2015. [PubMed: 24781753] [Full Text: https://doi.org/10.1038/ejhg.2014.76]
Mitchell, P. G., Magna, H. A., Reeves, L. M., Lopresti-Morrow, L. L., Yocum, S. A., Rosner, P. J., Geoghegan, K. F., Hambor, J. E. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97: 761-768, 1996. [PubMed: 8609233] [Full Text: https://doi.org/10.1172/JCI118475]
Patel, A. C., McAlister, W. H., Whyte, M. P. Spondyloepimetaphyseal dysplasia: clinical and radiologic investigation of a large kindred manifesting autosomal dominant inheritance, and a review of the literature. Medicine 72: 326-342, 1993. [PubMed: 8412645]
Pendas, A. M., Balbin, M., Llano, E., Jimenez, M. G., Lopez-Otin, C. Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). Genomics 40: 222-233, 1997. [PubMed: 9119388] [Full Text: https://doi.org/10.1006/geno.1996.4554]
Pendas, A. M., Matilla, T., Estivill, X., Lopez-Otin, C. The human collagenase-3 (CLG3) gene is located on chromosome 11q22.3 clustered to other members of the matrix metalloproteinase gene family. Genomics 26: 615-618, 1995. [PubMed: 7607691] [Full Text: https://doi.org/10.1016/0888-7543(95)80186-p]
Pendas, A. M., Santamaria, I., Alvarez, M. V., Pritchard, M., Lopez-Otin, C. Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics 37: 266-269, 1996. [PubMed: 8921407] [Full Text: https://doi.org/10.1006/geno.1996.0557]
Reboul, P., Pelletier, J.-P., Tardif, G., Cloutier, J.-M., Martel-Pelletier, J. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes: a role in osteoarthritis. J. Clin. Invest. 97: 2011-2019, 1996. [PubMed: 8621789] [Full Text: https://doi.org/10.1172/JCI118636]
Song, C., Li, N., Hu, X., Shi, Y., Chen, L., Zhou, T., Xu, X., Shen, J., Zhu, M. A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia. Europ. J. Med. Genet. 62: 103575, 2019. [PubMed: 30439533] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.009]
Spahr, A., Spahr-Hartmann, I. Dysostose metaphysaire familiale: etude de 4 cas dans une fratrie. Helv. Paediat. Acta 16: 836-849, 1961. [PubMed: 13915518]