Disease relevance of HEXA

• Tay-Sachs disease (TSD) results from mutations in HEXA that cause Hex A deficiency [1].
• Tay-Sachs disease (TSD) is a catastrophic neurodegenerative disorder caused by mutations in the HEXA gene [2].
• Mutations in the HEXA gene cause Tay-Sachs disease (TSD), a GM2 ganglioside storage disorder [3].
• A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype [4].
• Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively [5].

Psychiatry related information on HEXA

• In many reptile species, sexual differentiation of gonads is sensitive to temperature (temperature-dependent sex determination, TSD) during a critical period of embryonic development (thermosensitive period, TSP) [6].
• Hexosaminidase A deficiency should be considered in unexplained progressive neurologic disorders of childhood and adolescence, including isolated dementia [7].
• Subjects were submitted to partial (PSD) (n = 6) or total (TSD) (n = 6) sleep deprivation for 40 hours before placebo or ethanol conditions [8].
• Urinary levels of N-acetyl-beta-glucosaminidase (NAG) were measured in 58 patients with panic disorder [9].
• Elevated levels of N-acetyl-beta-glucosaminidase in affective disorders and chemical dependence [10].

High impact information on HEXA

• The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (alpha-subunit) and HEXB (beta-subunit) genes, respectively [11].
• We developed methods to detect the three mutations in the HEXA gene that occur with high frequency among Ashkenazi Jews: two mutations cause infantile Tay-Sachs disease, and the third causes the adult-onset form of the disease [12].
• In 23 of 27 cases of the common form of childhood acute lymphoblastic leukemia, the activity of hexosaminidase component I was greatly increased; the activity ratio of hexosaminidase I to hexosaminidase A was greater than 0.5 in 18 of these cases, whereas for other types of leukemia and for all normal cells tested, the ratio was less than 0 [13].
• We report a 57-year-old patient with a very mild phenotype, although residual hexosaminidase A activity in his cultured fibroblasts was less than 3% of normal activity, a level observed in juvenile onset patients [14].
• The genotype and the low level of residual hexosaminidase A activity would be expected to produce a juvenile Sandhoff phenotype in this patient, as well as in four of his six clinically normal siblings [14].

Chemical compound and disease context of HEXA

• A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family [15].
• The excretion of Nag per g creatinine differed significantly between the various histologic subgroups of glomerulonephritis but not between groups with various degrees of tubulointerstitial changes [16].
• 186 patients with advanced epithelial ovarian carcinoma were treated with either a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) or cyclophosphamide and hexamethylmelamine alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5) [17].
• We therefore constructed recombinant baculoviruses that allowed expression of HBx and the hexa histidine HBx fusion protein HBxHis in insect cells [18].
• The activities of both N-acetyl-beta-glucosaminidase and beta-glucuronidase were elevated in plasma during the first 24 h after the onset of chest pain in patients with acute myocardial infarction and the peak levels of N-acetyl-beta-glucosaminidase correlated well with those of creatine kinase [19].

Biological context of HEXA

• Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease [20].
• 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 [21].
• Analysis of the HEXA gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T538-->C, resulting in the missense Tyr180-->His [22].
• Of the 13 introns, 12 interrupt the coding sequences at homologous positions in the HEXA and HEXB genes [23].
• A "HEXA-like" band segregated with chromosome 15 (or X/15) but independently of chromosome 5 [24].

Anatomical context of HEXA

• Mono and bicistronic lentiviral vectors containing the HEXA or/and HEXB cDNAs were constructed and tested on human Sandhoff fibroblasts [25].
• Thus, in the lysosome the pro forms of hexosaminidase A and B undergo extensive proteolytic processing which, while specific in nature, has the appearance of removing easily accessible, nonessential domains, rather than contributing to biosynthetic maturation of function [26].
• Genetic variation of hexosaminidase A and arylsulfatase A activity. Correlation study in amnio-maternal pairs of cultured cells [27].
• Hexosaminidase A is present in relatively low concentrations in cell-free amniotic fluids from pregnancies with Tay-Sachs fetuses [28].
• Hexosaminidase A in amniotic fluid of Tay-Sachs fetuses [28].

Associations of HEXA with chemical compounds

• Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C1351G), resulting in the change of leucine to valine in position 451 [29].
• When human kidney hexosaminidase A was dissociated into its subunits by p-hydroxymercuribenzoate, three distinct proteins having isoelectric points of pH 7.2.5.4, and 4.3 were isolated [30].
• Fourteen primer sets have been utilized to analyze 80% of the coding region and 23/26 splice sites of the gene coding for the alpha chain of hexosaminidase A. Presumed deleterious mutations were discovered in 17/34 chromosomes believed to be carrying a beta-hexosaminidase A alpha-subunit gene mutation [31].
• The unusual clinical aspects and later onset in the patient must therefore be a result of residual hexosaminidase A activity associated with a mutant alpha subunit containing the second mutation, substitution of serine for proline at amino acid 25 owing to a C to T change at nucleotide 73 [32].
• Hexosaminidase A contained 1.65 residues of sialic acid per molecule, whereas no sialic acid was present in hexosaminidase B [33].

Regulatory relationships of HEXA

• The low level of Gm2 ganglioside hydrolase activity in the hexosaminidase A fraction could be enhanced by coincubation with column fractions which contain hexosaminidase B [34].

Other interactions of HEXA

• According to this model hexosaminidase A is composed of two subunits alpha2 and beta2, in which the two polypeptide chains are linked by a disulfide bridge [33].
• Lysosomal degradation of ganglioside GM2 by hexosaminidase A requires the presence of a small, non-enzymatic cofactor, the GM2-activator protein (GM2AP) [35].
• Urine excretion of N-acetyl-beta-glucosaminidase and beta 2-microglobulin was also abnormally high, despite normal blood urea nitrogen and serum creatinine, suggesting that these children had renal tubular dysfunction [36].
• Genetic mutations have been identified in the major motor neuron diseases, including ALS, spinal muscular atrophy, bulbospinal muscular atrophy (Kennedy's disease), the hereditary spastic paraplegias, and rarer conditions such as GM2 gangliosidosis (hexosaminidase A deficiency) [37].
• Increased fertility of heterozygotes with respect to decreased foetal loss among offspring of heterozygotes has been proposed by several authors as a possible explanation for the high gene frequency of CF, TSD and PKU in certain populations [38].

Analytical, diagnostic and therapeutic context of HEXA

• The HEXA exons were PCR amplified, and the products were analyzed for mutations by using restriction-enzyme digestion or single-strand gel electrophoresis [39].
• CONCLUSIONS: Multiple mutation detection and analysis within the Tay-Sachs disease gene (HEXA) is possible using single cells for clinical preimplantation genetic diagnosis [40].
• The polypeptide chains of hexosaminidase A (30 mg) were digested with trypsin, and peptides were isolated by reverse phase high pressure liquid chromatography and their amino acid sequences determined [21].
• beta-N-Acetylhexosaminidase (hexosaminidase) I, which has an intermediate charge character between those of hexosaminidases A(alpha beta 2) and B[beta beta)2), was purified 1,500-fold from human placenta by procedures including chromatographies on concanavalin A (Con A)-Sepharose and an immunoadsorbent column [41].
• This isoenzyme was determined by an immunological procedure, radial immunodiffusion, by which hexosaminidase A can be directly and specifically detected, even in the presence of excess amounts of hexosaminidase B [28].

References