Alternative titles; symbols
HGNC Approved Gene Symbol: ANXA7
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:73,375,101-73,414,058 (from NCBI)
Synexin is a calcium-dependent membrane-binding protein that not only fuses membranes but also acts as a voltage-dependent calcium channel.
Burns et al. (1989) isolated and sequenced a set of overlapping cDNA clones for human synexin. Its derived amino acid sequence shows strong homology in the C-terminal domain with a previously identified class of calcium-dependent membrane-binding proteins, including endonexin II (131230), lipocortin I (151690), calpactin I heavy chain (114085), and others.
Magendzo et al. (1991) cloned 3 variants of synexin cDNA from a human fibroblast cDNA library. Sequence analysis indicated that the variants were formed by alternative splicing and use of alternate polyadenylation signals. Northern blot analysis of fibroblasts revealed transcripts of 2.0 and 2.4 kb. Using primers designed to differentiate between these 2 forms by PCR, Magendzo et al. (1991) found the larger transcript, containing a 66-bp exon, in human and monkey brain, heart, and skeletal muscle. They found the variant lacking this exon in liver, lung, kidney, spleen, fibroblasts, and placenta. Western blot analysis indicated the presence of the larger protein in human skeletal muscle and the smaller protein in lung.
The ANX7 gene is located on chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene or genes associated with prostate and other cancers. To test this hypothesis, Srivastava et al. (2001) analyzed the action of the ANX7 gene on colony formation by human tumor cell lines. They also examined the expression of the ANX7 protein in a large number of prostate cancers using tumor tissue microarray technology. Finally, they tested a panel of primary and metastatic prostate cancers for evidence of loss of heterozygosity (LOH). They found that human tumor cell proliferation and colony formation were markedly reduced when the wildtype ANX7 gene was transfected into 2 prostate tumor cell lines. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays revealed a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using 4 microsatellite markers at or near the ANX7 locus and laser capture microdissected tumor cells, 35% of 20 primary prostate tumors showed LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including 1 homozygous deletion. Srivastava et al. (2001) concluded that the ANX7 gene exhibits many biologic and genetic properties expected of a tumor suppressor gene and may play a role in prostate cancer progression.
Caohuy et al. (1996) present experimental evidence, based on studies of recombinant human ANXA7 and isolated bovine chromaffin cells, that ANXA7 is a Ca(2+)-dependent GTP binding protein. ANXA7 was active in a chromaffin granule aggregation assays in the presence of Ca(2+) and GTP, and was deactivated upon GTP hydrolysis.
Shirvan et al. (1994) determined that the synexin gene contains 14 exons, including an alternatively spliced cassette exon, and spans approximately 34 kb of DNA. Only 5 of the 14 spliced exons are conserved compared to other annexins; the differences are particularly pronounced in the exons that encode the C-terminal third and fourth conserved repeats in the gene product. Shirvan et al. (1994) concluded that the ANXA7 gene may have diverged from the evolutionary pathway taken by both ANXA1 and ANXA2.
Zhang-Keck et al. (1994) found that the mouse homolog also contains 14 exons; it spans approximately 30 kb of genomic DNA.
Shirvan et al. (1994) isolated genomic clones of the ANXA7 gene and assigned the gene to 10q21.1-q21.2 by study of somatic cell hybrids and by in situ hybridization.
By study of Chinese hamster/mouse somatic cell hybrids and by linkage analyses in interspecific crosses, Zhang-Keck et al. (1994) demonstrated that the functional synexin gene is located on mouse chromosome 14 and that a pseudogene is located on chromosome 10.
By gene targeting, Srivastava et al. (1999) developed Anxa7-null mice. The null phenotype was lethal at embryonic day 10. Heterozygous mice were viable and fertile, but showed a defect in insulin secretion and an increased insulin content within isolated pancreatic islets. Electrooptical recordings suggested that the mutation altered Ca(2+) release by agonists of inositol trisphosphate.
Using mice with a different genetic background and an alternate strategy to introduce the null mutation, Herr et al. (2001) developed Anxa7 -/- mice that were viable, fertile, and showed no obvious defects. Analysis of insulin secretion from isolated islets revealed no evidence for the involvement of Anxa7 in Ca(2+)-dependent or cAMP-mediated exocytosis. In cardiomyocytes, however, they found a functional role for Anxa7 in electromechanical coupling. Cardiomyocytes from embryonic Anxa7-null mice displayed intact Ca(2+) homeostasis and unremarkable excitation-contraction coupling; however, adult Anxa7 -/- mice exhibited a decrease in frequency-induced cell shortening.
