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Gene Review

HEXB  -  hexosaminidase B (beta polypeptide)

Homo sapiens

Synonyms: Beta-N-acetylhexosaminidase subunit beta, Beta-hexosaminidase subunit beta, Cervical cancer proto-oncogene 7 protein, ENC-1AS, HCC-7, ...
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Disease relevance of HEXB

  • Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively [1].
  • Mutations in the HEXA or HEXB gene resulting in a beta-hexosaminidase deficiency cause Tay-Sachs or Sandhoff disease, respectively [2].
  • Mutations in either the HEXA gene or HEXB gene lead to an accumulation of GM2 ganglioside in neurons, resulting in the severe neurodegenerative disorders termed the GM2 gangliosidoses [3].
  • Because the 25-base-pair inversion is similar to mutations in the terminal exon of human HEXB, the domestic shorthair cat should serve as an appropriate model to study the molecular pathogenesis of human G(M2) gangliosidosis variant 0 (Sandhoff disease) [4].
  • The activity of the acidic glycohydrolase beta-N-acetylhexosaminidase, an enzyme system normally participating in the stepwise degradation of glycoproteins, glycolipids, and proteoglycans, appears to be modulated in lymphocytes and monocytes from peripheral blood of patients affected by multiple sclerosis during different stages of the disease [5].

Psychiatry related information on HEXB

  • A minority of patients with affective disorders experience mild elevations of the renal enzyme N-acetyl-beta-glucosaminidase (NAG) [6].
  • beta-Hexosaminidase B-isoforms (beta-hexosaminidase B, P, and intermediate forms; abbreviated herein as "Hex B") and serum carbohydrate-deficient transferrin (CDT) are two markers of alcohol abuse [7].
  • Association of levels of N-acetyl-beta-glucosaminidase with severity of psychiatric symptoms in panic disorder [8].

High impact information on HEXB

  • The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (alpha-subunit) and HEXB (beta-subunit) genes, respectively [9].
  • Increased excretion of urinary N-acetyl-beta-glucosaminidase in essential hypertension and its decline with antihypertensive therapy [10].
  • The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is increased in patients whose renal function is impaired by a variety of kidney diseases, and may provide an index of renal injury [10].
  • An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds [11].
  • Two mutations of the HEXB gene were identified in this patient, a partial 5' gene deletion (a null allele), and a C----T transition 8 nucleotides downstream from the intron 10/exon 11 junction affecting the splicing of the beta subunit-mRNA [11].

Chemical compound and disease context of HEXB

  • The molecular defects in the HEXB gene encoding the common beta-subunit of lysosomal beta-hexosaminidase A (beta-Hex A, alpha beta) and beta-Hex B (beta beta) were investigated in a Portuguese family affected with late onset Sandhoff disease (GM2-gangliosidosis variant 0) [12].
  • Like usual GM2 ganglioside containing N-acetylneuraminic acid (NeuAc) isolated from Tay-Sachs brain, GM2(NeuGc) in colon cancer could be converted into GM3(NeuGc) by human kidney beta-N-acetylhexosaminidase A in the presence of a GM2-specific activator protein isolated from guinea pig kidney [13].
  • Comparison of urinary albumin, retinol-binding protein and N-acetyl beta-glucosaminidase as predictors of progression of low level albuminuria in diabetes [14].
  • Effects of polymyxin B immobilized fiber on urinary N-acetyl-beta-glucosaminidase in patients with severe sepsis [15].
  • As part of a general safety study of iopamidol, a nonionic iodinated contrast agent, urine N-acetyl-beta-glucosaminidase enzyme assays were done to compare the renal toxicity of iopamidol with that of iothalamate and diatrizoate [16].

Biological context of HEXB

  • These data suggest a common origin of the HEXA and HEXB genes and account for the similar substrate specificities of the alpha-dimer subunit, hexosaminidase S, and hexosaminidase B [17].
  • By performing scanning mutagenesis on a 60-bp region within the 150-bp HEXB construct, we defined an essential promoter element of 12 bp that contained two potential AP-1 sites [3].
  • The few exceptions to this generalization are missense mutations at two codons in HEXA, causing the unique biochemical phenotype known as the B1-variant, and one codon in both the HEXB and GM2A genes [18].
  • The deletion removes approximately 16 kb of DNA including the HEXB promoter, exons 1-5 and part of intron 5 [19].
  • In addition, pHex cDNA was found homologous to multiple bands in digests of genomic human DNA totaling 43 kilobases (kb), all of which were mapped to chromosome 5 in somatic cell hybrids, as expected of the HEXB gene [20].

