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)

Congenital Disorders of Glycosylation (CDG) are human deficiencies in glycoprotein biosynthesis. Previous studies showed that 1 mM mannose corrects defective protein N-glycosylation in cultured fibroblasts from some CDG patients. We hypothesized that these CDG cells have limited GDP-mannose (GDP-Man) and that exogenous mannose increases the GDP-Man levels. Using a well established method to measure GDP-Man, we found that normal fibroblasts had an average of 23.5 pmol GDP-Man/10(6) cells, whereas phosphomannomutase (PMM)-deficient fibroblasts had only 2.3-2.7 pmol/10(6) cells. Adding 1 mM mannose to the culture medium increased the GDP-Man level in PMM-deficient cells to approximately 15.5 pmol/10(6) cells, but had no significant effect on GDP-Man levels in normal fibroblasts. Similarly, mannose supplementation increased GDP-Man from 4.6 pmol/10(6) cells to 24.6 pmol/10(6) cells in phosphomannose isomerase (PMI)-deficient fibroblasts. Based on the specific activity of the GDP-[(3)H]Man pool present in [2-(3)H]mannose labeled cells, mannose supplementation also partially corrected the impaired synthesis of mannosylphosphoryldolichol (Man-P-Dol) and Glc(0)(-)(3)Man(9)GlcNAc(2)-P-P-Dol. These results confirm directly that deficiencies in PMM and PMI result in lowered cellular GDP-Man levels that are corrected by the addition of mannose. In contrast to these results, GDP-Man levels in fibroblasts from a CDG-Ie patient, who is deficient in Man-P-Dol synthase, were normal and unaffected by mannose supplementation even though mannose addition was found to correct abnormal lipid intermediate synthesis in another study (Kim et al. [2000] J. Clin. Invest., 105, 191-198). The mechanism by which mannose supplementation corrects abnormal protein N-glycosylation in Man-P-Dol synthase deficient cells is unknown, but this observation suggests that the regulation of Man-P-Dol synthesis and utilization may be more complex than is currently understood.
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PMID:Mannose supplementation corrects GDP-mannose deficiency in cultured fibroblasts from some patients with Congenital Disorders of Glycosylation (CDG). 1092 9

A male infant is described who presented with persistent hyperinsulinaemic hypoglycaemia, responding to diazoxide treatment. However, this therapy was discontinued because of seizures as a consequence of disturbed water and electrolyte balance. Glucose homeostasis could only be maintained by subtotal pancreatectomy, which was performed at 3 8/12 years of age. He developed a severe thrombosis, whereon a congenital disorder of glycosylation (CDG) was suspected. An abnormal transferrin isoelectric focusing pattern was found and the diagnosis of CDG Ia was confirmed by enzyme and molecular genetic analysis. This is the first patient with phosphomannomutase deficiency (McKusick 601785) described presenting with severe hyperinsulinaemic hypoglycaemia.
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PMID:Hyperinsulinaemic hypoglycaemia--leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). 1191 19

Congenital disorder of glycosylation (CDG) type IA (phosphomannomutase deficiency) is the most common of a group of inherited metabolic disorders that are due to defective glycosylation of glycoproteins. CDG-IA is clinically characterized by major nervous system involvement and various organs are affected to a variable degree. Common clinical findings are skeletal changes including peculiar thoracic deformity and joint restriction, while a major radiological feature is diffuse osteopenia. The aim of this study was to measure bone density and biochemical markers of bone turnover in three patients with CDG-IA, whose age ranged between 14 and 27 years. We found that bone mass, as judged by standard densitometry, quantitative computed tomography and ultrasonography, was lower in patients than in age- and sex-matched healthy controls. Biochemical indexes of bone resorption including free pyridinoline levels in serum and pyridinoline and deoxypyridinoline urinary excretions were normal, whereas bone formation markers (serum osteocalcin and serum bone-specific alkaline phosphatase) activity were increased. These results suggest that low bone density is a component of CDG-IA, which should be considered among inherited metabolic diseases with decreased bone mass. We hypothesize that hypoglycosylation of noncollagenous bone proteins may contribute to the osteopenia observed in these patients. From a clinical point of view, our observation shows that bone density measurements can provide a quantitative assessment of bone involvement in such diseases.
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PMID:Assessment of skeletal status in patients with congenital disorder of glycosylation type IA. 1201 50

