Disease relevance of Hexb

• Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia [1].
• Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD) [2].
• To determine the role of these autoantibodies, the Fc receptor gamma gene (FcR gamma) was additionally disrupted in Hexb(-/-) mice, as it plays a key role in immune complex-mediated autoimmune diseases [2].
• Oral glucose tolerance (OGTT), glucosyltransferase and N-acetyl-beta-glucosaminidase (enzymes involved in synthesis and degradation of kidney glycoproteins, respectively) in the kidney and serum, 24-hr proteinuria, and light microscopy studies of the kidney were performed [3].

High impact information on Hexb

• 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) [4].
• Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease [5].
• We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes [6].
• 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 [7].
• 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 [8].

Chemical compound and disease context of Hexb

• In the Hexb mouse, a model of Sandhoff disease, lipid phosphate levels were elevated in surfactant from 3- and 4-month-old mice, which was mainly due to elevated levels of phosphatidylcholine [9].

Biological context of Hexb

• To explain the extensive epididymal abnormalities in the Hexb-/- mice, we propose that substrates for Hex, such as testis-derived glycolipids, cannot be catabolized and accumulate in lysosomes, leading to epididymal dysfunction and abnormalities in the epididymal luminal environment that supports sperm maturation [10].
• The functional significance of these findings was established by the enhanced sensitivity of neurons cultured from embryonic Hexb-/- mice to cell death induced by thapsigargin, a specific SERCA inhibitor, and by the enhanced sensitivity of Hexb-/- microsomes to calcium-induced calcium release [11].
• The ovarian function of Hexb(-/-) females was determined by superovulation studies [12].
• Since both the Hexb (-/-) sexes showed fertility, the results indicate that Hex A and Hex B (major isozymes of beta-hexosaminidase) may not be required for sperm-ovum interactions, in contrast to the widely accepted belief [12].
• Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway [13].

Anatomical context of Hexb

• The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2 [1].
• In Hexb-/- mice (Hex A and B-deficient), the epididymal defects were much more extensive and the cytoplasm of all cell types throughout the efferent ducts and epididymis was filled with pale, uncondensed, enlarged lysosomes [10].
• The extensive abnormalities in the Hexb-/- mice, in contrast to region-specific effects in the Hexa-/-mice, indicate an important and novel role for the Hex B isozyme in the epididymis and a region-specific role for Hex A in the initial segment/intermediate zone [10].
• At 1 and 3 months of age, the testes, efferent ducts, and epididymides of Hex-deficient (Hexb -/-) and wild-type (Hexb +/+) mice were perfuse fixed and analyzed by routine light and electron microscopy (LM and EM, respectively) as well as with immunocytochemistry employing antibodies to lysosomal proteins [14].
• In the testis, the morphological appearance and topographical arrangement of the cell types of the seminiferous epithelium of Hexb -/- mice were similar to those of wild-type animals at both ages [14].

Associations of Hexb with chemical compounds

• Microsomes from Hexb-/- mouse brain showed a significant reduction in the rate of Ca2+-uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), which was prevented by feeding Hexb-/- mice with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glycolipid synthesis that reduces GM2 storage [11].
• CR, which decreased circulating glucose and elevated ketone bodies, significantly improved rotorod performance and extended longevity in the Hexb-/- mice but had no significant effect on brain lipid composition or on cytoplasmic neuronal vacuoles [15].
• Although GM2 and GA2 were elevated, no significant differences were seen between the Hexb-/- and the Hexb+/- mice for most brain phospholipids and cholesterol [15].
• The use of urinary N-acetyl-beta-glucosaminidase in human renal toxicology. II. Elevation in human excretion after aspirin and sodium salicylate [16].
• Streptozotocin diabetes strongly reduced the N-acetyl-beta-glucosaminidase activity in the submaxillary glands of mice [17].

Other interactions of Hexb

• Assignment of genes encoding dihydrofolate reductase and hexosaminidase B to Mus musculus chromosome 13 [18].
• The numbers of macrophages, neutrophils and lymphocytes, N-Acetyl-beta-glucosaminidase (beta-NAG), and fibronectin increased in the BALF from MRL/l mice than that from MRL/n mice, but no significant differences were observed in total protein, beta-glucuronidase, acid phosphatase, or phospholipid level [19].
• The hearts were excised, homogenized, and the following enzymatic activities measured: N-Acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-glucosaminidase, aryl sulphatase, alpha-mannosidase, alpha-glucosidase, beta-galactosidase, beta glucosidase, total p-nitrophenyl phosphatase, acid phosphatase and 5'-phosphodiesterase type IV [20].

Analytical, diagnostic and therapeutic context of Hexb

• The specific isozymic variant was identified as beta-hexosaminidase B. beta-N-acetylglucosaminidase was localized to sperm acrosomes by biochemical and indirect immunofluorescence studies and was released during the acrosome reaction, as expected for an enzyme involved in zona penetration [21].

References