HEXA

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HEXA
Protein HEXA PDB 2gjx.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HEXA, TSD, hexosaminidase subunit alpha
External IDs MGI: 96073 HomoloGene: 20146 GeneCards: HEXA
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000520
NM_001318825

NM_010421

RefSeq (protein)

NP_000511
NP_001305754

NP_034551

Location (UCSC) Chr 15: 72.34 – 72.38 Mb Chr 9: 59.54 – 59.57 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse
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.[3][4]

Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines.[5] 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.[6]

Function[edit]

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.[7]

Gene mutations resulting in Tay–Sachs disease[edit]

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.[8]

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.[9]

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.[8]

Gene Therapies for Tay-Sachs[edit]

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[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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". The Journal of Biological Chemistry. 261 (18): 8407–13. PMID 3013851. 
  4. ^ Proia RL, Soravia E (April 1987). "Organization of the gene encoding the human beta-hexosaminidase alpha-chain". The Journal of Biological Chemistry. 262 (12): 5677–81. PMID 2952641. 
  5. ^ 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. 
  6. ^ Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN (April 2003). "Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease". Journal of Molecular Biology. 327 (5): 1093–109. PMC 2910754Freely accessible. PMID 12662933. doi:10.1016/S0022-2836(03)00216-X. 
  7. ^ Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN (June 2006). "Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis". Journal of Molecular Biology. 359 (4): 913–29. PMC 2910082Freely accessible. PMID 16698036. doi:10.1016/j.jmb.2006.04.004. 
  8. ^ a b 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. 
  9. ^ Boles DJ, Proia RL (March 1995). "The molecular basis of HEXA mRNA deficiency caused by the most common Tay-Sachs disease mutation". American Journal of Human Genetics. 56 (3): 716–24. PMC 1801160Freely accessible. PMID 7887427. 

Further reading[edit]

External links[edit]