HGNC Approved Gene Symbol: MMP21
Cytogenetic location: 10q26.2 Genomic coordinates (GRCh38): 10:125,766,453-125,775,821 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q26.2 | Heterotaxy, visceral, 7, autosomal | 616749 | Autosomal recessive | 3 |
The MMP21 gene encodes a member of the matrix metalloproteinase superfamily that is known to hydrolyze extracellular matrix components (summary by Perles et al., 2015)
By searching a genomic database using sequences conserved in the catalytic domains of gelatinases A (MMP2; 120360) and B (MMP9; 120361) as query, followed by PCR of a placenta cDNA library, Ahokas et al. (2002) cloned MMP21. The deduced 569-amino acid protein contains a typical N-terminal hydrophobic signal sequence, followed by a prodomain containing a conserved cysteine-switch; a furin (136950) recognition sequence; a catalytic domain with 3 conserved histidine residues; and a hemopexin (142290)-like domain. The proenzyme without the signal peptide has a calculated molecular mass of 62 kD; following activation by furin (136950), the processed enzyme has a calculated molecular mass of 49 kD. Northern blot analysis detected a 2.5-kb transcript in fetal liver. PCR detected expression of MMP21 at low levels in adult kidney, brain, lung, testis, ovary, colon, and leukocytes, and in fetal brain and liver. Expression was not detected in other adult and fetal tissues examined. RT-PCR analysis revealed 4 splice variants that cause a frameshift that stops translation before the hemopexin domain. Immunohistochemical staining detected MMP21 in epithelial components of various developing and adult tissues, as well as in cancer. MMP21 protein was detected in fetal neuroectoderm, in placenta, and in leukocytes.
Ahokas et al. (2002) determined that the MMP21 gene contains 7 exons and spans about 10 kb. The upstream untranslated region contains a TATA box.
Perles et al. (2015) found that shRNA knockdown of MMP21 resulted in increased NOTCH1 (190198) activity, suggesting that MMP21 is a negative regulator for NOTCH1 signaling.
By genomic sequence analysis, Ahokas et al. (2002) mapped the MMP21 gene to chromosome 10.
In 3 sibs, born of consanguineous Arab parents with autosomal visceral heterotaxy-7 (HTX7; 616749), Perles et al. (2015) identified a homozygous truncating mutation in the MMP21 gene (608416.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In affected members of 9 unrelated families with HTX7, Guimier et al. (2015) identified homozygous or compound heterozygous mutations in the MMP21 gene (see, e.g., 608416.0002-608416.0008). Mutations in the first 2 families were found by whole-exome or whole-genome sequencing; mutations in subsequent families were found by targeted sequencing of the MMP21 gene in 264 probands with heterotaxy and/or cardiac laterality defects. Functional studies of the variants were not performed, but expression of 1 of the missense mutations in mice resulted in an increased frequency of complex congenital heart defects and heterotaxy, suggesting a loss of function.
In 3 affected individuals from 2 unrelated families with HTX7, Akawi et al. (2015) identified compound heterozygous mutations in the MMP21 gene (608416.0009-608416.0012). The mutations, which were found by exome sequencing, segregated with the disorder in the families; functional studies were not performed. The patients were part of a very large study of 4,125 families with a variety of severe developmental disorders who underwent exome analysis.
Akawi et al. (2015) reported that 2 heterotaxy mouse models, 'Miri' and 'Koli,' which were identified from a phenotype-based ENU mutagenesis screen, carried pathogenic Mmp21 missense mutations (W177L and Y325N) affecting the zinc-binding domain. The mutant mice showed visceral heterotaxy with laterality heart defects commonly associated with heterotaxy. Features included dextrocardia, transposition of the great arteries, atrial and ventricular defects, abnormal vessel drainage, lung isomerism, inverted liver lobation, and dextrogastria. Videomicroscopy of the embryonic node showed normal cilia motility, suggesting that Mmp21 acts downstream of motile cilia.
By whole-exome sequencing in a large study of chemically mutagenized mice with various forms of congenital heart disease, Li et al. (2015) identified 91 recessive mutations in 61 genes, including the extracellular matrix-related gene Mmp21. Mice with Mmp21 mutations had congenital heart disease with laterality defects.
