HEXA gene is located on the long (q) arm of chromosome 15 at position 24.1.
Hexosaminidase A (alpha polypeptide), also known as HEXA, is an enzyme that in humans is encoded by the HEXAgene, located on the 15th chromosome.[5][6]
Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2gangliosides and other molecules containing terminal N-acetyl hexosamines.[7] 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.[8]
Function
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-neuraminic 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.[9]
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.[10]
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.[11]
Children born with Tay–Sachs usually die between two and 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.[10]
Gene therapies for Tay-Sachs
The HEXA gene is a protein encoding gene that codes for the lysosomal enzyme beta-hexosaminidase. This enzyme, combined with the GM2 activator protein, is responsible for the breakdown of ganglioside GM2 within the lysosome. Defects in the HEXA gene, however, prevent this degradation, leading to a buildup of toxins in brain and spinal cord cells. This fatal genetic disorder is called Tay-Sachs disease. Because the Tay-Sachs gene defect mainly affects neural cells, a patient with the HEXA mutation will experience a quick deterioration of motor and mental function before dying around the age of three or four.[citation needed]
A “knockout” model, which is a mouse that has been genetically modified to observe the effects of inactivation of or damage to certain genes, found that the mice that were administered the HEXA gene experienced many of the same symptoms of Tay-Sachs, with one exception: GM2 buildup was distributed differently in the brains of the mice than in those of a typical human Tay-Sachs patient. [citation needed] This model has allowed scientists to research gene therapies for HEXA defects. One study, done on mice, successfully reestablished beta-hexoaminidase levels and removed the toxic cell buildup by using a non-replicated Herpes simplex vector to code for the missing gene.[citation needed]
Taniike M, Yamanaka S, Proia RL, Langaman C, Bone-Turrentine T, Suzuki K (1995). "Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease". Acta Neuropathologica. 89 (4): 296–304. doi:10.1007/s004010050250. PMID7610760.
Martino S, Marconi P, Tancini B, Dolcetta D, De Angelis MG, Montanucci P, Bregola G, Sandhoff K, Bordignon C, Emiliani C, Manservigi R, Orlacchio A (August 2005). "A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease". Human Molecular Genetics. 14 (15): 2113–23. doi:10.1093/hmg/ddi216. PMID15961412.
Mahuran DJ (February 1991). "The biochemistry of HEXA and HEXB gene mutations causing GM2 gangliosidosis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1096 (2): 87–94. doi:10.1016/0925-4439(91)90044-A. PMID1825792.
Trop I, Kaplan F, Brown C, Mahuran D, Hechtman P (1993). "A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family". Human Mutation. 1 (1): 35–9. doi:10.1002/humu.1380010106. PMID1301189. S2CID40974834.
Fernandes M, Kaplan F, Natowicz M, Prence E, Kolodny E, Kaback M, Hechtman P (December 1992). "A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation". Human Molecular Genetics. 1 (9): 759–61. doi:10.1093/hmg/1.9.759. PMID1302612.
Whitley CB, Anderson RA, McIvor RS (April 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". Neuropediatrics. 23 (2): 96–101. doi:10.1055/s-2008-1071320. PMID1318511.
Hechtman P, Boulay B, De Braekeleer M, Andermann E, Melançon S, Larochelle J, Prevost C, Kaplan F (December 1992). "The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada". Human Genetics. 90 (4): 402–6. doi:10.1007/bf00220467. PMID1483696. S2CID3190945.
Nakai H, Byers MG, Nowak NJ, Shows TB (1991). "Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23----q24". Cytogenetics and Cell Genetics. 56 (3–4): 164. doi:10.1159/000133077. PMID1829032.
