Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.4.2.8 (phosphomannomutase)
238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbohydrate-deficient glycoprotein (CDG) syndromes are genetic multisystemic disorders characterized by defective N-glycosylation of serum and cellular proteins. The activity of phosphomannomutase was markedly deficient (< or = 10% of the control activity) in fibroblasts, liver and/or leucocytes of 6 patients with CDG syndrome type I. Other enzymes involved in the conversion of glucose to mannose 1-phosphate, as well as phosphoglucomutase, had normal activities. Phosphomannomutase activity was normal in fibroblasts of 2 patients with CDG syndrome type II. Since this enzyme provides the mannose 1-phosphate required for the initial steps of protein glycosylation, it is concluded that phosphomannomutase deficiency, which is first reported here for higher organisms, is a cause, and most likely the major one, of CDG syndrome type I.
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PMID:Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. 854 46

Isoelectrofocusing of serum sialotransferrins from patients with untreated hereditary fructose intolerance (HFI) shows a cathodal shift similar to that in carbohydrate-deficient glycoprotein (CDG) syndrome type I and in untreated galactosemia. This report is on serum lysosomal enzyme abnormalities in untreated HFI that are identical to those found in CDG syndrome type I but different from those in untreated galactosemia. CDG syndrome type I is due to phosphomannomutase deficiency, a defect in the early glycosylation pathway. It was found that fructose 1-phosphate is a potent competitive inhibitor (Ki congruent to 40 microM) of phosphomannose isomerase (EC 5.3.1.8), the first enzyme of the N-glycosylation pathway thus explaining the N-glycosylation disturbances in HFI.
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PMID:Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance. 891 Sep 43

Type I carbohydrate-deficient glycoprotein (CDG) syndrome is a genetic multisystem disorder generally without overt renal problems. We report a neonate with neurological abnormalities and congenital nephrotic syndrome of diffuse mesangial sclerosis type. Serum transferrin isoelectric focusing showed the typical abnormalities of type I CDG syndrome. Normal transferrin focusing findings in other patients with similar renal problems excluded the possibility of a secondary biochemical phenomenon. The diagnosis of type I CDG syndrome was confirmed by demonstration of a deficiency of phosphomannomutase. No evidence of pontocerebellar atrophy was found in imaging or at autopsy. We conclude that congenital nephrotic syndrome may occur in type I CDG syndrome, and that this diagnosis should be considered in patients with congenital nephrotic syndrome. Absence of pontocerebellar atrophy does not exclude the diagnosis of type I CDG syndrome.
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PMID:Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome. 898 53

We have cloned the human homologue of SEC53 or yeast phosphomannomutase (HGMW-approved symbol PMM1) from a liver cDNA library. This cDNA encodes a protein of 262 amino acids with a predicted molecular mass of 29 kDa and 54% identity with yeast phosphomannomutase. Expression of the human cDNA in Escherichia coli yielded an active phosphomannomutase, which was purified to homogeneity. Northern blot analysis of human tissues showed strong expression in liver, heart, brain, and pancreas and a lower expression in skeletal muscle. The gene was assigned to chromosome 22q13.1 by the use of hybrid cell lines and by fluorescence in situ hybridization. Most patients presenting with carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken disease) have a greatly reduced phosphomannomutase activity; the gene encoding this enzyme is a likely candidate for CDG1. Since the CDG1 locus maps else where in the genome (16p13), mutations in the phosphomannomutase gene encoded by chromosome 22 are not a major cause of CDG1.
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PMID:PMM (PMM1), the human homologue of SEC53 or yeast phosphomannomutase, is localized on chromosome 22q13. 907 Sep 17

The carbohydrate-deficient glycoprotein syndromes are multisystemic inherited diseases with severe nervous system involvement. There is indirect evidence for deficiency of phosphomannomutase in type I and direct evidence for a deficiency of N-acetylglucosaminyltransferase II in type II. The disease is characterized by carbohydrate deficiencies of a number glycoproteins, including serum sialotransferrins.
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PMID:[Metabolic disorders in patients with primary carbohydrate deficient glycoprotein syndrome]. 923 66

Patients with carbohydrate-deficient glycoprotein syndrome (CDGS) Type 1 underglycosylate many glycoproteins by failing to add entire N-linked carbohydrate chains to them. The primary defect in these patients has been reported as a > 90% deficiency in phosphomannomutase activity (PMM), the enzyme that converts mannose-6-phosphate to mannose-1-phosphate. This lesion reduces both the amount and the size of the lipid-linked oligosaccharide precursor. We have now analyzed the activity of PMM and the level of glycosylation in cultured fibroblasts as well as the level of blood mannose in seven CDGS Type 1 patients and their parents. All of these patients were approximately 95% deficient in PMM activity and their parents had an average of 51% of control PMM activity. Furthermore, parental fibroblasts showed reduced glycosylation and a higher proportion of truncated N-linked chains compared to those made by control fibroblasts. Addition of 0.25 mM mannose to the culture medium corrected both the underglycosylation and size of the oligosaccharide chains in CDGS Type 1 patients and their parents. Finally, serum from CDGS patients had considerably reduced mannose levels (5-40 microM) compared to normal controls (40-80 microM) and some parents were below normal (16-103 microM). These results suggest that the reduced blood mannose level is a consequence of the PMM deficiency. This is the first inherited disorder in human metabolism that shows a decrease in available mannose. Increasing blood mannose levels might correct some protein underglycosylation in these patients.
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PMID:Abnormal metabolism of mannose in families with carbohydrate-deficient glycoprotein syndrome type 1. 925 81