To investigate the mechanism by which the ANX7 gene controls tumor development, Srivastava et al. (2003) developed an Anx7 +/- knockout mouse. As hypothesized, these heterozygous mice had a cancer-prone phenotype. The emerging tumors expressed low levels of Anx7 protein. Nonetheless, the wildtype Anx7 allele was detectable in tumor tissue cells. Genome array analysis of hepatocellular carcinoma tissue indicated that the Anx7 +/- genotype is accompanied by profound reductions of expression of several other tumor suppressor genes, DNA repair genes, and apoptosis-related genes. In situ analysis by tissue imprinting from chromosomes in the primary tumor and spectral karyotyping analysis of derived cell lines identified chromosomal instability and clonal chromosomal aberrations. Furthermore, whereas 23% of the mutant mice developed spontaneous neoplasms, all mice exhibited growth anomalies, including gender-specific gigantism and organomegaly. Srivastava et al. (2003) concluded that haploinsufficiency of Anx7 expression drives disease progression to cancer because of genomic instability through a discrete signaling pathway involving other tumor suppressor genes, DNA-repair genes, and apoptosis-related genes.
Burns, A. L., Magendzo, K., Shirvan, A., Srivastava, M., Rojas, E., Alijani, M. R., Pollard, H. B. Calcium channel activity of purified human synexin and structure of the human synexin gene. Proc. Nat. Acad. Sci. 86: 3798-3802, 1989. [PubMed: 2542947] [Full Text: https://doi.org/10.1073/pnas.86.10.3798]
Caohuy, H., Srivastava, M., Pollard, H. B. Membrane fusion protein synexin (annexin VII) as a Ca(2+)/GTP sensor in exocytotic secretion. Proc. Nat. Acad. Sci. 93: 10797-10802, 1996. [PubMed: 8855260] [Full Text: https://doi.org/10.1073/pnas.93.20.10797]
Herr, C., Smyth, N., Ullrich, S., Yun, F., Sasse, P., Hescheler, J., Fleischmann, B., Lasek, K., Brixius, K., Schwinger, R. H. G., Fassler, R., Schroder, R., Noegel, A. A. Loss of annexin A7 leads to alterations in frequency-induced shortening of isolated murine cardiomyocytes. Molec. Cell. Biol. 21: 4119-4128, 2001. [PubMed: 11390641] [Full Text: https://doi.org/10.1128/MCB.21.13.4119-4128.2001]
Magendzo, K., Shirvan, A., Cultraro, C., Srivastava, M., Pollard, H. B., Burns, A. L. Alternative splicing of human synexin mRNA in brain, cardiac, and skeletal muscle alters the unique N-terminal domain. J. Biol. Chem. 266: 3228-3232, 1991. [PubMed: 1825209]
Shirvan, A., Srivastava, M., Wang, M. G., Cultraro, C., Magendzo, K., McBride, O. W., Pollard, H. B., Burns, A. L. Divergent structure of the human synexin (annexin VII) gene and assignment to chromosome 10. Biochemistry 33: 6888-6901, 1994. [PubMed: 7515686] [Full Text: https://doi.org/10.1021/bi00188a019]
Srivastava, M., Atwater, I., Glasman, M., Leighton, X., Goping, G., Caohuy, H., Miller, G., Pichel, J., Westphal, H., Mears, D., Rojas, E., Pollard, H. B. Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse. Proc. Nat. Acad. Sci. 96: 13783-13788, 1999. [PubMed: 10570150] [Full Text: https://doi.org/10.1073/pnas.96.24.13783]
Srivastava, M., Bubendorf, L., Srikantan, V., Fossom, L., Nolan, L., Glasman, M., Leighton, X., Fehrle, W., Pittaluga, S., Raffeld, M., Koivisto, P., Willi, N., Gasser, T. C., Kononen, J., Sauter, G., Kallioniemi, O. P., Srivastava, S., Pollard, H. B. ANX7, a candidate tumor suppressor gene for prostate cancer. Proc. Nat. Acad. Sci. 98: 4575-4580, 2001. [PubMed: 11287641] [Full Text: https://doi.org/10.1073/pnas.071055798]
Srivastava, M., Montagna, C., Leighton, X., Glasman, M., Naga, S., Eidelman, O., Ried, T., Pollard, H. B. Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse. Proc. Nat. Acad. Sci. 100: 14287-14292, 2003. [PubMed: 14608035] [Full Text: https://doi.org/10.1073/pnas.2235927100]
Zhang-Keck, Z.-Y., Srivastava, M., Kozak, C. A., Caohuy, H., Shirvan, A., Burns, A. L., Pollard, H. B. Genomic organization and chromosomal localization of the mouse synexin gene. Biochem. J. 301: 835-845, 1994. [PubMed: 8053909] [Full Text: https://doi.org/10.1042/bj3010835]