Disease relevance of GPAA1

• In this study, we observed that GPAA1 transcript in the HCCs (n = 93) showed a significantly higher expression level compared with their paralleled adjacent nontumor liver tissues, cirrhosis (n = 15) and normal (n = 16) liver tissues using real-time quantitative RT-PCR (p < 0.005) [1].
• Alterations in the 6p24 locus containing the GAAP-1 gene are frequent in acute myelogenous leukemia (AML), and AML-derived cell lines display reduced GAAP-1 mRNA levels [2].
• In a mouse model of GSD-II, we demonstrate that infection of the murine liver with a modified adenovirus (Ad) vector encoding human GAA (hGAA) resulted in long-term persistence of the vector in liver tissues for at least 6 months [3].
• We describe a sporadic case with onset at 53 years of age and a novel VLOFA phenotype mimicking multiple system atrophy (MSA) of cerebellar type associated with minimal GAA1 expansion [4].
• Very late-onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type [4].

High impact information on GPAA1

• A 5' fragment containing the base-pair substitution was ligated to the remaining 3' cDNA from a GAA 1 allele and cloned into an expression vector, and the hybrid cDNA was transiently expressed in SV40-transformed GAA-deficient fibroblasts [5].
• However, the acyl group is usually absent from GPI-anchored proteins (GPI-APs) on the cell surface due to inositol deacylation that occurs in the endoplasmic reticulum (ER) soon after GPI-anchor attachment [6].
• Systematic replacement of the attachment site serine with all possible amino acids indicated that alanine, aspartate, asparagine, glycine, or serine efficiently support GPI anchor attachment while valine and glutamate are partially effective [7].
• Together, these results suggest that GAAP-1 acts as a gatekeeper at a critical point in the tumour suppressor gene pathway [2].
• Skeletal muscle cell cultures from an affected patient were also transduced with Ad-hGAA [8].

Biological context of GPAA1

• Here, we report structures and chromosome loci of human and mouse GPAA1 genes [9].
• Every protein fated to receive the glycophosphatidylinositol (GPI) anchor post-translational modification has a C-terminal GPI-anchor attachment signal sequence [10].
• Increased expression of glycosyl-phosphatidylinositol anchor attachment protein 1 (GPAA1) is associated with gene amplification in hepatocellular carcinoma [1].
• Glycosyl-phosphatidylinositol (GPI) anchor attachment protein 1 (GPAA1) transcript level was frequently up-regulated in our earlier study on gene expression profile [1].
• We then modulated the GPAA1 expression level in HCC cells (Hep3B) by transfection experiments, which was shown to positively regulate cell adhesion ability (p = 0.004) and proliferation rate (p = 0.037) [1].

Anatomical context of GPAA1

• Overexpression of antisense hGAA1 in human K562 cells significantly reduced the production of a reporter GPI-anchored protein [11].
• Recombinant hGAA is identified in a lysosomal location in these muscle cells by immunocytochemistry, and enzyme activity is transferred to deficient skeletal muscle cells grown in coculture [8].
• Similar recombinant CHO cell lines were produced that expressed the glycosylphosphatidylinositol-(GPI-) anchored FR type beta and a truncated form of FR type beta (FR-beta delta), in which the normal carboxyl-terminal signal for GPI anchor attachment was deleted [12].
• The sensory action potential amplitude at the wrist (wSAP) and at the medial malleolus (m mal SAP) and the percentage of myelinated fibres with diameter larger than 7, 9, and 11 microm in the sural nerve were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) expanded allele in each pair [13].

Associations of GPAA1 with chemical compounds

• All other substitutions including cysteine (permitted at the attachment site in other GPI-anchored proteins) abolish both GPI anchor attachment and transport to the cell surface, resulting in accumulation of uncleaved fusion protein in internal compartments (endoplasmic reticulum and Golgi) [7].

Other interactions of GPAA1

• There is a human pseudo GPAA1 gene (GPAA1P1) that is located at 2q12-->q14 [9].

Analytical, diagnostic and therapeutic context of GPAA1

• The mouse GPAA1 gene (Gpaa1) bearing AG at the 3' splice site prepared by site-directed mutagenesis was functional, indicating that any nucleotide is allowed at the 3' end of a minor class intron [9].
• Molecular cloning of human homolog of yeast GAA1 which is required for attachment of glycosylphosphatidylinositols to proteins [11].
• Glycogen storage in multiple muscles of old GSD-II mice can be rapidly cleared after a single intravenous injection with a modified adenoviral vector expressing hGAA [14].
• To investigate the potential for disease reversibility in old GSD-II mice, we studied their responsiveness to exogenous hGAA exposure via a gene therapy approach that we have previously shown to be efficacious in young GAA-KO mice [14].
• 3. After isoelectric focusing the GAA2 isozyme migrated cathodally with respect to the GAA1 isozyme, whereas with the previous starch-gel electrophoresis method their relative positions were reversed [15].

References