Anatomical context of HEXB

  • We demonstrate here that elimination of GM2 ganglioside (GM2) accumulated in the fibroblastic cell line derived from SD mice (FSD) did not occur when the HEXB gene only was transfected [21].
  • We have cloned and fully characterized a deletion at the HEXB gene from fibroblasts of a patient with the infantile form of Sandhoff disease [19].
  • One of 13 cDNA clones derived from her lymphocyte HEXB mRNA lacked the last four nucleotides "GTTG" of exon 8, which created a premature termination codon at 11 codons downstream [22].
  • Analysis of the HEXB mRNA from leukocytes of deltaTG/WT individuals by RT-PCR of the 3'UTR showed that the deltaTG allele is present at lower level than the WT allele [23].
  • In vivo transcription of the mutant HEXB gene fragment in CHO cells resulted in deletion of the "GTTG." The mutation has not been found in 40 DNA samples from anonymous donors, indicating that this is not a polymorphism in the Cypriot population [22].

Associations of HEXB with chemical compounds


Regulatory relationships of HEXB


Other interactions of HEXB

  • A list of genes was produced in which the MLH1 and HEXB genes were among the top 1% of candidates, thus validating the strategy [28].
  • The genes responsible for these disorders are HEXA (Tay-Sachs disease and variants), HEXB (Sandhoff disease and variants), and GM2A (AB variant of GM2 gangliosidosis) [29].
  • None of the inhibitors affected protein synthesis, DNA synthesis, the PTH-enhanced secretion of beta-glucuronidase, and N-acetyl-beta-glucosaminidase, or the spontaneous release of lactate dehydrogenase [30].
  • Two possible structures are suggested that are compatible with the experimental data: (a) a hexosaminidase B like structure with higher extent of glycosylation; (b) a hexameter of beta chain, possibly arranged as three beta2 subunits [31].
  • Nuclear run-off assays indicated that glutathione peroxidase was regulated by oxygen tension at the transcriptional level, while hexosaminidase B and total mRNA synthesis levels remained unchanged [32].

