Alternative titles; symbols
HGNC Approved Gene Symbol: ADAM9
Cytogenetic location: 8p11.22 Genomic coordinates (GRCh38): 8:38,996,973-39,105,261 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p11.22 | Cone-rod dystrophy 9 | 612775 | Autosomal recessive | 3 |
McKie et al. (1996) obtained a random PCR product from a human myeloma cell library. They cloned a full-length cDNA and named the gene MCMP for 'myeloma cell metalloproteinase.' The sequence of the cDNA predicted a 660-amino acid polypeptide containing several domains: a signal peptide, a zinc-dependent metalloproteinase domain, a disintegrin-like domain, a cysteine-rich domain, an epidermal growth factor-like region, and a putative transmembrane domain. Northern blot analysis revealed that MCMP produces a 3.8-kb mRNA, which was present in all tested myeloma cell lines. The expressed sequence tag (EST) database contains sequences of MCMP cDNAs derived from other human tissues. McKie et al. (1996) concluded that MCMP is a member of the ADAM ('a disintegrin and metalloproteinase') family and exhibits a number of characteristics of class III reprolysins.
Weskamp et al. (1996) cloned mouse and human ADAM9. The deduced mouse protein contains 845 amino acids, and the longest human clone identified predicts a protein of 819 amino acids. The human protein lacks amino acids corresponding to mouse residues 752 to 777. Northern blot analysis of human and mouse tissues revealed ubiquitous expression. Western blot analysis of mouse lung extracts showed a strong band with an apparent molecular mass of about 84 kD and 2 weaker bands of 115 and 60 kD.
By PCR, Hotoda et al. (2002) cloned ADAM9 from a human glioblastoma cell cDNA library. They identified clones corresponding to the full-length 819-amino acid protein and to a splice variant encoding a deduced 656-amino acid protein, which they designated ADAM9s. ADAM9s contains a deletion within the EGF-like domain and consequently lacks the transmembrane and cytoplasmic domains. RT-PCR detected expression of both variants in all tissues examined, with higher expression of ADAM9s in liver and heart. Western blot analysis of the culture medium of COS cells transfected with ADAM9s revealed secretion of ADAM9 proteins with apparent molecular masses of 86 and 55 kD. Hotoda et al. (2002) suggested that the upper band represents the inactive form containing the prodomain, while the lower band represents the active form without the prodomain.
Using a yeast 2-hybrid analysis with the cytoplasmic tails of several ADAM proteins as bait, Nelson et al. (1999) found that MAD2L2 (604094) interacts with MDC9 (ADAM9) and ADAM15 (605548) strongly and with ADAM19 (603640) weakly, but not with TACE (ADAM17; 603639), which interacts with MAD2L1 (601467). Further binding analyses determined that the interaction of MAD2L2 with ADAM9 is mediated through a proline-rich SH3-ligand domain of ADAM9.
Howard et al. (1999) demonstrated that the SH3 domains of endophilin-1 (604465) and sorting nexin-9 (605952) interact with the cytoplasmic domains of ADAM9 and ADAM15.
Zhou et al. (2001) showed that the ADAM9 disintegrin domain is a binding partner for myeloma but not lymphoblastoid cell lines. Adhesion to the disintegrin domain could be inhibited by antibody to integrin alpha-V (ITGAV; 193210)/beta-5 (ITGB5; 147561) but not by antibodies to other subunits or by RGD motif-containing peptides. Zhou et al. (2001) pointed out that ADAM9 is a disintegrin that lacks an RGD motif. Flow cytometric analysis demonstrated that myeloma cells, but not lymphoblastoid cells, express ITGAV/ITGB5 on the cell membrane.
By transfecting double-stranded RNA corresponding to several ADAMs, Asai et al. (2003) determined that the alpha-secretase activity displayed by a human glioblastoma cell line toward amyloid precursor protein (APP; 104760) was catalyzed by the combined activity of ADAM9, ADAM10 (602192), and ADAM17.
By coexpression of APP and ADAM9 in COS cells, Hotoda et al. (2002) found that phorbol ester treatment increased the digestion of APP, with cleavage exclusively at the alpha-secretory site.
Parry et al. (2009) determined that the ADAM9 gene contains 22 exons.
In affected members of 4 consanguineous families with recessively inherited early-onset cone-rod dystrophy (CORD9; 612775), Parry et al. (2009) identified mutations in the ADAM9 gene (602713.0001-602713.0004). Two were nonsense mutations and the other 2 affected splicing and appeared to lead to nonsense changes, strongly suggesting that ADAM9 was absent in these patients because of nonsense-mediated decay.
In 3 affected members of a consanguineous Egyptian family with cone-rod dystrophy, El-Haig et al. (2014) identified homozygosity for a splice site mutation in the ADAM9 gene (602713.0005) that segregated with the disorder in the family.
Weskamp et al. (2002) found that during normal mouse development, Adam9 mRNA is ubiquitously expressed, with particularly high expression in the developing mesenchyme, heart, and brain. Mice lacking Adam9 appeared to develop normally. They were viable and fertile and had no major pathologic changes. Embryonic fibroblasts isolated from Adam9-null mice showed constitutive and stimulated Hbegf (126150) shedding comparable to that of wildtype mice, and mutant hippocampal neurons showed normal App secretase cleavage products, suggesting functional compensation or redundancy involving other ADAM family members.
After identifying homozygous null mutations in ADAM9 in patients with cone-rod dystrophy, Parry et al. (2009) reanalyzed Adam9 null mice. The 12-month-old mice showed an abnormal gap between the photoreceptor outer segments and the retinal pigment epithelium. Electron microscopy revealed extended, malformed vesiculated RPE apical processes and disrupted contact with POS. However, photoreceptors and other neural layers appeared structurally normal at this age. At 20 months of age, Adam9-null mice showed evidence of further degeneration.
