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Gene Review

Hexa  -  hexosaminidase A

Mus musculus

Synonyms: Beta-N-acetylhexosaminidase subunit alpha, Beta-hexosaminidase subunit alpha, Hex-1, Hexosaminidase subunit A, N-acetyl-beta-glucosaminidase subunit alpha
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Disease relevance of Hexa

  • Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease [1].
  • Hexa- and tetra-valent preparations without Klebsiella were not protective in the models tested [2].
  • These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation [3].
  • The severe neurodegenerative disorder, Tays-Sachs disease, is caused by a beta-hexosaminidase alpha-subunit deficiency which prevents the formation of lysosomal heterodimeric alpha-beta enzyme, hexosaminidase A (HexA) [4].
  • Beta-N-Acetylhexosaminidase is a lysosomal enzyme; mutation in this protein leads to Tay-Sachs or Sandhoff disease [5].

High impact information on Hexa

  • Each gene encodes a subunit for the heterodimeric lysosomal enzyme, beta-hexosaminidase A (alpha beta), as well as for the homodimers beta-hexosaminidase B (beta beta) and S (alpha alpha) [6].
  • Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease [3].
  • All types of macrophages studied were found to release considerable amounts of lysosomal hydrolases (beta-glucuronidase, N-acetyl-beta-glucosaminidase, alpha-mannosidase, and acid phosphatase) into the medium [7].
  • The mutant mice displayed < 1% of normal beta-hexosaminidase A activity and accumulated GM2 ganglioside in their central nervous system in an age-dependent manner [1].
  • In the B16 melanomas cathepsin B and N-acetyl-beta-glucosaminidase activities were found in both L-1 and L-2 fractions [8].

Biological context of Hexa

  • We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes [9].
  • Here we find that neuron death in Hexb-/- mice is associated with apoptosis occurring throughout the CNS, while Hexa-/- mice were minimally involved at the same age [10].
  • The Hexa-/- male mice were fertile; however, litter sizes were reduced [11].
  • Hexa- and decapeptides have been identified with sequence homologies that define four motifs: 1, (E)TPXWM/LM/L; 2, W/YXWM/ LYE; 3, DWXDW; and 4, (Ar)WDGQ(Ar) [12].
  • We have also been able to establish a syntenic relationship between the gene locus responsible for the expression of hexosaminidase A and those responsible for mannosephosphate isomerase and pyruvate kinase-3 and to assign the gene for hexosaminidase B to chromosome 5 in man [13].

Anatomical context of Hexa

  • The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2 [14].
  • In the epididymis of the Hex A-deficient Hexa-/- mice, there was a large increase in the size and number of lysosomes in the initial segment/intermediate zone [11].
  • At 5 weeks and at 3, 5, and 12 months, the testes, efferent ducts and epididymides of Hex A-deficient (Hexa -/-) and wild-type (Hexa +/+) mice were perfuse fixed and analyzed by routine light and electron microscopy as well as with immunocytochemistry employing antibodies to lysosomal enzymes [15].
  • Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system [16].
  • In the testis, the seminiferous epithelium of Hexa -/- mice appeared comparable to that of wild-type mice in appearance and topographical arrangement of its cell types at all ages examined [15].

Associations of Hexa with chemical compounds

  • The subunits dimerize to yield three isozymes, beta-hexosaminidase A (alpha beta), B (beta beta), and S (alpha alpha), that have the capacity to degrade a variety of substrates containing beta-linked N-acetylglucosamine and N-acetylgalactosamine residues [17].
  • Constitutive expression of beta-N-acetylhexosaminidase in a microglial cell line: transcriptional modulation by lipopolysaccharide and serum factors [18].
  • Beta-N-acetylhexosaminidase in the urine, kidney and serum of bromobenzene-intoxicated mice [19].
  • N-Acetyl beta-glucosaminidase [beta-2-acetamido-2-deoxy-D-glucoside acetylamido-deoxyglucohydrolase; EC] in the submandibular gland of mice was found to be androgen-dependent; the specific activities in males, females, and castrated males were 0.25, 0.11, and 0.11 unit/mg protein, respectively [20].
  • In particular, control cells show two hexosaminidase isoenzymes corresponding to hexosaminidase A and B, whereas cells treated with calcium ionophore A-23187 express a third isoenzyme form with properties similar to hexosaminidase S [21].