Analytical, diagnostic and therapeutic context of HEXB


  1. The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease. Maier, T., Strater, N., Schuette, C.G., Klingenstein, R., Sandhoff, K., Saenger, W. J. Mol. Biol. (2003) [Pubmed]
  2. 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]
  3. Promoters for the human beta-hexosaminidase genes, HEXA and HEXB. Norflus, F., Yamanaka, S., Proia, R.L. DNA Cell Biol. (1996) [Pubmed]
  4. An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Martin, D.R., Krum, B.K., Varadarajan, G.S., Hathcock, T.L., Smith, B.F., Baker, H.J. Exp. Neurol. (2004) [Pubmed]
  5. Beta-N-acetylhexosaminidase in peripheral blood lymphocytes and monocytes in the different forms and stages of multiple sclerosis. Orlacchio, A., Martino, S., Sarchielli, P., Gallai, V., Emiliani, C. J. Neurochem. (1998) [Pubmed]
  6. Elevation of the renal enzyme N-acetyl-beta-glucosaminidase in affectively disordered patients. Garvey, M.J., Furlong, C., Schaffer, C.B., Adelman, R. Acta psychiatrica Scandinavica. (1988) [Pubmed]
  7. Increases and time-course variations in beta-hexosaminidase isoenzyme B and carbohydrate-deficient transferrin in serum from alcoholics are similar. Hultberg, B., Isaksson, A., Berglund, M., Alling, C. Alcohol. Clin. Exp. Res. (1995) [Pubmed]
  8. Association of levels of N-acetyl-beta-glucosaminidase with severity of psychiatric symptoms in panic disorder. Garvey, M.J., Noyes, R. Psychiatry research. (1996) [Pubmed]
  9. 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]
  10. Increased excretion of urinary N-acetyl-beta-glucosaminidase in essential hypertension and its decline with antihypertensive therapy. Alderman, M.H., Melcher, L., Drayer, D.E., Reidenberg, M.M. N. Engl. J. Med. (1983) [Pubmed]
  11. An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds. McInnes, B., Potier, M., Wakamatsu, N., Melancon, S.B., Klavins, M.H., Tsuji, S., Mahuran, D.J. J. Clin. Invest. (1992) [Pubmed]
  12. Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) homozygosity for the Ile207-->Val substitution is not associated with a clinical or biochemical phenotype. Redonnet-Vernhet, I., Mahuran, D.J., Salvayre, R., Dubas, F., Levade, T. Biochim. Biophys. Acta (1996) [Pubmed]
  13. Specific expression of unusual GM2 ganglioside with Hanganutziu-Deicher antigen activity on human colon cancers. Hirabayashi, Y., Kasakura, H., Matsumoto, M., Higashi, H., Kato, S., Kasai, N., Naiki, M. Jpn. J. Cancer Res. (1987) [Pubmed]
  14. Comparison of urinary albumin, retinol-binding protein and N-acetyl beta-glucosaminidase as predictors of progression of low level albuminuria in diabetes. O'Brien, S.F., Powrie, J.K., Watts, G.F. Ann. Clin. Biochem. (1997) [Pubmed]
  15. Effects of polymyxin B immobilized fiber on urinary N-acetyl-beta-glucosaminidase in patients with severe sepsis. Nakamura, T., Kawagoe, Y., Matsuda, T., Ueda, Y., Koide, H. ASAIO journal (American Society for Artificial Internal Organs : 1992) (2004) [Pubmed]
  16. Renal toxicity of contrast agents: iopamidol, iothalamate, and diatrizoate. Gale, M.E., Robbins, A.H., Hamburger, R.J., Widrich, W.C. AJR. American journal of roentgenology. (1984) [Pubmed]
  17. Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase. Extensive homology between the alpha- and beta-subunits and studies on Tay-Sachs disease. Korneluk, R.G., Mahuran, D.J., Neote, K., Klavins, M.H., O'Dowd, B.F., Tropak, M., Willard, H.F., Anderson, M.J., Lowden, J.A., Gravel, R.A. J. Biol. Chem. (1986) [Pubmed]
  18. Biochemical consequences of mutations causing the GM2 gangliosidoses. Mahuran, D.J. Biochim. Biophys. Acta (1999) [Pubmed]
  19. Structure and distribution of an Alu-type deletion mutation in Sandhoff disease. Neote, K., McInnes, B., Mahuran, D.J., Gravel, R.A. J. Clin. Invest. (1990) [Pubmed]
  20. Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase. O'Dowd, B.F., Quan, F., Willard, H.F., Lamhonwah, A.M., Korneluk, R.G., Lowden, J.A., Gravel, R.A., Mahuran, D.J. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  21. Inefficiency in GM2 ganglioside elimination by human lysosomal beta-hexosaminidase beta-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice. Itakura, T., Kuroki, A., Ishibashi, Y., Tsuji, D., Kawashita, E., Higashine, Y., Sakuraba, H., Yamanaka, S., Itoh, K. Biol. Pharm. Bull. (2006) [Pubmed]
  22. Novel splice site mutation at IVS8 nt 5 of HEXB responsible for a Greek-Cypriot case of Sandhoff disease. Furihata, K., Drousiotou, A., Hara, Y., Christopoulos, G., Stylianidou, G., Anastasiadou, V., Ueno, I., Ioannou, P. Hum. Mutat. (1999) [Pubmed]
  23. A frequent TG deletion near the polyadenylation signal of the human HEXB gene: occurrence of an irregular DNA structure and conserved nucleotide sequence motif in the 3' untranslated region. Kleiman, F.E., Ramírez, A.O., Dodelson de Kremer, R., Gravel, R.A., Argaraña, C.E. Hum. Mutat. (1998) [Pubmed]
  24. Interrelationship of hexosaminidases A and B: conformation of the common and the unique subunit theory. Srivastava, S.K., Wiktorowicz, J.E., Awasthi, Y.C. Proc. Natl. Acad. Sci. U.S.A. (1976) [Pubmed]
  25. In vivo chloroquine-induced inhibition of insulin degradation in a diabetic patient with severe insulin resistance. Blazar, B.R., Whitley, C.B., Kitabchi, A.E., Tsai, M.Y., Santiago, J., White, N., Stentz, F.B., Brown, D.M. Diabetes (1984) [Pubmed]
  26. Chemical characterization and subunit structure of human N-acetylhexosaminidases A and B. Geiger, B., Arnon, R. Biochemistry (1976) [Pubmed]
  27. Characterization of an activating factor required for hydrolysis of Gm2 ganglioside catalyzed by hexosaminidase A. Hechtman, P. Can. J. Biochem. (1977) [Pubmed]
  28. A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. Noensie, E.N., Dietz, H.C. Nat. Biotechnol. (2001) [Pubmed]
  29. The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci. Cordeiro, P., Hechtman, P., Kaplan, F. Genet. Med. (2000) [Pubmed]
  30. Inhibition of bone resorption by selective inactivators of cysteine proteinases. Hill, P.A., Buttle, D.J., Jones, S.J., Boyde, A., Murata, M., Reynolds, J.J., Meikle, M.C. J. Cell. Biochem. (1994) [Pubmed]
  31. Biochemical and immunochemical characterization of hexosaminidase P. Geiger, B., Calef, E., Arnon, R. Biochemistry (1978) [Pubmed]
  32. The regulation of glutathione peroxidase gene expression by oxygen tension in cultured human cardiomyocytes. Cowan, D.B., Weisel, R.D., Williams, W.G., Mickle, D.A. J. Mol. Cell. Cardiol. (1992) [Pubmed]
  33. Inheritance of the enzyme defect in a new hexosaminidase deficiency disease. Johnson, W.G., Chutorian, A.B. Ann. Neurol. (1978) [Pubmed]
  34. Hexosaminidase A in amniotic fluid of Tay-Sachs fetuses. Geiger, B., Navon, R., Arnon, R. Clin. Chem. (1978) [Pubmed]
  35. Complete analysis of the glycosylation and disulfide bond pattern of human beta-hexosaminidase B by MALDI-MS. Schuette, C.G., Weisgerber, J., Sandhoff, K. Glycobiology (2001) [Pubmed]
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