In a large Brazilian family with autosomal recessive cone-rod dystrophy (CORD9; 612775), originally reported by Danciger et al. (2001), Parry et al. (2009) identified a homozygous G-to-A transition at the +1 position of intron 11 of the ADAM9 gene (1130+1G-A), abolishing the splice site. The mutation was present in homozygosity in all affected family members and was not found in any unaffected family members, nor in 190 ethnically matched control individuals.
In a consanguineous Pakistani family with autosomal recessive cone-rod dystrophy (CORD9; 612775), Parry et al. (2009) identified homozygosity for a 766C-T transition in exon 9 of the ADAM9 gene, resulting in an arg256-to-ter (R256X) substitution. This mutation was not identified in 138 ethnically matched control individuals.
In a consanguineous Tunisian Jewish family segregating autosomal recessive cone-rod dystrophy (CORD9; 612775), Parry et al. (2009) identified homozygosity for a 490C-T transition in the ADAM9 gene, resulting in an arg-to-ter substitution at codon 164 (R164X). This mutation segregated with the phenotype and was not identified in 105 ethnically matched control individuals.
In a consanguineous Arab Muslim family segregating autosomal recessive cone-rod dystrophy (CORD9; 612775), Parry et al. (2009) identified homozygosity for an intronic change in the ADAM9 gene (411-8A-G). This mutation activated a cryptic splice acceptor site giving rise only to an aberrant transcript. The mutant transcript had 7 additional basepairs added to the beginning of exon 6 and was predicted to introduce a frameshift resulting in premature termination (Arg137SerfsTer16). This mutation was not identified in 160 ethnically matched individuals.
In an affected mother and 2 of her sons from a consanguineous Egyptian family with cone-rod dystrophy (CORD9; 612775), El-Haig et al. (2014) identified homozygosity for a splice site mutation (c.1396-2A-G) in intron 13 of the ADAM9 gene. The father and 4 of their other children were heterozygous for the mutation, which was not found in 906 ethnically matched controls or in 96 Caucasian controls. Functional studies were not reported.
Asai, M., Hattori, C., Szabo, B., Sasagawa, N., Maruyama, K., Tanuma, S., Ishiura, S. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem. Biophys. Res. Commun. 301: 231-235, 2003. [PubMed: 12535668] [Full Text: https://doi.org/10.1016/s0006-291x(02)02999-6]
Danciger, M., Hendrickson, J., Lyon, J., Toomes, C., McHale, J. C., Fishman, G. A. Inglehearn, C. F., Jacobson, S. G., Farber, D. B. CORD9 a new locus for arCRD: mapping to 8p11, estimation of frequency, evaluation of a candidate gene. Invest. Ophthal. Vis. Sci. 42: 2458-2465, 2001. [PubMed: 11581183]
El-Haig, W. M., Jakobsson, C., Favez, T., Schorderet, D. F., Abouzeid, H. Novel ADAM9 homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract. Brit. J. Ophthal. 98: 1718-1723, 2014. [PubMed: 25091951] [Full Text: https://doi.org/10.1136/bjophthalmol-2014-305231]
Hotoda, N., Koike, H., Sasagawa, N., Ishiura, S. A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem. Biophys. Res. Commun. 293: 800-805, 2002. [PubMed: 12054541] [Full Text: https://doi.org/10.1016/S0006-291X(02)00302-9]
Howard, L., Nelson, K. K., Maciewicz, R. A., Blobel, C. P. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J. Biol. Chem. 274: 31693-31699, 1999. [PubMed: 10531379] [Full Text: https://doi.org/10.1074/jbc.274.44.31693]
McKie, N., Dallas, D. J., Edwards, T., Apperley, J. F., Russell, R. G. G., Croucher, P. I. Cloning of a novel membrane-linked metalloproteinase from human myeloma cells. Biochem. J. 318: 459-462, 1996. [PubMed: 8809033] [Full Text: https://doi.org/10.1042/bj3180459]
Nelson, K. K., Schlondorff, J., Blobel, C. P. Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2-beta. Biochem. J. 343: 673-680, 1999. [PubMed: 10527948]
Parry, D. A., Toomes, C., Bida, L., Danciger, M., Towns, K. V., McKibbin, M., Jacobson, S. G., Logan, C. V., Ali, M., Bond, J., Chance, R., Swendeman, S., and 15 others. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am. J. Hum. Genet. 84: 683-691, 2009. [PubMed: 19409519] [Full Text: https://doi.org/10.1016/j.ajhg.2009.04.005]
Weskamp, G., Cai, H., Brodie, T. A., Higashyama, S., Manova, K., Ludwig, T., Blobel, C. P. Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Molec. Cell. Biol. 22: 1537-1544, 2002. [PubMed: 11839819] [Full Text: https://doi.org/10.1128/MCB.22.5.1537-1544.2002]
Weskamp, G., Kratzschmar, J., Reid, M. S., Blobel, C. P. MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J. Cell Biol. 132: 717-726, 1996. [PubMed: 8647900] [Full Text: https://doi.org/10.1083/jcb.132.4.717]
Zhou, M., Graham, R., Russell, G., Croucher, P. I. MDC-9 (ADAM-9/meltrin gamma) functions as an adhesion molecule by binding the alpha-V/beta-5 integrin. Biochem. Biophys. Res. Commun. 280: 574-580, 2001. [PubMed: 11162558] [Full Text: https://doi.org/10.1006/bbrc.2000.4155]