Perles et al. (2015) found that morpholino knockdown of the mmp21 ortholog in zebrafish resulted in a dose-dependent induction of positional heart-looping defects. Mutant embryos also showed abnormal expression pattern of the left-identity marker 'southpaw' (spaw), suggesting that the heart-looping defect is associated with abnormal left-right patterning. Mutant embryos also showed upregulation of NOTCH1 target genes. Normal embryos showed mmp21 expression close to and rostral to Kupffer vesicle prior to establishment of left-right asymmetry.
Guimier et al. (2015) found that expression of mmp21 in zebrafish embryos was restricted to Kupffer vesicle, and morpholino knockdown resulted in randomized heart looping. Introduction of the human missense mutation I226T (608416.0002) into mice resulted in an increased frequency of complex congenital heart defects, situs inversus, and heterotaxy compared to controls.
In 3 sibs, born of consanguineous Arab parents with autosomal visceral heterotaxy-7 (HTX7; 616749), Perles et al. (2015) identified a homozygous 2-bp deletion (c.1024_1025delAA, NM_147191) in the MMP21 gene, resulting in a frameshift and premature termination (K342fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the ExAC database (June 2015). RT-PCR of patient cells showed expression of MMP21, suggesting that the transcript is not subject to nonsense-mediated mRNA decay, and predicting the translation of a truncated protein lacking the hemopexin repeat domain.
In a pair of European dizygotic twins with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified compound heterozygous mutations in the MMP21 gene: a c.677T-C transition (c.677T-C, NM_147191.1), resulting in an ile226-to-thr (I226T) substitution in the peptidase domain, and a c.1203G-A transition, resulting in a trp401-to-ter (W401X; 608416.0003) substitution in the HX2 domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations were filtered against the dbSNP (build 135), Exome Variant Server, and 1000 Genomes Project (March 2015) databases, as well as an in-house database of over 5,000 exomes. Both mutations were found at very low frequencies in the ExAC database. Introduction of the I226T mutation into mice resulted in an increased frequency of complex congenital heart defects, situs inversus, and heterotaxy compared to controls. The findings in mice were similar to those found in ENU-induced mutants, suggesting a loss of function.
For discussion of the c.1203G-A transition (c.1203G-A, NM_147191.1) in the MMP21 gene, resulting in a trp401-to-ter (W401X; 608416.0003) substitution, that was found in compound heterozygous state in a family with autosomal visceral heterotaxy-7 (HTX7; 616749) by Guimier et al. (2015), see 608416.0002.
In 2 Hispanic brothers with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified compound heterozygous mutations in the MMP21 gene: a 1-bp deletion (c.365delT, NM_147191.1), resulting in a frameshift and premature termination (Met122SerfsTer55) in the prodomain, and a deletion of exons 1-3 (608416.0005). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing or microarray analysis, segregated with the disorder in the family The mutations were not found in the ExAC database (March 2015). Functional studies of the variants and studies of patient cells were not performed.
For discussion of the deletion of exons 1-3 (chr10.127,460,914-127,466,819, GRCh37) in the MMP21 gene that was found in compound heterozygous state in a family with autosomal visceral heterotaxy-7 (HTX7; 616749) by Guimier et al. (2015), see 608416.0004.
In a boy, born of consanguineous parents from North Africa, with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified a homozygous c.1A-G transition (c.1A-G, NM_147191.1) in the MMP21 gene, resulting in a met1-to-? substitution. The unaffected parents were heterozygous for the mutation. The mutation had a very low frequency in the ExAC database (March 2015). Functional studies of the variant and studies of patient cells were not performed.
In a boy, born of consanguineous Turkish parents, with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified a homozygous c.961G-C transversion (c.961G-C, NM_147191.1) in the MMP21 gene, resulting in an ala321-to-pro (A321P) substitution in the peptidase domain. The unaffected parents were heterozygous for the mutation. The results were confirmed by linkage analysis. The mutation had a very low frequency in the ExAC database (March 2015). Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs, born of consanguineous Turkish parents, with autosomal visceral heterotaxy-7 (HTX7; 616749), Guimier et al. (2015) identified a homozygous c.1078C-T transition (c.1078C-T, NM_147191.1) in the MMP21 gene, resulting in an arg360-to-cys (R360C) substitution in the HX1 domain. The unaffected parents were heterozygous for the mutation. The results were confirmed by linkage analysis and homozygosity mapping. The mutation was not found in the ExAC database (March 2015). Functional studies of the variant and studies of patient cells were not performed.
