Disease relevance of GAA

• A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II [1].
• RESULTS: Germline missense mutation at codon 289 (AAA to GAA, Lys to Glu) and deletion of the wild-type allele were detected in the polyps of 2 patients with Cowden disease in the same family [2].
• An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II glycogenosis, is genetically and clinically heterogeneous [3].
• OBJECTIVE: Friedreich's ataxia patients are homozygous for expanded alleles of a GAA triplet-repeat sequence in the FXN gene [4].
• Yeast functional assay revealed a mutation of p53 at the 258th codon (AAA [K] instead of GAA [E]) in one cell line, 70W, out of six human melanoma cell lines analyzed (SK-mel-23, SK-mel-24, SK-mel-118, TXM18, 70W, and G361) [5].

Psychiatry related information on GAA

• "Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation [6].

High impact information on GAA

• Indeed, both purified proteins bound preferentially to RNA sequences containing GAA repeats, characteristic of many enhancer elements [7].
• FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles [8].
• The STM7 gene on chromosome 9 was recently 'excluded' as a candidate for Friedreich's ataxia following the identification of an expanded intronic GAA triplet repeat in the adjacent gene, X25, in patients with the disease [9].
• CONCLUSIONS: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling [10].
• BACKGROUND: Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function [10].

Chemical compound and disease context of GAA

• Acid maltase or acid alpha-glucosidase (GAA) is a lysosomal enzyme that hydrolyzes glycogen to glucose and is deficient in glycogen storage disease type II [11].
• A nonsense mutation was identified at codon 526 (GAA to TAA, glutamine to termination) in two cell lines (UMSCC22A and UMSCC22B) derived from the primary tumor and lymph node metastasis of the same patient [12].
• The results confirm that GAA is a useful compound to induce experimental hyperhomocysteinemia and indicate that eritadenine can effectively counteract the hyperhomocysteinemic effect of GAA [13].
• For more than 30 years, guanidinoacetic acid (GAA), together with other guanidino compounds, has been proposed as an important marker for renal failure, in kidney transplantation, and for renal metabolism, especially for the metabolic activity of the renal proximal tubules [14].
• The present results suggest that in patients with hyperargininemia other factors such as arginine and its metabolites including GVA, GAA, ArgA and homoarginine may cause the neurological symptoms [15].

Biological context of GAA

• Constitutively over-expressed Hes-1 and Notch-1 repressed GAA gene expression [1].
• The major p53 binding site in the p21WAF1/CIP1 promoter resembles the GAA CATG TTC form of the consensus [16].
• 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 [17].
• In order to determine the molecular basis for the GAA 2 allozyme, we constructed a cDNA and a genomic DNA library from a GAA 2 cell line and determined the nucleotide sequence of the coding region [17].
• This amino acid substitution is consistent with the more basic pI of the GAA 2 enzyme [17].

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

• To evaluate enzyme replacement therapy for GSD II patients, we have expressed human GAA cDNA in Chinese hamster ovary-K1 cells utilising a vector that places the cDNA under the transcriptional control of the human polypeptide chain elongation factor 1 alpha gene promoter [25].
• Results indicate GAA hyperalimentation can promote weight gain in catabolic CDT patients with inadequate prior nutritional intake (as in groups 1 and 14) but cannot reverse weight loss when the primary clinical setting is advanced metabolic bone disease and myopathy due to hyperparathyroidism (group 2) [26].
• Caveolin-3 and dystrophin were expressed on the vacuolar membranes in lysosomal glycogen storage disease with normal acid maltase, hypokalemic myopathy, and centronuclear myopathy [27].

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].

References