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Gene Review

GAA  -  glucosidase, alpha; acid

Homo sapiens

Synonyms: Acid maltase, Aglucosidase alfa, Lysosomal alpha-glucosidase
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Disease relevance of GAA


Psychiatry related information on GAA


High impact information on GAA


Chemical compound and disease context of GAA


Biological context of GAA


Anatomical context of GAA

  • Previously, we have isolated and sequenced the cDNA for GAA and transiently expressed the cDNA in deficient fibroblasts [17].
  • Glycogen storage disease type II (GSD II), Pompe's disease, is caused by the deficiency of acid alpha-D-glucosidase (GAA) in lysosome and is the most common form of GSD in Taiwan. Most cases are the infantile form [18].
  • Using anti-GAA monoclonal antibody, GAA was demonstrated on the regenerated myocytes by immunohistochemical staining and absent on the contralateral muscle of the same birds [18].
  • Nevertheless, T lymphocytes infiltration was noted in both the rcAAV-GAA and hepes (medium) injected muscles and more prominent in the rcAAV-GAA-injected site [18].
  • GAA -/- mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions [19].

Associations of GAA with chemical compounds

  • GAA is synthesized as a 110-kDa precursor containing N-linked carbohydrates modified with mannose 6-phosphate groups [20].
  • Genomic DNA clones of human acid alpha glucosidase (GAA) and thymidine kinase (TK1) were used to map the exact location and order of these genes on human chromosome 17 [21].
  • We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein [19].
  • This finding confirms the exclusion of GAA from 17q25----17qter reported by Nickel et al [22].
  • Besides an increase of GAA and a decrease of CT and CTN in plasma, 24-h urine, brain and muscle of KO mice, we observed a significant increase of other GCs in brain and muscle that was sometimes reflected in plasma and/or urine [23].

Enzymatic interactions of GAA

  • Acid alpha-glucosidase (GAA) hydrolyzes alpha-1, 4 and alpha-1, 6 glucosidic linkages of oligosaccharides and degrades glycogen in the lysosomes [24].

Regulatory relationships of GAA


Other interactions of GAA

  • Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells [1].
  • We now show that the osteosarcoma cell lines have lost one TP53 allele and contain a mutation in exon 8 codon 286 [GAA to AAA (Glu to Lys)] in the remaining allele [28].
  • We showed that the patient and his father shared a variant TF gene bearing a GAA to AAA transition at codon 394 [29].
  • Both MLL and hCDCrel contained homologous CT, TTTGTG, and GAA sequences within a few base pairs of their respective breakpoints, which may have been important in uniting these two genes by translocation [30].
  • To study LOH at the MLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of the MLL gene and a GA (mllGAn) repeat in the 5' flanking region of the gene, approximately 2 kb upstream of the translation initiation codon [31].

Analytical, diagnostic and therapeutic context of GAA

  • NcoI and StyI digestion of cDNA, amplified by PCR from reverse-transcribed RNA, demonstrated that greater than 95% of the GAA mRNA in GM 244 was derived from the allele carrying the missense mutation [32].
  • By sequence analysis we have identified the mutations in the lysosomal alpha-glucosidase gene (GAA) of two unrelated patients, who have one and two copies, respectively, of the same missense mutation [33].
  • Using acid maltase deficient (AMD) Japanese quail as the animal model, rcAAV-GAA 0.1 ml per site (1 x 10(9)-10) particles), totally 10 different sites to make 1 ml (1 x 10(1)0-11) particles), was injected into unilateral deep pectoral muscle of AMD quails [18].
  • Localization and ordering of acid alpha-glucosidase (GAA) and thymidine kinase (TK1) by fluorescence in situ hybridization [21].
  • METHODS: Retrospective study of 52 FA patients (mean age 26.9+/-12.1 years; mean disease duration 10.6+/-7.6 years) homozygous for GAA expansion [34].


