HGNC Approved Gene Symbol: ADAMTS9
Cytogenetic location: 3p14.1 Genomic coordinates (GRCh38) : 3:64,515,654-64,688,000 (from NCBI)
ADAMTS9 is a member of the large ADAMTS family of zinc-dependent proteases. For a general description of the ADAMTS gene family, see ADAMTS1 (605174).
Using a fragment of rat Adamts9 to probe a human spinal cord library, followed by the identification of overlapping clones and 5-prime and 3-prime RACE in placenta and fetus cDNA libraries, Clark et al. (2000) identified a cDNA encoding ADAMTS9. The deduced 1,072-amino acid protein has a structure similar to other ADAMTS family members. Like ADAMTS1 and ADAMTS4 (603876), ADAMTS9 has an asp instead of the second gly in the metalloprotease domain. ADAMTS9 contains 1 internal TSP1 repeat and 3 C-terminal TSP1-like submotifs. Similar to other ADAMTS proteins, Northern blot analysis detected low levels of ADAMTS9 expression. RT-PCR analysis revealed expression in ovary, pancreas, heart, lung, placenta, and, notably, adult kidney, as well as strong expression in all fetal tissues examined. Using hybridization to cDNA libraries, ADAMTS9 expression was also detected in spinal cord and brain.
By screening human fetal brain cDNAs for the potential to encode large proteins, Nagase et al. (2000) isolated an ADAMTS9 cDNA, which they called KIAA1312, that encodes a deduced 1,471-amino acid protein. RT-PCR followed by ELISA detected very low levels of ADAMTS9 expression in lung, liver, kidney, and spinal cord.
By database analysis using known ADAMTS sequences as probe, followed PCR and RACE of a cDNA library, Somerville et al. (2003) cloned ADAMTS9. The deduced 1,935-amino acid protein has a calculated molecular mass of 216 kD, and the mature enzyme has a predicted molecular mass of 184 kD. ADAMTS9 has a C-terminal array of 14 thrombospondin type I repeats (TSRs), and the cysteine signatures of ADAMTS9 modules contain an even number of cysteines with potential to form intrachain disulfide bonds and share similarity with several other ADAMTS family members. ADAMTS9 contains a signal peptide, 5 consensus furin cleavage sites, 9 N-linked glycosylation sites, 1 potential site for glycosaminoglycan (GAG) attachment, 3 CSVTCG motifs that may mediate binding to the cell surface molecule CD36 (173510), and 2 BBXB motifs that mediate heparin and sulfatide binding. The ADAMTS9 zinc-binding site is identical to that of ADAMTS1 and ADAMTS15 (607509). ADAMTS9 shares 48% amino acid identity with ADAMTS20 (611681). Northern blot analysis of human tissues detected strong expression of an 8.0-kb transcript in heart, placenta, skeletal muscle, kidney, and pancreas with a 4.5-kb transcript in kidney and ovary. Immunofluorescence microscopy localized ADAMTS9 to the extracellular matrix and the cell surface in transfect COS-1 cells.
Yoshina et al. (2012) reported that ADAMTS9 contains a C-terminal GON domain following the thrombospondin array. The GON domain is similar to a domain in C. elegans Gon1, a protein essential for gonad development.
Somerville et al. (2003) determined that the ADAMTS9 gene contains 39 exons spanning 137 kb.
Using FISH, Clark et al. (2000) mapped the ADAMTS9 gene to chromosome 3p21.1-p14.3, a region of frequent deletions and rearrangements in renal cell carcinomas, breast cancers, uterine cervical carcinomas, and vulvar carcinomas. By PCR analysis of a radiation hybrid panel, Clark et al. (2000) mapped ADAMTS9 more precisely to 3p14.3-p14.2.
Somerville et al. (2003) showed that ADAMTS9-transfected COS-1 cells proteolytically cleaved bovine versican (118661) and aggrecan (155760). Proteolytic activity required the catalytic domain as well as ancillary domains, including the TSRs.
Lo et al. (2007) identified a 1.61-Mb tumor suppressive critical region on chromosome 3p14.2 encompassing the ADAMTS9 gene by using microcell-mediated chromosome transfer to a human esophageal squamous cell cancer (ESCC) line SLMT1 (see 133239) and subsequent mouse tumorigenicity assays. Tumor-suppressed hybrid cells showed normal ADAMTS9 expression levels, whereas 15 of 16 esophageal cancer cell lines showed decreased or absent expression. Downregulation of ADAMTS9 was also found in 40 to 50% of primary esophageal tumor tissues. ADAMTS9 promoter hypermethylation was detected in the cell lines that showed decreased or absent expression, and demethylation drug treatment resulted in ADAMTS9 reexpression. The findings suggested that ADAMTS9 may contribute to the development of esophageal cancer.
Yoshina et al. (2012) found that deletion or depletion of Gon1 in nematode or ADAMTS9 in HEK293 cells disrupted the structure of the endoplasmic reticulum (ER) and interfered with ER-to-Golgi transport of test proteins. Transfection of cells with the GON domain in the absence of protease activity rescued the ER phenotype. Yoshina et al. (2012) concluded that nematode Gon1 and human ADAMTS9 have an extracellular function in extracellular matrix degradation and an intracellular function in ER-to-Golgi transport.
