HEXA

Hexosaminidase A (alpha polypeptide)
PDB rendering based on 2gjx.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1QBC​, 2GJX​, 2GK1​
Identifiers
Symbols	HEXA ; TSD
External IDs	OMIM: 606869 MGI: 96073 HomoloGene: 20146 ChEMBL: 1250415 GeneCards: HEXA Gene
EC number	3.2.1.52
Gene ontology Molecular function • beta-N-acetylhexosaminidase activity • acetylglucosaminyltransferase activity • protein heterodimerization activity Cellular component • membrane • azurophil granule • lysosomal lumen • extracellular exosome Biological process • carbohydrate metabolic process • glycosaminoglycan biosynthetic process • sphingolipid metabolic process • glycosphingolipid metabolic process • glycosaminoglycan metabolic process • chondroitin sulfate metabolic process • chondroitin sulfate catabolic process • hyaluronan metabolic process • hyaluronan catabolic process • keratan sulfate metabolic process • keratan sulfate catabolic process • small molecule metabolic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3073	15211
Ensembl	ENSG00000213614	ENSMUSG00000025232
UniProt	P06865	P29416
RefSeq (mRNA)	NM_000520	NM_010421
RefSeq (protein)	NP_000511	NP_034551
Location (UCSC)	Chr 15: 72.34 – 72.38 Mb	Chr 9: 59.54 – 59.57 Mb
PubMed search

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 HEXA gene, located on the 15th chromosome.^[1][2]

Hexosaminidase A and the cofactor G_M2 activator protein catalyze the degradation of the G_M2 gangliosides and other molecules containing terminal N-acetyl hexosamines.^[3] 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 G_M2 gangliosides, which is the main cause of Tay–Sachs disease.^[4]

Function

Even though the alpha and beta subunits of hexosaminidase A can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze G_M2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuramanic residue of G_M2 gangliosides. The alpha subunit can hydrolyze G_M2 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 G_M2 activator protein (G_M2AP) 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 G_M2 gangliosides into G_M3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from G_M2 gangliosides.^[5]

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 G_M2 ganglioside, and as a result, they end up storing 100 to 1000 times more G_M2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone.^[6]

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.^[7]

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.^[6]

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. [8]

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. [9] 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. [10]

References

1. 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. PMID 3013851.
2. Proia RL, Soravia E (April 1987). "Organization of the gene encoding the human beta-hexosaminidase alpha-chain". J. Biol. Chem. 262 (12): 5677–81. PMID 2952641.
3. 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.
4. Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN (April 2003). "Crystal Structure of Human β-Hexosaminidase B: Understanding the Molecular Basis of Sandhoff and Tay–Sachs Disease". J. Mol. Biol. 327 (5): 1093–109. doi:10.1016/S0022-2836(03)00216-X. PMC 2910754. PMID 12662933.
5. Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN (June 2006). "Crystallographic Structure of Human β-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis". J. Mol. Biol. 359 (4): 913–29. doi:10.1016/j.jmb.2006.04.004. PMC 2910082. PMID 16698036.
6. Ozand PT, Nyhan WL, Barshop BA (2005). "Part Thirteen Lipid Storage Disorders: Tay-Sachs disease/hexosaminidase A deficiency". Atlas of metabolic diseases. London: Hodder Arnold. pp. 539–546. ISBN 0-340-80970-1.
7. Boles, Debra J. and Richard L. Proia (1995). "The molecular basis of HEXA mRNA deficiency caused by the most common Tay-Sachs disease mutation". Am. J. Hum. Genet. 56 (3): 716–724. PMC 1801160. PMID 7887427.

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^[2]

^[3]

Further reading

• Mahuran DJ (1991). "The biochemistry of HEXA and HEXB gene mutations causing GM2 gangliosidosis". Biochim. Biophys. Acta 1096 (2): 87–94. doi:10.1016/0925-4439(91)90044-A. PMID 1825792.
• Myerowitz R (1997). "Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene". Hum. Mutat. 9 (3): 195–208. doi:10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7. PMID 9090523.
• Mahuran DJ (1999). "Biochemical consequences of mutations causing the GM2 gangliosidoses". Biochim. Biophys. Acta 1455 (2–3): 105–38. doi:10.1016/S0925-4439(99)00074-5. PMID 10571007.
• Gilbert F, Kucherlapati R, Creagan RP, et al. (1975). "Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes". Proc. Natl. Acad. Sci. U.S.A. 72 (1): 263–7. doi:10.1073/pnas.72.1.263. PMC 432284. PMID 1054503.
• 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. PMID 1301189.
• Akalin N, Shi HP, Vavougios G, et al. (1993). "Novel Tay-Sachs disease mutations from China". Hum. Mutat. 1 (1): 40–6. doi:10.1002/humu.1380010107. PMID 1301190.
• 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. PMID 1301938.
• 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. PMID 1302612.
• McDowell GA, Mules EH, Fabacher P, et al. (1992). "The presence of two different infantile Tay-Sachs disease mutations in a Cajun population". Am. J. Hum. Genet. 51 (5): 1071–7. PMC 1682822. PMID 1307230.
• 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". Neuropediatrics 23 (2): 96–101. doi:10.1055/s-2008-1071320. PMID 1318511.
• Triggs-Raine BL, Mules EH, Kaback MM, et al. (1992). "A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: Implications for carrier screening". Am. J. Hum. Genet. 51 (4): 793–801. PMC 1682803. PMID 1384323.
• 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. PMID 1483696.
• Mules EH, Hayflick S, Miller CS, et al. (1992). "Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals". Am. J. Hum. Genet. 50 (4): 834–41. PMC 1682641. PMID 1532289.
• 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. PMID 1533633.
• Navon R, Proia RL (1991). "Tay-Sachs disease in Moroccan Jews: deletion of a phenylalanine in the alpha-subunit of beta-hexosaminidase". Am. J. Hum. Genet. 48 (2): 412–9. PMC 1683003. PMID 1825014.
• Mules EH, Dowling CE, Petersen MB, et al. (1991). "A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black GM2-gangliosidosis (Tay-Sachs disease) patients". Am. J. Hum. Genet. 48 (6): 1181–5. PMC 1683116. PMID 1827945.
• 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. PMID 1829032.
• 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. PMID 1830584.
• dos Santos MR, Tanaka A, sá Miranda MC, et al. (1991). "GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal". Am. J. Hum. Genet. 49 (4): 886–90. PMC 1683169. PMID 1832817.

External links

• Hexosaminidase A at the US National Library of Medicine Medical Subject Headings (MeSH)
• EC 3.2.1.52
• National Tay-Sach’s Disease Site

1. HEXA hexodaminidase subunit alpha [Homo spaniens (human)]. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/gene/3073
2. Masako Taniike, Shoji Yamanaka, Richard L. Proia, Clarita Langaman, Teresa Bone-Turrentine, Kinuko Suzuki. (1995) Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease. Act Neuropathologica: 89(4), 296-304.
3. Martino, S., Marconi, P., Tancini, B., Dolcetta, D., De Angelis, M. C., Montanucci, P., & ... Orlacchio, A. (2005). A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease. Human Molecular Genetics: 14(15), 2113-2123.