In a patient and his deceased sib (a fetus) with autosomal visceral heterotaxy-7 (HTX7; 616749), Akawi et al. (2015) identified compound heterozygous mutations in the MMP21 gene: a c.847C-T transition (c.847C-T, NM_147191.1), resulting in a his283-to-tyr (H283Y) substitution, and a c.947G-A transition, resulting in a trp316-to-ter (W316X; 608416.0010) substitution. The mutations, which were identified by exome sequencing, segregated with the disorder in the family. Functional studies were not performed, but molecular modeling suggested that the H283Y mutation would severely reduce zinc binding.
For discussion of the c.947G-A transition (c.947G-A, NM_147191.1) in the MMP21 gene, resulting in a trp316-to-ter (W316X) substitution, that was found in compound heterozygous state in a family with autosomal visceral heterotaxy-7 (HTX7; 616749) by Akawi et al. (2015), see 608416.0009.
In a boy with autosomal visceral heterotaxy-7 (HTX7; 616749), Akawi et al. (2015) identified compound heterozygous mutations in the MMP21 gene: a c.854T-C transition (c.854T-C, NM_147191.1), resulting in an ile285-to-thr (I285T) substitution, and a 2-bp deletion, resulting in a frameshift and premature termination (608416.0012). The mutations, which were identified by exome sequencing, segregated with the disorder in the family. Functional studies were not performed, but molecular modeling suggested that the I285T mutation could lead to conformational shifts that would affect zinc binding. In addition to cardiac malformations, the patient had global developmental delay and dysmorphic facial features.
For discussion of the 2-bp deletion in the MMP21 gene (c.1380_1381delGA, NM_147191.1), resulting in a frameshift and in premature termination (Lys461ValfsTer14), that was found in compound heterozygous state in a patient with autosomal visceral heterotaxy-7 (HTX7; 616749) by Akawi et al. (2015), see 608416.0011.
Ahokas, K., Lohi, J., Lohi, H., Elomaa, O., Karjalainen-Lindsberg, M.-L., Kere, J., Saarialho-Kere, U. Matrix metalloproteinase-21, the human orthologue for XMMP, is expressed during fetal development and in cancer. Gene 301: 31-41, 2002. [PubMed: 12490321] [Full Text: https://doi.org/10.1016/s0378-1119(02)01088-0]
Akawi, N., McRae, J., Ansari, M., Balasubramanian, M., Blyth, M., Brady, A. F., Clayton, S., Cole, T., Deshpande, C., Fitzgerald, T. W., Foulds, N., Francis, R., and 30 others. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genet. 47: 1363-1369, 2015. [PubMed: 26437029] [Full Text: https://doi.org/10.1038/ng.3410]
Guimier, A., Gabriel, G. C., Bajolle, F., Tsang, M., Liu, H., Noll, A., Schwartz, M., El Malti, R., Smith, L. D., Klena, N. T., Jimenez, G., Miller, N. A., and 24 others. MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. Nature Genet. 47: 1260-1263, 2015. [PubMed: 26437028] [Full Text: https://doi.org/10.1038/ng.3376]
Li, Y., Klena, N. T., Gabriel, G. C., Liu, X., Kim, A. J., Lemke, K., Chen, Y., Chatterjee, B., Devine, W., Damerla, R. R., Chang, C., Yagi, H., and 17 others. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 521: 520-524, 2015. [PubMed: 25807483] [Full Text: https://doi.org/10.1038/nature14269]
Perles, Z., Moon, S., Ta-Shma, A., Yaacov, B., Francescatto, L., Edvardson, S., Rein, A. J. J. T., Elpeleg, O., Katsanis, N. A human laterality disorder caused by a homozygous deleterious mutation in MMP21. J. Med. Genet. 52: 840-847, 2015. [PubMed: 26429889] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103336]