Nandadasa et al. (2019) found that ADAMTS9 and ADAMTS20 localized at the base of primary cilium of mouse and human cells. ADAMTS9 was secreted after its propeptide was cleaved extracellularly by furin (136950). Secreted ADAMTS9 was internalized by clathrin-mediated endocytosis and transported to primary cilium in a highly dynamic process necessary for ciliogenesis. ADAMTS9 and ADAMTS20 acted as proteases for cleavage of the extracellular matrix (ECM) component versican, and ADAMTS9 and ADAMTS20 catalytic activities were essential and functionally redundant during ciliogenesis. Loss of ADAMTS9 significantly reduced ciliogenesis, which could be restored by overexpression of ADAMTS9 or ADAMTS20. Further analysis revealed that ADAMTS9 function affected basal body maturation and ciliary vesicle growth stages during ciliogenesis.
Associations Pending Confirmation
For discussion of a possible association between variation near the ADAMTS9 gene and age-related macular degeneration, see ARMD1 (603075).
Nandadasa et al. (2015) generated mice expressing a C-terminally truncated Adamts9 mutant that was constitutively membrane-anchored and restricted to the cell surface. Unlike the Adamts9-null allele, this hypomorphic allele was sufficient for mutant mice to survive past gastrulation (i.e., embryonic day 7.0, or E7.0), but not beyond E15.5. Mutant mouse embryos had impaired umbilical cord growth with failed reorientation of vascular smooth muscle cells (VSMCs). Transmission electron microscopy and immunofluorescence analysis showed that loss of Adamts9 function altered ECM dynamics and impaired VSMC proliferation and differentiation. Immunostaining analysis demonstrated that altered ECM dynamics in umbilical cord disrupted the radial orientation of primary cilium, accompanied by compromised Shh (600725) and Pdgfr-beta (PDGFRB; 173410) pathways, the 2 major pathways regulating VSMC recruitment and differentiation. Conditional deletion of Adamts9 in developing hind limbs, lung mesenchyme, and umbilical cord mesenchyme, but not VSMC-specific deletion, recapitulated the phenotype of mice carrying the Adamts9 hypomorphic allele.
Nandadasa et al. (2019) found that loss of Adamts9 and Adamts20 in mouse embryos resulted in severe developmental defects with impaired ciliogenesis and Shh signaling. Mutant mouse embryos displayed abnormal ECM dynamics in neural tubes. In yolk sac, where Adamts20 is not expressed, loss of Adamts9 alone resulted in defective angiogenesis, cilia, Hh signaling, and abnormal ECM. Analysis in ADAMTS9-null RPE1 cells demonstrated that ciliogenesis defects were independent of Shh signaling and cleavage of versican.
Clark, M. E., Kelner, G. S., Turbeville, L. A., Boyer, A., Arden, K. C., Maki, R. A. ADAMTS9, a novel member of the ADAM-TS/metallospondin gene family. Genomics 67: 343-350, 2000. [PubMed: 10936055] [Full Text: https://doi.org/10.1006/geno.2000.6246]
Lo, P. H. Y., Leung, A. C. C., Kwok, C. Y. C., Cheung, W. S. Y., Ko, J. M. Y., Yang, L. C., Law, S., Wang, L. D., Li, J., Stanbridge, E. J., Srivastava, G., Tang, J. C. O., Tsao, S. W., Lung, M. L. Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9. Oncogene 26: 148-157, 2007. [PubMed: 16799631] [Full Text: https://doi.org/10.1038/sj.onc.1209767]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Nandadasa, S., Kraft, C. M., Wang, L. W., O'Donnell, A., Patel, R., Gee, H. Y., Grobe, K., Cox, T. C., Hildebrandt, F., Apte, S. S. Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis. Nature Commun. 10: 953, 2019. Note: Electronic Article. [PubMed: 30814516] [Full Text: https://doi.org/10.1038/s41467-019-08520-7]
Nandadasa, S., Nelson, C. M., Apte, S. ADAMTS9-mediated extracellular matrix dynamics regulates umbilical cord vascular smooth muscle differentiation and rotation. Cell Rep. 11: 1519-1528, 2015. [PubMed: 26027930] [Full Text: https://doi.org/10.1016/j.celrep.2015.05.005]
Somerville, R. P. T., Longpre, J.-M., Jungers, K. A., Engle, J. M., Ross, M., Evanko, S., Wight, T. N., Leduc, R., Apte, S. S. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J. Biol. Chem. 278: 9503-9513, 2003. [PubMed: 12514189] [Full Text: https://doi.org/10.1074/jbc.M211009200]
Yoshina, S., Sakaki, K., Yonezumi-Hayashi, A., Gengyo-Ando, K., Inoue, H., Iino, Y., Mitani, S. Identification of a novel ADAMTS9/GON-1 function for protein transport from the ER to the Golgi. Molec. Biol. Cell 23: 1728-1741, 2012. [PubMed: 22419820] [Full Text: https://doi.org/10.1091/mbc.E11-10-0857]