Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schistosome parasites utilize hemoglobin as a major protein source for their metabolism. Degradation of hemoglobin has been hypothesized to be mediated by both cysteine and aspartyl proteases secreted into the lumen of the parasite intestine. We now show that two distinct types of irreversible cysteine protease-specific inhibitors both arrest schistosome hemoglobin degradation in vitro. Arrest of hemoglobin degradation is followed by death of developing schistosomula 1 week later. Schistosome infected mice treated by a dose of 2 mg inhibitor per day for 1 week early in infection, and 2 weeks at the time of egg production, showed a significant reduction in worm burden, hepatomegaly, and the number of eggs produced per female worm. Histopathology showed a minimal immune response to those eggs which were produced, consistent with a delay in egg production relative to untreated infections. By tagging the inhibitor with biotin, specific cysteine protease targets were identified in extracts of schistosome worms.
Mol Biochem Parasitol 1996 Oct 30
PMID:Cysteine protease inhibitors block schistosome hemoglobin degradation in vitro and decrease worm burden and egg production in vivo. 889 33

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

Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non-invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.
Hum Mol Genet 1998 May
PMID:Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. 953 91

Sialuria, a disorder of sialic acid (NeuAc) metabolism characterized by increased free NeuAc in the cytoplasm of cells, is due to failure of CMP-Neu5Ac to feedback inhibit UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase. We now describe the fifth patient in the world with sialuria, a 7-year-old Portuguese girl with developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 micromol of free NeuAc/mg creatinine. The patient's fibroblasts stored excess free NeuAc in the cytosolic fraction, and fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 microM CMP-Neu5Ac (normal, 79%). The patient's UDP-GlcNAc 2-epimerase gene displayed an R266Q mutation in only one allele, consistent with known sialuria mutations and with the proposed dominant nature of this disorder. Extensive description of sialuria patients will help to define the clinical and biochemical spectrum of this disease.
Mol Genet Metab 1999 Jun
PMID:Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics. 1035 12

We report a new type of fatal mitochondrial disorder caused by selective deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn from a consanguineous marriage presented severe lactic acidosis, cardiomegaly and hepatomegaly and died from heart failure after 2 days. The activity of oligomycin-sensitive ATPase was only 31-34% of the control, both in muscle and heart, but the activities of cytochrome c oxidase, citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic and western blot analysis revealed selective reduction of ATPase complex but normal levels of the respiratory chain complexes I, III and IV. The same selective deficiency of ATPase was found in cultured skin fibroblasts which showed similar decreases in ATPase content, ATPase hydrolytic activity and level of substrate-dependent ATP synthesis (20-25, 18 and 29-33% of the control, respectively). Pulse-chase labelling of patient fibroblasts revealed low incorporation of [(35)S]methionine into assembled ATPase complexes, but increased incorporation into immunoprecipitated ATPase subunit beta, which had a very short half-life. In contrast, no difference was found in the size and subunit composition of the assembled and newly produced ATPase complex. Transmitochondrial cybrids prepared from enucleated fibroblasts of the patient and rho degrees cells derived from 143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP synthesis and ATPase content, when compared with control cybrids. Likewise, the pattern of [(35)S]methionine labelling of ATPase was found to be normal in patient cybrids. We conclude that the generalized deficiency of mitochondrial ATPase described is of nuclear origin and is caused by altered biosynthesis of the enzyme.
Hum Mol Genet 1999 Oct
PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

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

Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD). 1193 61

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

Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare type of glycogen storage disease (GSD). It is caused by homozygous or compound heterozygous mutations within GLUT2, the gene encoding the most important facilitative glucose transporter in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. To date, 112 patients have been reported in the literature. Most patients have the typical combination of clinical symptoms: hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy, and severely stunted growth. In 63 patients, mutation analysis has revealed a total of 34 different GLUT2 mutations with none of them being particularly frequent. No specific therapy is available for FBS patients. Symptomatic treatment is directed towards a stabilization of glucose homeostasis and compensation for renal losses of various solutes. In addition to the clinical and molecular genetic aspects of FBS, this review discusses the pathophysiology of the disease and compares it to recent findings in GLUT2 deficient transgenic animals. An overview is also provided on recently discovered members of the rapidly growing family of facilitative glucose transporters, which are novel candidates for congenital disorders of carbohydrate metabolism.
Curr Mol Med 2002 Mar
PMID:Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport. 1194 37

Attenuated Salmonella strains have shown excellent efficacy as mucosal vaccine delivery systems. In the present report, several recombinant strains of Salmonella enterica serovar Typhimurium, engineered to express defined murine cytokines, were used to study their potential immunoregulatory capacity in the mouse model of typhoid fever. Specifically, recombinant strains expressing IL-2 (known as GIDIL2) or TNF-alpha (GIDTNF) were compared with the parental, non-cytokine-secreting, strain (BRD509) for their ability to induce a variety of immune responses in susceptible BALB/c mice. Our findings indicate that bacterially-expressed cytokines are functional in vivo and do induce a unique pattern of responses, quite distinct from that induced by BRD509 organisms. Both the type and magnitude of specific immune parameters were affected. These included the capacity to induce an inflammatory response resulting in a state of profound splenomegaly and hepatomegaly, activation of individual immune cells (particularly macrophages and other myeloid lineage cells), and the induction of nitric oxide (NO) secretion. Furthermore, a structural analysis using light as well as electron microscopy was undertaken to examine the host cellular response to infection with the different bacterial strains. The results indicate that cytokine expression by the invading pathogen can dramatically influence host immunity from a very early stage following infection. These findings may well have important consequences for the potential utilization of bacterial vector-encoded cytokines in immunoregulation in different disease settings.
Mol Immunol 2002 May
PMID:Cytokine expression by attenuated intracellular bacteria regulates the immune response to infection: the Salmonella model. 1200 71


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