  1. The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway. Yan, B., Raben, N., Plotz, P. J. Biol. Chem. (2002) [Pubmed]
  2. Mutational abrogation of the PTEN/MMAC1 gene in gastrointestinal polyps in patients with Cowden disease. Chi, S.G., Kim, H.J., Park, B.J., Min, H.J., Park, J.H., Kim, Y.W., Dong, S.H., Kim, B.H., Lee, J.I., Chang, Y.W., Chang, R., Kim, W.K., Yang, M.H. Gastroenterology (1998) [Pubmed]
  3. Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II. Boerkoel, C.F., Exelbert, R., Nicastri, C., Nichols, R.C., Miller, F.W., Plotz, P.H., Raben, N. Am. J. Hum. Genet. (1995) [Pubmed]
  4. Progressive gaa expansions in dorsal root ganglia of Friedreich's ataxia patients. De Biase, I., Rasmussen, A., Endres, D., Al-Mahdawi, S., Monticelli, A., Cocozza, S., Pook, M., Bidichandani, S.I. Ann. Neurol. (2007) [Pubmed]
  5. Induction of apoptosis in melanoma cell lines by p53 and its related proteins. Yamashita, T., Tokino, T., Tonoki, H., Moriuchi, T., Jin, H.Y., Omori, F., Jimbow, K. J. Invest. Dermatol. (2001) [Pubmed]
  6. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nishino, I., Fu, J., Tanji, K., Yamada, T., Shimojo, S., Koori, T., Mora, M., Riggs, J.E., Oh, S.J., Koga, Y., Sue, C.M., Yamamoto, A., Murakami, N., Shanske, S., Byrne, E., Bonilla, E., Nonaka, I., DiMauro, S., Hirano, M. Nature (2000) [Pubmed]
  7. Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing. Tacke, R., Tohyama, M., Ogawa, S., Manley, J.L. Cell (1998) [Pubmed]
  8. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Rötig, A., de Lonlay, P., Chretien, D., Foury, F., Koenig, M., Sidi, D., Munnich, A., Rustin, P. Nat. Genet. (1997) [Pubmed]
  9. The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase. Carvajal, J.J., Pook, M.A., dos Santos, M., Doudney, K., Hillermann, R., Minogue, S., Williamson, R., Hsuan, J.J., Chamberlain, S. Nat. Genet. (1996) [Pubmed]
  10. Clinical and genetic abnormalities in patients with Friedreich's ataxia. Dürr, A., Cossee, M., Agid, Y., Campuzano, V., Mignard, C., Penet, C., Mandel, J.L., Brice, A., Koenig, M. N. Engl. J. Med. (1996) [Pubmed]
  11. Sequence of the cDNA and 5'-flanking region for human acid alpha-glucosidase, detection of an intron in the 5' untranslated leader sequence, definition of 18-bp polymorphisms, and differences with previous cDNA and amino acid sequences. Martiniuk, F., Mehler, M., Tzall, S., Meredith, G., Hirschhorn, R. DNA Cell Biol. (1990) [Pubmed]
  12. DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma. Kim, S.K., Fan, Y., Papadimitrakopoulou, V., Clayman, G., Hittelman, W.N., Hong, W.K., Lotan, R., Mao, L. Cancer Res. (1996) [Pubmed]
  13. Dietary eritadenine suppresses guanidinoacetic Acid-induced hyperhomocysteinemia in rats. Fukada, S., Setoue, M., Morita, T., Sugiyama, K. J. Nutr. (2006) [Pubmed]
  14. Stable isotope dilution method for the determination of guanidinoacetic acid by gas chromatography/mass spectrometry. Fingerhut, R. Rapid Commun. Mass Spectrom. (2003) [Pubmed]
  15. Guanidino compounds in hyperargininemia. Mizutani, N., Hayakawa, C., Ohya, Y., Watanabe, K., Watanabe, Y., Mori, A. Tohoku J. Exp. Med. (1987) [Pubmed]
  16. Mutation of conserved domain II alters the sequence specificity of DNA binding by the p53 protein. Freeman, J., Schmidt, S., Scharer, E., Iggo, R. EMBO J. (1994) [Pubmed]
  17. Identification of the base-pair substitution responsible for a human acid alpha glucosidase allele with lower "affinity" for glycogen (GAA 2) and transient gene expression in deficient cells. Martiniuk, F., Bodkin, M., Tzall, S., Hirschhorn, R. Am. J. Hum. Genet. (1990) [Pubmed]
  18. Adeno-associated virus-mediated transfer of human acid maltase gene results in a transient reduction of glycogen accumulation in muscle of Japanese quail with acid maltase deficiency. Lin, C.Y., Ho, C.H., Hsieh, Y.H., Kikuchi, T. Gene Ther. (2002) [Pubmed]
