Gene/Protein Disease Symptom Drug Enzyme Compound
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Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients' genotype. While the molecular basis for the GSD-I disorders are now known and symptomatic therapies are available, many aspects of the diseases are still poorly understood, and there are no cures. Recently developed animal models of the disorders are now being exploited to delineate the disease more precisely and develop new, more causative therapies.
Curr Mol Med 2002 Mar
PMID:Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. 1194 31

Deficiency of the glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type III (GSD-III), an autosomal recessive disease affecting glycogen metabolism. Most GSD-III patients have AGL deficiency in both the liver and muscle (type IIIa), but some have it in the liver but not muscle (type IIIb). Cloning of human AGL cDNAs and determination of the genomic structure and mRNA isoforms of AGL have allowed for the study of GSD-III at the molecular level. In turn, the resulting information has greatly facilitated our understanding of the molecular basis of this storage disease with remarkable clinical and enzymatic variability. In this review, we summarize all 31 GSD-III mutations in the literature and discuss their clinical and laboratory implications. Most of the mutations are nonsense mutations caused by a nucleotide substitution or small insertion or deletion; only one is caused by a missense amino acid change. Some important genotype-phenotype correlation have emerged, in particular, that exon 3 mutations (17delAG and Q6X) are specifically associated with GSD-IIIb. Three other mutations have appeared to have some phenotype correlation. Specifically, the splice mutation IVS32-12A>G was found in GSD-III patients having mild clinical symptoms, while the mutations 3965delT and 4529insA are associated with a severe phenotype and early onset of clinical manifestations. A molecular diagnostic scheme has been proposed to diagnose GSD-III noninvasively. The characterization of AGL mutations in GSD-III patients has also helped the structure-function analysis of this bifunctional enzyme important for glycogen metabolism.
Curr Mol Med 2002 Mar
PMID:Molecular characterization of glycogen storage disease type III. 1194 33

Glycogen storage disease type IV (GSD-IV), also known as Andersen disease or amylopectinosis (MIM 23250), is a rare autosomal recessive disorder caused by a deficiency of glycogen branching enzyme (GBE) leading to the accumulation of amylopectin-like structures in affected tissues. The disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestations. The human GBE cDNA is approximately 3-kb in length and encodes a 702-amino acid protein. The GBE amino acid sequence shows a high degree of conservation throughout species. The human GBE gene is located on chromosome 3p14 and consists of 16 exons spanning at least 118 kb of chromosomal DNA. Clinically the classic Andersen disease is a rapidly progressive disorder leading to terminal liver failure unless liver transplantation is performed. Several mutations have been reported in the GBE gene in patients with classic phenotype. Mutations in the GBE gene have also been identified in patients with the milder non-progressive hepatic form of the disease. Several other variants of GSD-IV have been reported: a variant with multi-system involvement including skeletal and cardiac muscle, nerve and liver; a juvenile polysaccharidosis with multi-system involvement but normal GBE activity; and the fatal neonatal neuromuscular form associated with a splice site mutation in the GBE gene. Other presentations include cardiomyopathy, arthrogryposis and even hydrops fetalis. Polyglucosan body disease, characterized by widespread upper and lower motor neuron lesions, can present with or without GBE deficiency indicating that different biochemical defects could result in an identical phenotype. It is evident that this disease exists in multiple forms with enzymatic and molecular heterogeneity unparalleled in the other types of glycogen storage diseases.
Curr Mol Med 2002 Mar
PMID:The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. 1194 34

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
Hum Mol Genet 2002 Sep 01
PMID:Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. 1218 68

We describe a Chinese patient with glycogen storage disease type 1b presenting with failure to thrive and protuberant abdomen. The neutropenia was mild and the patient did not have fasting hypoglycemia. Direct DNA sequencing of the G6PT1 gene revealed the patient to be a compound heterozygote of a novel missense mutation, Y24H, and another missense mutation, P191L, which we had described previously. The mother is heterozygous for the Y24H mutation and the father is heterozygous for the P191L mutation. Y24H and P191L may be ethnic-specific mutations as they have not been reported in other populations. The DNA-based diagnosis of GSD 1b will enable us to make an accurate determination of carrier status and to perform prenatal diagnosis of this disease.
Mol Genet Metab 2002 Nov
PMID:Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b. 1240 73