Other interactions of Hexa

  • Similarities between the elements present in Gm2a and Hexa promoters might in part explain their similar expression patterns in mouse tissues [22].
  • The mouse model of Tay-Sachs disease (Hexa -/-) has been described as behaviorally indistinguishable from wild type until at least 1 year of age due to a sialidase-mediated bypass of the metabolic defect that reduces the rate of GM2 ganglioside accumulation [16].
  • Lysosomal acid sphingomyelinase activity, measured with a synthetic substrate, was found to be 10-60% of BALB/c mouse control levels in liver, spleen, and cerebellum, while two other lysosomal enzymes, N-acetyl-beta-glucosaminidase and beta-glucuronidase, were increased 2-8-fold in the same tissues [23].

Analytical, diagnostic and therapeutic context of Hexa


  1. Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease. Yamanaka, S., Johnson, M.D., Grinberg, A., Westphal, H., Crawley, J.N., Taniike, M., Suzuki, K., Proia, R.L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Protective effects of orally administered, Klebsiella-containing bacterial lysates in mice. Kuenen, J.D., van Dijke, E.E., Hol, C., Bootsma, H.J., Verhoef, J., van Dijk, H. FEMS Immunol. Med. Microbiol. (1994) [Pubmed]
  3. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Sango, K., Yamanaka, S., Hoffmann, A., Okuda, Y., Grinberg, A., Westphal, H., McDonald, M.P., Crawley, J.N., Sandhoff, K., Suzuki, K., Proia, R.L. Nat. Genet. (1995) [Pubmed]
  4. Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice. Guidotti, J.E., Mignon, A., Haase, G., Caillaud, C., McDonell, N., Kahn, A., Poenaru, L. Hum. Mol. Genet. (1999) [Pubmed]
  5. Beta-N-acetylhexosaminidase activity in mouse oocytes and preimplantation embryos. Sermon, K., Nijs, M., Lissens, W., Van Steirteghem, A.C., Liebaers, I. Hum. Reprod. (1991) [Pubmed]
  6. Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Sango, K., McDonald, M.P., Crawley, J.N., Mack, M.L., Tifft, C.J., Skop, E., Starr, C.M., Hoffmann, A., Sandhoff, K., Suzuki, K., Proia, R.L. Nat. Genet. (1996) [Pubmed]
  7. Secretion of lysosomal hydrolases by stimulated and nonstimulated macrophages. Schnyder, J., Baggiolini, M. J. Exp. Med. (1978) [Pubmed]
  8. Cathepsin B: association with plasma membrane in metastatic tumors. Sloane, B.F., Rozhin, J., Johnson, K., Taylor, H., Crissman, J.D., Honn, K.V. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  9. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Liu, Y., Hoffmann, A., Grinberg, A., Westphal, H., McDonald, M.P., Miller, K.M., Crawley, J.N., Sandhoff, K., Suzuki, K., Proia, R.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Huang, J.Q., Trasler, J.M., Igdoura, S., Michaud, J., Hanal, N., Gravel, R.A. Hum. Mol. Genet. (1997) [Pubmed]
  11. Characterization of the testis and epididymis in mouse models of human Tay Sachs and Sandhoff diseases and partial determination of accumulated gangliosides. Trasler, J., Saberi, F., Somani, I.H., Adamali, H.I., Huang, J.Q., Fortunato, S.R., Ritter, G., Gu, M., Aebersold, R., Gravel, R.A., Hermo, L. Endocrinology (1998) [Pubmed]
  12. Peptide libraries define the fine specificity of anti-polysaccharide antibodies to Cryptococcus neoformans. Valadon, P., Nussbaum, G., Boyd, L.F., Margulies, D.H., Scharff, M.D. J. Mol. Biol. (1996) [Pubmed]