  19. Correction of glycogen storage disease type II by enzyme replacement with a recombinant human acid maltase produced by over-expression in a CHO-DHFR(neg) cell line. Martiniuk, F., Chen, A., Donnabella, V., Arvanitopoulos, E., Slonim, A.E., Raben, N., Plotz, P., Rom, W.N. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  20. Lysosomal acid alpha-glucosidase consists of four different peptides processed from a single chain precursor. Moreland, R.J., Jin, X., Zhang, X.K., Decker, R.W., Albee, K.L., Lee, K.L., Cauthron, R.D., Brewer, K., Edmunds, T., Canfield, W.M. J. Biol. Chem. (2005) [Pubmed]
  21. Localization and ordering of acid alpha-glucosidase (GAA) and thymidine kinase (TK1) by fluorescence in situ hybridization. Kuo, W.L., Hirschhorn, R., Huie, M.L., Hirschhorn, K. Hum. Genet. (1996) [Pubmed]
  22. Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization. Honig, J., Martiniuk, F., D'Eustachio, P., Zamfirescu, C., Desnick, R., Hirschhorn, K., Hirschhorn, L.R., Hirschhorn, R. Ann. Hum. Genet. (1984) [Pubmed]
  23. Biochemical and behavioural phenotyping of a mouse model for GAMT deficiency. Torremans, A., Marescau, B., Possemiers, I., Van Dam, D., D'Hooge, R., Isbrandt, D., De Deyn, P.P. J. Neurol. Sci. (2005) [Pubmed]
  24. Molecular cloning of acid alpha-glucosidase cDNA of Japanese quail (Coturnix coturnix japonica) and the lack of its mRNA in acid maltase deficient quails. Kunita, R., Nakabayashi, O., Wu, J.Y., Hagiwara, Y., Mizutani, M., Pennybacker, M., Chen, Y.T., Kikuchi, T. Biochim. Biophys. Acta (1997) [Pubmed]
  25. Isolation and characterisation of a recombinant, precursor form of lysosomal acid alpha-glucosidase. Fuller, M., Van der Ploeg, A., Reuser, A.J., Anson, D.S., Hopwood, J.J. Eur. J. Biochem. (1995) [Pubmed]
  26. Prolonged hyperalimentation in catabolic chronic dialysis therapy patients. Piraino, A.J., Firpo, J.J., Powers, D.V. JPEN. Journal of parenteral and enteral nutrition. (1981) [Pubmed]
  27. Caveolin-3 and sarcoglycans in the vacuolar myopathies and centronuclear myopathy. Inose, M., Higuchi, I., Nakagawa, M., Kashio, N., Osame, M. Muscle Nerve (1999) [Pubmed]
  28. A TP53 mutation detected in cells established from an osteosarcoma, but not in the retinoblastoma of a patient with bilateral retinoblastoma and multiple primary osteosarcomas. Hovig, E., Andreassen, A., Fangan, B.M., Børresen, A.L. Cancer Genet. Cytogenet. (1992) [Pubmed]
  29. Molecular analysis of the transferrin gene in a patient with hereditary hypotransferrinemia. Asada-Senju, M., Maeda, T., Sakata, T., Hayashi, A., Suzuki, T. J. Hum. Genet. (2002) [Pubmed]
  30. t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Megonigal, M.D., Rappaport, E.F., Jones, D.H., Williams, T.M., Lovett, B.D., Kelly, K.M., Lerou, P.H., Moulton, T., Budarf, M.L., Felix, C.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. Loss of heterozygosity and microsatellite instability at the MLL locus are common in childhood acute leukemia, but not in infant acute leukemia. Webb, J.C., Golovleva, I., Simpkins, A.H., Kempski, H., Reeves, B., Sturt, N., Chessells, J.M., Brickell, P.M. Blood (1999) [Pubmed]
  32. Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele. Zhong, N., Martiniuk, F., Tzall, S., Hirschhorn, R. Am. J. Hum. Genet. (1991) [Pubmed]
  33. The effect of a single base pair deletion (delta T525) and a C1634T missense mutation (pro545leu) on the expression of lysosomal alpha-glucosidase in patients with glycogen storage disease type II. Hermans, M.M., De Graaff, E., Kroos, M.A., Mohkamsing, S., Eussen, B.J., Joosse, M., Willemsen, R., Kleijer, W.J., Oostra, B.A., Reuser, A.J. Hum. Mol. Genet. (1994) [Pubmed]
  34. Influence of GAA expansion size and disease duration on central nervous system impairment in Friedreich's ataxia: contribution to the understanding of the pathophysiology of the disease. Santoro, L., Perretti, A., Lanzillo, B., Coppola, G., De Joanna, G., Manganelli, F., Cocozza, S., De Michele, G., Filla, A., Caruso, G. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. (2000) [Pubmed]
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