HGNC Approved Gene Symbol: ADAMTS7
Cytogenetic location: 15q25.1 Genomic coordinates (GRCh38): 15:78,759,206-78,811,464 (from NCBI)
ADAMTS7 is a member of the large ADAMTS family of zinc-dependent proteases. For a general description of the ADAMTS gene family, see ADAMTS1 (605174).
By searching an EST database using the protein sequences of human ADAMTS1 to ADAMTS4 (603876) and a C. elegans ADMATS as queries, Hurskainen et al. (1999) identified ADAMTS5 (605007), ADAMTS6 (605008), and ADAMTS7. They isolated cDNAs encompassing an ADAMTS7 coding sequence which they believed to be complete. The predicted 997-amino acid ADAMTS7 protein has a domain structure characteristic of ADAMTSs. Beginning at the N terminus, it has a preproregion containing a potential furin cleavage site and a putative cysteine-switch, a catalytic domain containing a typical reprolysin-type zinc-binding signature and a 'met turn,' a disintegrin-like domain, a conserved thrombospondin module, a cysteine-rich domain, a spacer domain, and a second, less conserved thrombospondin module. The mature ADAMTS7 protein has 2 potential N-linked glycosylation sites. Northern blot analysis detected a 5-kb ADAMTS7 transcript in all human tissues examined, namely brain, heart, lung, liver, pancreas, kidney, skeletal muscle, and placenta; skeletal muscle expressed an additional 7-kb transcript. Mouse Adamts7 was expressed at low levels throughout mouse development.
Somerville et al. (2004) reported that full-length human ADAMTS7, which they called ADAMTS7B, contains 1,686 amino acids, has a calculated molecular mass of 181 kD, and shares 67% identity with its mouse ortholog. Full-length ADAMTS7 contains an N-terminal signal peptide, followed by a prodomain, a catalytic domain with a conserved zinc-binding active site, a disintegrin (see 601533)-like domain, a thrombospondin (see 188060) type I repeat, a cysteine-rich domain, a spacer domain, 3 more TSRs, a serine/threonine-rich mucin (see 158340) domain, 4 more TSRs, and a C-terminal protease and lacunin (PLAC) domain. In addition, full-length ADAMTS7 has 7 furin recognition sequences in its prodomain, 10 N-glycosylation sites, a heparin-binding motif in TSR1, a CD36 (173510)-binding motif in TSR4, and a glycosaminoglycan (GAG) attachment site in the mucin domain. Full-length ADAMTS7 and ADAMTS12 (606184) are highly homologous and constitute a distinct ADAMTS phylogenetic clade. Somerville et al. (2004) determined that full-length ADAMTS7 and the shorter variant reported by Hurskainen et al. (1999) are produced through alternative splicing. Northern blot analysis showed wide expression of ADAMTS7 in human and mouse tissues. Expression of full-length mouse Adamts7 in HEK293F cells showed that mature Adamts7 was secreted and posttranslationally modified by N- and O-glycosylation.
Bai et al. (2009) found that human ADAMTS7 associated with the cell surface and extracellular matrix in transfected rat chondrosarcoma cells.
Using quantitative PCR, Bauer et al. (2015) detected highest Adamts7 mRNA expression in mouse heart, brain, lung, intestine and adrenal gland, with lower expression in liver, spleen, kidney, brown fat, thyroid, and skeletal muscle. Immunohistochemical studies showed that ADAMTS7 was expressed in human atherosclerosis. Immunofluorescence analysis of primary human aortic smooth muscle cells revealed ADAMTS7 in cytoplasmic granules and at the cell membrane, where it localized to the migrating edge and podosome-like structures.
Somerville et al. (2004) determined that the ADAMTS7 gene contains 24 coding exons and spans 52.3 kb.
By somatic cell hybrid analysis, Hurskainen et al. (1999) mapped the human ADAMTS7 gene to chromosome 15.
Somerville et al. (2004) stated that the ADAMTS7 gene maps to chromosome 15q24.