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), a 10 transmembrane domain endoplasmic reticulum protein. To date, 69 G6PT mutations, including 28 missenses and 2 codon deletions, have been identified in GSD-Ib patients. We previously characterized 15 of the missense and one codon deletion mutations using a pSVL-based expression assay. A lack of sensitivity in this assay limited the discrimination between mutations that lead to loss of function and mutations that leave a low residual activity. We now report an improved G6PT assay, based on an adenoviral vector-mediated expression system and its use in the functional characterization of all 30 codon mutations found in GSD-Ib patients. Twenty of the naturally occurring mutations completely abolish microsomal G6P uptake activity while the other 10 mutations, including 5 previously characterized ones, partially inactivate the transporter. This information should greatly facilitate genotype-phenotype correlation. We also report a structure-function analysis of G6PT. In addition to the 3 destabilizing mutations reported previously, we now show that the G50R, C176R, V235del, G339C and G339D mutations also compromise the G6PT stability. Mutation analysis of the amino-terminal domain of G6PT shows that it is required for optimal G6P uptake activity. Finally, we show that degradation of both wild-type and mutant G6PT is inhibited by a potent proteasome inhibitor, lactacystin, demonstrating that G6PT is a substrate for proteasome-mediated degradation.
Hum Mol Genet 2002 Dec 01
PMID:Structure-function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib. 1244 4

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
Hum Mol Genet 2003 Oct 01
PMID:Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter. 1292 67

Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creuzfeldt-Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia, and alpha-synuclein mutations cause autosomal dominant Parkinson's disease. In all these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and in these cases the whole protein is deposited. In Alzheimer's disease, mutations in APP or presenilin 1 or 2 cause autosomal dominant disease and these are the substrate and proteases, respectively, which are responsible for the production of the deposited peptide, Abeta. Thus, in all cases, the mutations lead to the disease by a mechanism that involves the deposition process. We briefly review this remarkably predictable biology, but also point out that it seems sporadic forms of all these diseases are predisposed to by genetic variability at the same loci, strongly suggesting that the quantity of the normal protein produced influences risk for the sporadic forms of the disease. The evidence for this assertion is strongest in Parkinson's disease (PD), where genetic variability in alpha-synuclein expression affects risk of developing disease, although the oldest evidence for the notion that increased expression of normal sequence protein can lead to disease comes from the observation of Alzheimer's disease in trisomy 21 cases. From these observations, we make predictions concerning the etiology and pathogenesis of neurodegenerative diseases in general.
Hum Mol Genet 2004 Apr 01
PMID:The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. 1497 59

Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation.
Mol Genet Metab 2004 Nov
PMID:DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. 1554 99

Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid alpha-glucosidase (GAA; acid maltase) can be corrected by liver-targeted gene therapy in GSD-II, if secretion of GAA is accompanied by receptor-mediated uptake in cardiac and skeletal muscle. An adeno-associated virus (AAV) vector encoding human (h) GAA was pseudotyped as AAV8 (AAV2/8) and injected intravenously into immunodeficient GSD-II mice. High levels of hGAA were maintained in plasma for 24 weeks following AAV2/8 vector administration. A marked increase in vector copy number in the liver was demonstrated for the AAV2/8 vector compared to the analogous AAV2/2 vector. GAA deficiency in the heart and skeletal muscle was corrected with the AAV2/8 vector in male GSD-II mice, consistent with receptor-mediated uptake of hGAA. Male GSD-II mice demonstrated complete correction of glycogen storage in heart and diaphragm with the AAV2/8 vector, while female GSD-II mice had correction only in the heart. A biomarker for GSD-II was reduced in both sexes following AAV2/8 vector administration. Therefore, GAA production with an AAV2/8 vector in a depot organ, the liver, generated evidence for efficacious gene therapy in a mouse model for GSD-II.
Mol Ther 2005 Jan
PMID:Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II. 1558 6


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