  13. Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes. Gilbert, F., Kucherlapati, R., Creagan, R.P., Murnane, M.J., Darlington, G.J., Ruddle, F.H. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  14. Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. Phaneuf, D., Wakamatsu, N., Huang, J.Q., Borowski, A., Peterson, A.C., Fortunato, S.R., Ritter, G., Igdoura, S.A., Morales, C.R., Benoit, G., Akerman, B.R., Leclerc, D., Hanai, N., Marth, J.D., Trasler, J.M., Gravel, R.A. Hum. Mol. Genet. (1996) [Pubmed]
  15. II. Characterization and development of the regional- and cellular-specific abnormalities in the epididymis of mice with beta-hexosaminidase A deficiency. Adamali, H.I., Somani, I.H., Huang, J.Q., Gravel, R.A., Trasler, J.M., Hermo, L. J. Androl. (1999) [Pubmed]
  16. Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system. Miklyaeva, E.I., Dong, W., Bureau, A., Fattahie, R., Xu, Y., Su, M., Fick, G.H., Huang, J.Q., Igdoura, S., Hanai, N., Gravel, R.A. Brain Res. (2004) [Pubmed]
  17. Structure and expression of the mouse beta-hexosaminidase genes, Hexa and Hexb. Yamanaka, S., Johnson, O.N., Norflus, F., Boles, D.J., Proia, R.L. Genomics (1994) [Pubmed]
  18. Constitutive expression of beta-N-acetylhexosaminidase in a microglial cell line: transcriptional modulation by lipopolysaccharide and serum factors. Beccari, T., Orlacchio, A., Costanzi, E., Grazia Appolloni, M., Laurenzi, A., Bocchini, V. J. Neurosci. Res. (1997) [Pubmed]
  19. Beta-N-acetylhexosaminidase in the urine, kidney and serum of bromobenzene-intoxicated mice. Tassi, C., Beccari, T., Casini, A., Orlacchio, A. Clin. Chim. Acta (1992) [Pubmed]
  20. Androgenic regulation of N-acetyl beta-glucosaminidase activity in the submandibular glands of mice. Hosoi, K., Kobayashi, S., Hiramatsu, M., Minami, N., Ueha, T. J. Biochem. (1979) [Pubmed]
  21. Calcium ionophore A-23187 inhibits the secretion of beta-hexosaminidase from the GG2EE mouse macrophage cell line. Beccari, T., Datti, A., Orlacchio, A., Farinelli, S., Blasi, E. Biochem. Int. (1992) [Pubmed]
  22. Structural organization and expression of the gene for the mouse GM2 activator protein. Bertoni, C., Appolloni, M.G., Stirling, J.L., Li, S.C., Li, Y.T., Orlacchio, A., Beccari, T. Mamm. Genome (1997) [Pubmed]
  23. Lysosome lipid storage disorder in NCTR-BALB/c mice. III. Isolation and analysis of storage inclusions from liver. Bhuvaneswaran, C., Morris, M.D., Shio, H., Fowler, S. Am. J. Pathol. (1982) [Pubmed]
  24. Disruption of murine Hexa gene leads to enzymatic deficiency and to neuronal lysosomal storage, similar to that observed in Tay-Sachs disease. Cohen-Tannoudji, M., Marchand, P., Akli, S., Sheardown, S.A., Puech, J.P., Kress, C., Gressens, P., Nassogne, M.C., Beccari, T., Muggleton-Harris, A.L. Mamm. Genome (1995) [Pubmed]
  25. Immunostimulatory effects of platinum compounds: correlation between sensitizing properties in vivo and modulation of receptor-mediated endocytosis in vitro. Schuppe, H.C., Kulig, J., Kühn, U., Lempertz, U., Kind, P., Knop, J., Becker, D. Int. Arch. Allergy Immunol. (1997) [Pubmed]
  26. Cloning and sequence analysis of a cDNA encoding the alpha-subunit of mouse beta-N-acetylhexosaminidase and comparison with the human enzyme. Beccari, T., Hoade, J., Orlacchio, A., Stirling, J.L. Biochem. J. (1992) [Pubmed]
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