Congenital disorder of glycosylation Ia (CDG-Ia) is an autosomal recessive disease, characterized by the impaired biosynthesis of the N-linked oligosaccharide chains of proteins due to a deficiency of phosphomannomutase (PMM), the enzyme converting mannose-6-phosphate into mannose-1-phosphate. We investigated the consequences of the altered N-linked glycoprotein (GP) biosynthesis on the quantity and quality of glycosphingolipids (GSLs) in fibroblasts of CDG-Ia patients. First, we found that CDG-Ia fibroblasts contain an increased amount of total GSLs when compared with normal fibroblasts. Further, we assessed by metabolic labeling of CDG-Ia fibroblasts with radioactive sugar precursors, including galactose and N-acetylmannosamine, that a diminished biosynthesis of cellular GPs is antagonized by an increased biosynthesis of GSLs. An increased GSL biosynthesis was also observed by means of radiolabeled lipid precursors including sphingosine and lactosylceramide. Notably, also the degradation of GLSs is slowed down in CDG-Ia fibroblasts. Finally, when we labeled normal human fibroblasts and CHO cells with radioactive galactose in the presence and absence of deoxymannojirimycin (dMM), an inhibitor of N-glycan processing, we found that this cellular model mimics what occurs in CDG-Ia fibroblasts. Since an inverse relationship between GP expression and GSL content does exist, we assume that increased glycosphingolipid biosynthesis is secondary to protein hypoglycosylation. Altogether, our data suggest that the cell metabolic machinery may be able to partially re-equilibrate protein hypoglycosylation with increased biosynthesis of glycosphingolipids, possibly to preserve the overall physico-chemical equilibrium of the outer layer of the plasma membrane.
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PMID:Increased biosynthesis of glycosphingolipids in congenital disorder of glycosylation Ia (CDG-Ia) fibroblasts. 1240 8

A Japanese boy had clinical features of congenital disorder of glycosylation type Ia (CDG Ia, also known as carbohydrate-deficient-glycoprotein syndrome, previously), and enzymatic and molecular assay of phosphomannomutase confirmed this diagnosis. During infancy, the patient showed delayed mental and motor development, hypotonia, ataxia, hepatomegaly, liver dysfunction, abnormal coagulation system and cerebellar hypoplasia. At present, though he is 3 years and 8 months old, he cannot utter meaningful words or sit by himself. These findings suggested that he had one of the severe phenotypes of Japanese CDG Ia. Mutational analysis demonstrated heterozygosity for the missense mutation in exon 4 (P113L) and a novel nonsense mutation in exon 7 (R194X). We report his clinical course and the results of molecular assay, and discuss correlation between clinical severity and genotype.
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PMID:Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia. 1312 99

Phosphomannomutase (PMM) deficiency causes congenital disorder of glycosylation (CDG)-Ia, a broad spectrum disorder with developmental and neurological abnormalities. PMM converts mannose 6-phosphate (M6P) to mannose-1-phosphate, a precursor of GDP-mannose used to make Glc(3)Man(9)GlcNAc(2)-P-P-dolichol (lipid-linked oligosaccharide; LLO). LLO, in turn, is the donor substrate of oligosaccharyltransferase for protein N-linked glycosylation. Hepatically produced N-linked glycoproteins in CDG-Ia blood are hypoglycosylated. Upon labeling with [(3)H]mannose, CDG-Ia fibroblasts have been widely reported to accumulate [(3)H]LLO intermediates. Since these are thought to be poor oligosaccharyltransferase substrates, LLO intermediate accumulation has been the prevailing explanation for hypoglycosylation in patients. However, this is discordant with sporadic reports of specific glycoproteins (detected with antibodies) from CDG-Ia fibroblasts being fully glycosylated. Here, fluorophore-assisted carbohydrate electrophoresis (FACE, a nonradioactive technique) was used to analyze steady-state LLO compositions in CDG-Ia fibroblasts. FACE revealed that low glucose conditions accounted for previous observations of accumulated [(3)H]LLO intermediates. Additional FACE experiments demonstrated abundant Glc(3)Man(9)GlcNAc(2)-P-P-dolichol, without hypoglycosylation, CDG-Ia fibroblasts grown with physiological glucose. This suggested a "missing link" to explain hypoglycosylation in CDG-Ia patients. Because of the possibility of its accumulation, the effects of M6P on glycosylation were explored in vitro. Surprisingly, M6P was a specific activator for cleavage of Glc(3)Man(9)GlcNAc(2)-P-P-dolichol. This led to futile cycling the LLO pathway, exacerbated by GDP-mannose/PMM deficiency. The possibilities that M6P may accumulate in hepatocytes and that M6P-stimulated LLO cleavage may account for both hypoglycosylation and the clinical failure of dietary mannose therapy with CDG-Ia patients are discussed.
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PMID:Analysis of glycosylation in CDG-Ia fibroblasts by fluorophore-assisted carbohydrate electrophoresis: implications for extracellular glucose and intracellular mannose 6-phosphate. 1570 48

