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 3.2.1.30] 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

• We have used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene [24].
• Hexa- and tetrachloroplatinates were confirmed to be highly immunogenic, inducing vigorous primary immune responses in the draining PLN following single subcutaneous injections [25].
• Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice [4].
• Cloning and sequence analysis of a cDNA encoding the alpha-subunit of mouse beta-N-acetylhexosaminidase and comparison with the human enzyme [26].
• beta-N-Acetylhexosaminidase isoenzymes were separated from the kidney, serum and urine of normal mice and mice intoxicated with bromobenzene, using DEAE-cellulose chromatography [19].

References