Hartz (2013) mapped the ADAMTS7 gene to chromosome 15q25.1 based on an alignment of the ADAMTS7 sequence (GenBank AF140675) with the genomic sequence (GRCh37).
Using alpha-2-macroglobulin as substrate, Somerville et al. (2004) showed that full-length ADAMTS7 was an active metalloproteinase. However, it could not process peptide bonds in versican (VCAN; 118661) and aggrecan (ACAN; 155760) typically processed by ADAMTS proteases.
Using quantitative real-time PCR, Liu et al. (2006) found that ADAMTS7 was upregulated in rheumatoid arthritic cartilage and synovium compared with normal controls. ADAMTS7 expression was also slightly upregulated in osteoarthritic cartilage. Using a yeast 2-hybrid screen, Liu et al. (2006) observed that rat Adamts7 binds human COMP (600310), an extracellular matrix protein that interacts with several partners and is prominent in cartilage. The interaction was confirmed by protein pull-down and immunoprecipitation experiments. Domain analysis revealed that the C-terminal thrombospondin repeats of Adamts7 interact with the EGF-like domain of COMP. Either full-length rat Adamts7 or the isolated catalytic domain (amino acids 217 to 468) of human ADAMTS7 digested COMP in a dose- and time-dependent manner. The reaction required zinc and functioned in a pH range between 7.5 and 9.5.
The mouse embryonic mesenchymal stem cell line C3H10T1/2 can be induced to differentiate into chondrocytes in high-density cultures in the presence of BMP2 (112261). Bai et al. (2009) found that overexpression of human ADAMTS7 inhibited C3H10T1/2 cell chondrocyte differentiation. Mutation of conserved histidine residues in the catalytic domain of ADAMTS7 inactivated its proteolytic activity against the noncollagen cartilage protein Comp (600310) and permitted chondrocyte differentiation. Similar results were obtained with human mesenchymal stem cells. Proteolytically active human ADAMTS7 strongly inhibited chondrocyte hypertrophy, mineralization, and bone length in fetal mouse metatarsals. Pthrp (PTHLH; 168470) enhanced Adamts7 expression during late chondrogenesis in mouse, and addition of anti-Adamts7 antibody abolished Pthrp-mediated inhibition of chondrocyte hypertrophy, mineralization, and bone lengthening. Yeast 2-hybrid analysis and coimmunoprecipitation analysis of native human chondrocytes showed that ADAMTS7 associated with the chondrogenic growth factor GEP (GRN; 138945). The proteolytic activity of ADAMTS7 inactivated the chondrogenic effect of GEP. Bai et al. (2009) concluded that ADAMTS7 is a potent negative regulator of chondrocyte differentiation and endochondral bone growth.
Pu et al. (2013) found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Immunostaining revealed that vascular smooth muscle cells that accumulated ADAMTS7 were located mostly near the intima-media border and the fibrous cap. ADAMTS7 stains were detected both within cells and in the extracellular spaces.
Associations Pending Confirmation
Several genomewide association studies (Schunkert et al., 2011; Reilly et al., 2011; Coronary Artery Disease C4D Genetics Consortium, 2011) had revealed an association between a variation in the ADAMTS7 locus and susceptibility to coronary artery disease. In a population-based study cohort, Pu et al. (2013) observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a serine-to-proline substitution in the prodomain of the protease ADAMTS7. Pu et al. (2013) found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of vascular smooth muscle cells of the G/G genotype contained less of the cleaved form of thrombospondin-5 (COMP; 600310), an ADAMTS7 substrate produced by vascular smooth muscle cells that inhibits vascular smooth muscle cell migration. Furthermore, Pu et al. (2013) found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by vascular smooth muscle cells of the G/G genotype and that the ser-to-pro substitution affected ADAMTS7 prodomain cleavage. Pu et al. (2013) concluded that the results of their study indicated that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and vascular smooth muscle cell migration, with the variant associated with protection from atherosclerosis and coronary artery disease rendering a reduction in ADAMTS7 function.
