Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Glycogen debranching enzyme and acid alpha-glucosdase are responsible for glycogen degradation in human. The formal enzyme is a multifunctional enzyme with two independent catalytic activities occurring on a single polypeptide, while the latter is a lysosomal enzyme which matures through extensive glycosylation and phosphorylation and proteolytic processing. Deficiency of glycogen debranching enzyme and acid alpha-glucosidase cause glycogen storage disease type III and II, respectively. Baculovirus/insect expression system was used to produce both GDE and GAA. Both enzymes were found to be catalytically and antigenically active. The majority of recombinant GDE is present in the medium (70%). Uptake experiment indicated that GAA produced in the insect cells could not be absorbed into the GSD type II patient fibroblasts through mannose-6-phosphate receptor mediated endocytosis. Uptake experiment combined with immunoblot analysis indicated there are differences in the posttranslational modification and processing between insect cells and mammalian cells.
Biochem Mol Biol Int 1996 Jul
PMID:Expression of catalytically active human multifunctional glycogen-debranching enzyme and lysosomal acid alpha-glucosidase in insect cells. 884 44

Two Maltese puppies with massive hepatomegaly and failure to thrive had isolated deficient glucose-6-phosphatase (G-6-Pase) activity in liver and kidney and pathological findings compatible with GSD-Ia. To identify the mutation, we cloned G-6-Pase canine cDNA by RT-PCR with primers from the murine G-6-Pase gene sequence. The canine G-6-Pase cDNA is 2346 bp, with a 5' untranslated region of 87 bp, a coding region of 1071 bp, and a 3' untranslated region of 1185 bp. The difference between the canine and human sequences is in the 3' untranslated region. A greater than 90% amino acid sequence homology was seen with canine, human, murine, and rat G-6-Pase. G-6-Pase cDNA from affected and control puppies revealed complete homology except at nt position 450, which showed a guanine to cytosine (G to C) transversion resulting in substitution of a methionine by isoleucine at codon 121 (M121I) in all five clones studied. The loss of an NcoI restriction site on genomic DNA amplified with primers flanking the mutation allowed us to prove that affected puppies were homozygous for the mutation and parents were heterozygous carriers. The mutant G-6-Pase cDNA had 15 times less enzyme activity than wild-type cDNA following transient transfection. Northern blot analysis of puppies with GSD-Ia revealed increased G-6-Pase mRNA, compared to normal controls. Increased G-6-Pase mRNA was also seen in normal fasted puppies compared to littermates in the fed state, suggesting that the increased G-6-Pase mRNA is a physiologic response to fasting. This is the first report of a molecularly confirmed naturally occurring animal model of GSD-Ia. The establishment of a breeding colony of this dog strain will facilitate studies on the role of G-6-Pase gene in glucose homeostasis, in pathophysiology of disease, and development of novel therapeutic approaches such as gene therapy.
Biochem Mol Med 1997 Aug
PMID:Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. 925 82

Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the third found only in North African Jews with GSD-IIIa. Here we report two frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. A novel point mutation of a single T deletion at cDNA position 3964 (3964delT) was first detected in an African American patient, who has a severe phenotype and early onset of clinical symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, previously implicated as a IIIb mutation in a Japanese patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the molecular defects in the GSD-III patients tested. Our molecular and clinical data suggest a genotype-phenotype correlation for each of these mutations. Furthermore, this current study, coupled with our previous reports, describes the molecular tools necessary for the development of a DNA-based diagnostic test for GSD-III.
Mol Genet Metab 2000 Jan
PMID:Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. 1065 53

Glycogen storage disease type II (GSD-II), also known as Pompe disease, is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme. Currently, there is no treatment for this fatal disorder. However, several lines of research suggest the possibility of future treatment. Enzyme replacement strategies hold the greatest hope for patients currently affected by GSD-II, but future strategies could include in vivo or ex vivo gene therapy approaches and/or mesenchymal stem cell or bone-marrow transplantation approaches. Each of the approaches might eventually be combined to further improve the overall clinical efficacy of any one treatment regimen. The lessons learned from GSD-II research will also benefit a great number of individuals affected by other genetic disorders.
Mol Med Today 2000 Jun
PMID:Towards a molecular therapy for glycogen storage disease type II (Pompe disease). 1084 Mar 83

