Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2gangliosides and other molecules containing terminal N-acetyl hexosamines. Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis of GM2 gangliosides, which is the main cause of Tay–Sachs disease.
Even though the alpha and beta subunits of hexosaminidase A can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze GM2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuramanic residue of GM2 gangliosides. The alpha subunit can hydrolyze GM2 gangliosides because it contains a loop structure consisting of the amino acids: Gly-280, Ser-281, Glu-282, and Pro-283. The loop is absent in the beta subunit, but it serves as an ideal structure for the binding of the GM2 activator protein (GM2AP) in the alpha subunit. A combination of Arg-424 and the amino acids that cause the formation of the loop allow the alpha subunit to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides.
Gene mutations resulting in Tay–Sachs disease
There are numerous mutations that lead to hexosaminidase A deficiency including gene deletions, nonsense mutations, and missense mutations. Tay–Sachs disease occurs when hexosaminidase A loses its ability to function. People with Tay–Sachs disease are unable to remove the GalNAc residue from the GM2 ganglioside, and as a result, they end up storing 100 to 1000 times more GM2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone.
The most common mutation, which occurs in over 80 percent of Tay–Sachs patients, results from a four base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early stop codon, which causes the Hex A deficiency.
Children born with Tay–Sachs usually die between two to six years of age from aspiration and pneumonia. Tay–Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. There is no cure for Tay–Sachs disease.
^Korneluk RG, Mahuran DJ, Neote K, Klavins MH, O'Dowd BF, Tropak M, Willard HF, Anderson MJ, Lowden JA, Gravel RA (June 1986). "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". J. Biol. Chem.261 (18): 8407–13. PMID3013851.
^Proia RL, Soravia E (April 1987). "Organization of the gene encoding the human beta-hexosaminidase alpha-chain". J. Biol. Chem.262 (12): 5677–81. PMID2952641.
^Knapp S, Vocadlo D, Gao Z, Kirk B, Lou J, Withers SG (1996). "NAG-thiazoline, an N-acetylbeta-hexosaminidase inhibitor that implicates acetamido participation". J. Am. Chem. Soc.118 (28): 6804–6805. doi:10.1021/ja960826u.
Trop I, Kaplan F, Brown C et al. (1993). "A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family". Hum. Mutat.1 (1): 35–9. doi:10.1002/humu.1380010106. PMID1301189.CS1 maint: Explicit use of et al. (link)
Akerman BR, Zielenski J, Triggs-Raine BL et al. (1993). "A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies". Hum. Mutat.1 (4): 303–9. doi:10.1002/humu.1380010407. PMID1301938.CS1 maint: Explicit use of et al. (link)
Fernandes M, Kaplan F, Natowicz M et al. (1993). "A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation". Hum. Mol. Genet.1 (9): 759–61. doi:10.1093/hmg/1.9.759. PMID1302612.CS1 maint: Explicit use of et al. (link)
Whitley CB, Anderson RA, McIvor RS (1992). "Heterozygosity for the "DN allele" (G533-greater than A) of the beta-hexosaminidase alpha subunit gene identified by direct DNA sequencing in a family with the B1 variant of GM2-gangliosidosis". Neuropediatrics23 (2): 96–101. doi:10.1055/s-2008-1071320. PMID1318511.
Hechtman P, Boulay B, De Braekeleer M et al. (1993). "The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada". Hum. Genet.90 (4): 402–6. doi:10.1007/bf00220467. PMID1483696.CS1 maint: Explicit use of et al. (link)
Weitz G, Proia RL (1992). "Analysis of the glycosylation and phosphorylation of the alpha-subunit of the lysosomal enzyme, beta-hexosaminidase A, by site-directed mutagenesis". J. Biol. Chem.267 (14): 10039–44. PMID1533633.
Nakai H, Byers MG, Nowak NJ, Shows TB (1991). "Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23----q24". Cytogenet. Cell Genet.56 (3–4): 164. doi:10.1159/000133077. PMID1829032.
Nishimoto J, Tanaka A, Nanba E, Suzuki K (1991). "Expression of the beta-hexosaminidase alpha subunit gene with the four-base insertion of infantile Jewish Tay-Sachs disease". J. Biol. Chem.266 (22): 14306–9. PMID1830584.