Bauer et al. (2015) found that Adamts7 -/- mice had no obvious abnormalities, reproduced normally, and appeared healthy under chow-fed conditions. Adamts7 deficiency reduced atherosclerosis in both Ldlr (606945)-knockout and Apoe (107741)-knockout hyperlipidemic mice compared with controls. Adamts7 -/- mice had reduced neointimal response to mechanical vascular injury and maintained vascular smooth muscle cell (VSMC) phenotype during early phases of inflammatory stress and mechanical injury. Examination of the time course of Adamts7 vascular expression demonstrated that Adamts7 was induced transiently and expressed only during earlier stages of atherogenesis in mice, likely via inflammatory and hyperlipidemic triggers.
Bai, X.-H., Wang, D.-W., Kong, L., Zhang, Y., Luan, Y., Kobayashi, T., Kronenberg, H. M., Yu, X.-P., Liu, C. ADAMTS-7, a direct target of PTHrP, adversely regulates endochondral bone growth by associating with and inactivating GEP growth factor. Molec. Cell. Biol. 29: 4201-4219, 2009. [PubMed: 19487464] [Full Text: https://doi.org/10.1128/MCB.00056-09]
Bauer, R. C., Tohyama, J., Cui, J., Cheng, L., Yang, J., Zhang, X., Ou, k., Paschos, G. K., Zheng, X. L., Parmacek, M. S., Rader, D. J., Reilly, M. P. Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice. Circulation 131: 1202-1213, 2015. [PubMed: 25712206] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.114.012669]
Coronary Artery Disease C4D Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies 5 new loci for coronary artery disease. Nature Genet. 43: 339-344, 2011. [PubMed: 21378988] [Full Text: https://doi.org/10.1038/ng.782]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/16/2013.
Hurskainen, T. L., Hirohata, S., Seldin, M. F., Apte, S. S. ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases: general features and genomic distribution of the ADAM-TS family. J. Biol. Chem. 274: 25555-25563, 1999. [PubMed: 10464288] [Full Text: https://doi.org/10.1074/jbc.274.36.25555]
Liu, C., Kong, W., Ilalov, K., Yu, S., Xu, K., Prazak, L., Fajardo, M., Sehgal, B., Di Cesare, P. E. ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. FASEB J. 20: 988-990, 2006. [PubMed: 16585064] [Full Text: https://doi.org/10.1096/fj.05-3877fje]
Pu, X., Xiao, Q., Kiechl, S., Chan, K., Ng, F. L., Gor, S., Poston, R. N., Fang, C., Patel, A., Senver, E. C., Shaw-Hawkins, S., Willeit, J., Liu, C., Zhu, J., Tucker, A. T., Xu, Q., Caulfield, M. J., Ye, S. ADAMTS17 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. Am. J. Hum. Genet. 92: 366-374, 2013. [PubMed: 23415669] [Full Text: https://doi.org/10.1016/j.ajhg.2013.01.012]
Reilly, M. P., Li, M., He, J., Ferguson, J. F., Stylianou, I. M., Mehta, N. N., Burnett, M. S., Devaney, J. M., Knouff, C. W., Thompson, J. R., Home, B. D., Stewart, A. F. R., and 22 others. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377: 383-392, 2011. [PubMed: 21239051] [Full Text: https://doi.org/10.1016/S0140-6736(10)61996-4]
Schunkert, H., Konig, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F. R., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., and 155 others. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genet. 43: 333-338, 2011. [PubMed: 21378990] [Full Text: https://doi.org/10.1038/ng.784]
Somerville, R. P. T., Longpre, J.-M., Apel, E. D., Lewis, R. M., Wang, L. W., Sanes, J. R., Leduc, R., Apte, S. S. ADAMTS7B, the full-length product of the ADAMTS7 gene, is a chondroitin sulfate proteoglycan containing a mucin domain. J. Biol. Chem. 279: 35159-35175, 2004. [PubMed: 15192113] [Full Text: https://doi.org/10.1074/jbc.M402380200]