The purpose of this study was to investigate the usefulness of urinary lactate measurements to assess the adequacy of dietary treatment in patients with type I glycogen storage disease (GSD-I). We determined the correlation of urine and blood lactate concentrations in 21 GSD-I patients during 24-h admissions to the General Clinical Research Center (GCRC) during which hourly blood samples and aliquots of every void were obtained. In all but 1 patient, we found a good correlation between blood lactate concentrations and urinary lactate excretion. One patient did not excrete lactate in significant amounts despite elevated blood lactate concentrations. In 17 patients, the highest blood lactate concentrations occurred during the night. Markedly elevated nighttime average blood lactate concentrations above 3.5 mmol/l resulted in a urinary lactate concentration above the normal limit of 0.067 mmol/mmol creatinine in the first morning urine specimen. Mildly elevated nighttime blood lactate concentrations (between 2.2 and 3.5 mmol/l) led to urinary lactate concentrations that were either normal or moderately elevated. All patients with normal blood lactate concentrations during the night also had normal first morning urinary lactate concentrations. The degree of urinary lactate excretion in relation to blood lactate concentrations varied by individual. Urinary filter paper specimens, collected at home during the night and in the morning and mailed to the laboratory, were used to monitor the dietary compliance of 5 GSD-I patients at home over a period of 6 to 9 weeks prior to their GCRC admissions. These data suggested variable degrees of dietary control. In conclusion, the urinary lactate concentration is a useful parameter to monitor therapy of GSD-I patients at home. To be interpretable, the baseline urinary lactate concentration in relation to the blood lactate concentration has to be determined.
Mol Genet Metab 2000 Jul
PMID:Urinary lactate excretion to monitor the efficacy of treatment of type I glycogen storage disease. 1092 73

The profile of norethisterone and newly developed derivatives thereof were assessed by in vitro binding and transactivation assays on progesterone (PR) as well as on androgen (AR) receptors and by subcutaneous treatment in in vivo models. The following in vivo models were performed: A McPhail test for progestational activity in immature rabbits, an ovulation inhibition test in cycling rats and a Hershberger test for androgenic activity in immature orchidectomised rats. The compounds tested were: norethisterone (NET), 11-methylene-NET (11-NET), Delta(15)-NET (15-NET), 18-methyl-NET (18-NET, Levonorgestrel, LNG), 11-methylene-Delta(15)-NET (11, 15-NET), 11-methylene-18-methyl-NET (11,18-NET, 3-keto-desogestrel, Etonogestrel, ETG), (Delta(15)-18-methyl-NET (15,18-NET, Gestodene, GSD) and 11-methylene-Delta(15)-18-methyl-NET (11,15,18-NET). Compared to the non-substituted compound NET, the binding to and agonistic activity via PR was increased for all the three mono-substituted compounds, although the stimulatory effect of 15-NET was only twofold. Compounds with 18-methyl in combination with Delta(15) (GSD), with 11-methylene (ETG) or with both combined showed clear synergistic effects, leading to equipotent compounds. If the 18-methyl group was lacking as in 11,15-NET, potency was lower than for ETG or GSD, but higher than for 18-NET (LNG). A correlation coefficient of 0.9 was found between binding affinity and agonistic potency. With respect to the AR binding and transactivation activities, the 18-methyl group potentiated androgenic in vitro activity (LNG). The 11-methylene group increased relative binding affinity in NET, but reduced androgenic activity clearly when also other substituents were present (11,15-NET, ETG and 11,15,18-NET). The Delta(15) bond alone did not change the binding in NET, but decreased androgen binding, induced by the 18-methyl substituent, in GSD and 11,15,18-NET. Transactivation activity was also diminished in the compounds having a Delta(15) bond. In the McPhail test mono-substitution of NET increased the progestagenic in vivo activity three to five times. Bi- and tri-substitution enhanced the activity further. With respect to ovulation inhibition mono-substitution of NET resulted in three to nine times more potent compounds, whereas bi- and tri-substitution increased potency further, except for 11,15-NET, which was as active as 11-NET. The relative progestagenic potencies in the McPhail and ovulation inhibition tests, correlated significantly with those of the relative binding affinity values (correlation coefficient of 0. 91 and 0.93, respectively) and relative transactivation activity values (0.88 and 0.81) for the PR. In the Hershberger test, all the compounds increased androgenic activity with respect to growth of ventral prostate weight compared to NET, with the exception of 11, 15-NET and 11,15,18-NET. The androgenic activity was negligible for these latter compounds. The androgenicity of both 18-NET (LNG) and 15,18-NET (GSD), on the other hand, was significantly higher than that of 11,18-NET (ETG). The results of this in vivo test are in line with the AR binding and transactivation activity values (correlation coefficients of 0.86 and 0.88). In addition, selectivity indices were calculated by dividing the progestational potencies by androgenic potencies for both in vitro and in vivo assays. ETG and GSD had clearly higher in vitro and in vivo indices than the other compounds with NET and LNG having the lowest indices. Because the androgenicity of 11,15-NET and 11,15,18-NET was very low, no exact selectivity ratios could be calculated for these compounds. From these experiments we may conclude that small structural modifications exert enhancement of progestational activity and a clear reduction in androgenicity leading to very selective progestagenic compounds. The influence of bi-substitution is additive over mono-substitution, whereas tri-substition is not additive. (ABSTRACT TRUNCATED)
J Steroid Biochem Mol Biol 2000 Oct
PMID:Influence of the substitution of 11-methylene, delta(15), and/or 18-methyl groups in norethisterone on receptor binding, transactivation assays and biological activities in animals. 1108 27