The effects on isoelectrofocusing patterns of serum glycoproteins were studied in a patient with CDG syndrome type I and phosphomannomutase deficiency during 3 weeks of continuous intravenous mannose infusion. Doses of 5.7 g/kg/day led to stable serum mannose levels up to 2.0 mmol/l and were well tolerated without signs of liver or renal toxicity. While most of the pathological glycoprotein patterns, including alpha1-antitrypsin, typical for CDG syndrome type I remained unchanged, mannose infusion led to a unique change of the isoelectrofocusing pattern of serum sialotransferrins with appearance of two extra bands after 3 weeks of treatment.
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PMID:Continuous mannose infusion in carbohydrate-deficient glycoprotein syndrome type I. 935 Sep 1

Phosphomannomutase (PMM) catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, which is a substrate for the synthesis of GDP-mannose. This nucleotide sugar is then used in the synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins. In the yeast Saccharomyces cerevisiae, SEC53, a gene required for viability, encodes PMM. Given the importance of PMM in glycoprotein synthesis, it is surprising that very little is known about the enzyme in higher eukaryotes. Recently, an autosomal recessive human disease, Carbohydrate-deficient glycoprotein syndrome type I (CDGS-I) has been correlated with severely reduced PMM activity. Here we report the isolation of a cDNA encoding human PMM, a protein of 29 kDa that is 55% identical and 66% similar to yeast Sec53p. Northern blot analysis shows a single 1.4 kb transcript that is ubiquitously expressed, although levels vary markedly among tissues. Expression of the human cDNA in a temperature-sensitive mutant sec53 yeast strain confers growth at the restrictive temperature, strongly suggesting that this gene encodes a functional PMM. Finally, when expressed in BHK cells, PMM is localized exclusively to the cytosol corresponding to its localization in yeast.
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PMID:Cloning and characterization of human phosphomannomutase, a mammalian homologue of yeast SEC53. 937 85

The search for the carbohydrate-deficient glycoprotein syndrome type I (CDG1) gene has revealed the existence of a family of phosphomannomutase (PMM) genes in humans. Two expressed PMM genes, PMM1 and PMM2 , are located on chromosome bands 22q13 and 16p13, respectively, and a processed pseudogene PMM2 psi is located on chromosome 18p. Mutations in PMM2 are the cause of CDG type IA whereas no disorder has been associated with defects in PMM1 as yet. Here, we describe the genomic organization of these paralogous genes. There is a 65% identity of the coding sequence, and all intron/exon boundaries have been conserved. The processed pseudogene is more closely related to PMM2 . Remarkably, several base substitutions in PMM2 that are associated with disease are also present at the corresponding positions in the pseudogene. Thus, mutations that occur at a slow rate in the active gene in the population have also accumulated in the pseudogene.
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PMID:Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. 942 21

The carbohydrate-deficient glycoprotein syndrome (CDGS) is a group of disorders characterized biochemically by abnormal glycosylation of serum and cellular glycoproteins. It has been classified into four forms on the basis of the isoelectric focusing pattern of serum transferrin and difference in clinical presentation. A deficiency of phosphomannomutase (PMM) has been reported in most patients with type 1. Seven of our eight CDGS patients, classified clinically as type 1, were shown to have a deficiency of phosphomannomutase in their fibroblast or lymphoblastoid cells (0.04-0.2 nmol/min per mg, compared with a control range of 1.0-2.1 nmol/min per mg). The eighth patient, who had many clinical features of the severe neonatal form of CDGS type 1, but lacked definite signs of CNS and ocular involvement, had a normal phosphomannomutase activity in his fibroblasts. There were approximately equal amounts of disialo- and tetrasialotransferrin and only a trace amount of asialotransferrin in the serum and ascitic fluid of this patient. The disialo- and tetrasialotransferrin isoforms were purified by ion-exchange chromatography and analysed by SDS-PAGE. The disialotransferrin had a lower molecular mass than the tetrasialotransferrin, consistent with the absence of an N-linked glycan. The N-linked glycans released enzymically from both isoforms consisted exclusively of disialylated biantennary chains, suggesting that disialotransferrin results from underglycosylation, as in the PMM-deficient CDGS type 1 patients. It is concluded that the clinical and biochemical phenotype in CDGS type 1 can result from more than one basic defect.
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PMID:A case of the carbohydrate-deficient glycoprotein syndrome type 1 (CDGS type 1) with normal phosphomannomutase activity. 942 52


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