Glycogen storage disease type 1 (GSD 1) comprises a group of autosomal recessive inherited metabolic disorders caused by deficiency of the microsomal multicomponent glucose-6-phosphatase system. Of the two known transmembrane proteins of the system, malfunction of the catalytic subunit (G6Pase) characterizes GSD 1a. GSD 1 non-a is characterized by defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport due to mutations in G6PT (glucose-6-phosphate translocase gene) encoding a microsomal transporter protein. Mutations in G6Pase and G6PT account for approximately 80 and approximately 20% of GSD 1 cases, respectively. G6Pase and G6PT work in concert to maintain glucose homeostasis in gluconeogenic organs. Whereas G6Pase is exclusively expressed in gluconeogenic cells, G6PT is ubiquitously expressed and its deficiency generally causes a more severe phenotype. Rapid confirmation of clinically suspected diagnosis of GSD 1, reliable carrier testing, and prenatal diagnosis are facilitated by mutation analyses of the chromosome 11-bound G6PT gene as well as the chromosome 17-bound G6Pase gene.
Mol Genet Metab 2001 Jun
PMID:Molecular genetics of type 1 glycogen storage disease. 1138 47

In the tilapia Oreochromis niloticus, sex is determined genetically (GSD), by temperature (TSD) or by temperature/genotype interactions. Functional masculinization can be achieved by applying high rearing temperatures during a critical period of sex differentiation. Estrogens play an important role in female differentiation of non-mammalian vertebrates. The involvement of aromatase, was assessed during the natural (genetic all-females and all-males at 27 degrees C) and temperature-induced sex differentiation of tilapia (genetic all-females at 35 degrees C). Gonads were dissected between 486--702 degree x days. Aromatase gene expression was analyzed by virtual northern and semi-quantitative RT-PCR revealing a strong expression during normal ovarian differentiation concomitant with high levels (465 +/- 137 fg/g) of oestradiol-17 beta (E2-17 beta). This was encountered in gonads after the onset of ovarian differentiation (proliferation of both stromal and germ cells prior to ovarian meiosis). Genetic males exhibited lower levels of aromatase gene expression and E2-17 beta quantities (71 +/- 23 fg/ g). Aromatase enzyme activity in fry heads established a sexual dimorphism in the brain, with high activity in females (377.9 pmol/head/hr) and low activity in males (221.53 pmol/head/hr). Temperature induced the masculinization of genetic females to a different degree in each progeny, but in all cases repression of aromatase expression was encountered. Genetic males at 35 degrees C also exhibited a repression of aromatase expression. Aromatase brain activity decreased by nearly three-fold in the temperature-masculinized females with also a reduction observed in genetic males at 35 degrees C. This suggests that aromatase repression is required in the gonad (and perhaps in the brain) in order to drive differentiation towards testis development. Mol. Reprod. Dev. 59:265-276, 2001.
Mol Reprod Dev 2001 Jul
PMID:Aromatase plays a key role during normal and temperature-induced sex differentiation of tilapia Oreochromis niloticus. 1142 12

Glycogen storage disease type 1 (GSD-1), also known as von Gierke disease, is a group of autosomal recessive metabolic disorders caused by deficiencies in the activity of the glucose-6-phosphatase (G6Pase) system that consists of at least two membrane proteins, glucose-6-phosphate transporter (G6PT) and G6Pase. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum (ER) and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Therefore, G6PT and G6Pase work in concert to maintain glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Both manifest functional G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-1b patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa. The G6Pase gene maps to chromosome 17q21 and encodes a 36-kDa glycoprotein that is anchored to the ER by 9 transmembrane helices with its active site facing the lumen. Animal models of GSD-1a have been developed and are being exploited to delineate the disease more precisely and to develop new therapies. The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by 10 transmembrane helices. A functional assay for the recombinant G6PT protein has been established, which showed that G6PT functions as a G6P transporter in the absence of G6Pase. However, microsomal G6P uptake activity was markedly enhanced in the simultaneous presence of G6PT and G6Pase. The cloning of the G6PT gene now permits animal models of GSD-1b to be generated. These recent developments are increasing our understanding of the GSD-l disorders and the G6Pase system, knowledge that will facilitate the development of novel therapeutic approaches for these disorders.
Curr Mol Med 2001 Mar
PMID:The molecular basis of type 1 glycogen storage diseases. 1189 41

Lysosomal storage diseases are an intriguing target for gene therapy approaches, as transduction of a "depot" organ with a transgene encoding a lysosomal enzyme can be followed by secretion, systemic distribution, downstream uptake, and lysosomal targeting of the enzyme into non-transduced tissues. These benefits are of utmost importance when considering gene therapy approaches for glycogen storage disease type-II (GSD-II). GSD-II is a prototypical lysosomal storage disorder caused by lack of intralysosomal acid alpha-glucosidase (GAA) activity. Lack of GAA can result in a proximal limb myopathy and respiratory and cardiac failure, each due to abnormal glycogen accumulation in the skeletal muscles or cardiac tissues, respectively. After converting the liver into a "depot" organ, we found that intravenous injection of the [E1-,polymerase-]AdGAA vector allowed for hepatic secretion of GAA over an at least 20-fold dosage range. We noted that very low plasma GAA levels (derived from hepatic secretion of GAA) can allow for GAA uptake by muscle tissues (skeletal or cardiac), but significantly higher plasma GAA levels are required before glycogen "cross-correction" can occur in these same tissues. We also demonstrated that liver-specific enhancer/promoters prolonged GAA transgene expression from persistent [E1-,polymerase-] adenovirus based vector genomes for at least 180 days, and significantly diminished the amounts of neutralizing anti-GAA antibodies elicited in this animal model. Finally, we demonstrated that skeletal muscles can also serve as a "depot" organ for GAA secretion, allowing for secretion of GAA and its uptake by noninfected distal tissues, although glycogen reductions in non-injected muscles were not achieved by the latter approach.
Mol Ther 2002 Apr
PMID:Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction. 1194 71


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