Congenital disorder of Glycosylation type Ia is an autosomal recessive disorder, characterized by a central nervous system dysfunction and multiorgan failure associated with defective N-glycosylation and phosphomannomutase (PMM) deficiency related to mutations in the PMM2 gene (mRNA U85773.1, gene ID 5373). More than 75 different mutations have been previously described. In our study, 38 different mutations were found in 52 French families with CDG-Ia. Eleven mutations had not been previously published in CDG-Ia patients: eight missense and three splice mutations. We studied the PMM activity of eight novel recombinant mutant proteins in an E. coli expression system, comparing them with the wild type protein, c.422 G>A (R141H), and c.415 G>A (E139K) mutant proteins. We also studied the previously described c.590 C>A (E197A) found on the same allele as c.394 A>T (I132F). All mutant proteins studied except E197A had decreased activity and/or were thermolabile, and were pathogenic mutations. Haplotype studies revealed a founder effect for E139K mutation, only described in France and found in seven CDG-Ia families (7.6%). In contrast, at least two different haplotypes were observed for the R141H mutation in France, studied in 23 families. The R141H seems to be a combination of the "old" R141H mutation found all over Europe and a second "French" R141H, and could be substantially older than E139K.
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PMID:A new insight into PMM2 mutations in the French population. 1584 18

Congenital disorder of glycosylation Ia (CDGIa) is an autosomal recessive disease that is caused by mutations in the gene PMM2 encoding phosphomannomutase, an enzyme that synthesizes mannose-1-phosphate, an important intermediate for the N-glycan biosynthesis. Here, we investigated the susceptibility of CDGIa fibroblasts to cell death induction. CDGIa fibroblasts were more sensitive than control fibroblasts to staurosporine-induced apoptosis. Supplementation with mannose, which corrects N-glycosylation in CDGIa fibroblasts, did not abrogate their higher sensitivity to staurosporine. These results show that the sensitivity of CDGIa fibroblasts to apoptosis is not directly related to their defective N-glycosylation.
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PMID:Defect of N-glycosylation is not directly related to congenital disorder of glycosylation Ia fibroblast sensitivity to staurosporine-induced cell death. 1608 95

Congenital disorder of glycosylation type 1a (CDG-1a) is a congenital disease characterized by severe defects in nervous system development. It is caused by mutations in alpha-phosphomannomutase (of which there are two isozymes, alpha-PMM1 and alpha-PPM2). Here we report the x-ray crystal structures of human alpha-PMM1 in the open conformation, with and without the bound substrate, alpha-D-mannose 1-phosphate. Alpha-PMM1, like most haloalkanoic acid dehalogenase superfamily (HADSF) members, consists of two domains, the cap and core, which open to bind substrate and then close to provide a solvent-exclusive environment for catalysis. The substrate phosphate group is observed at a positively charged site of the cap domain, rather than at the core domain phosphoryl-transfer site defined by the Asp(19) nucleophile and Mg(2+) cofactor. This suggests that substrate binds first to the cap and then is swept into the active site upon cap closure. The orientation of the acid/base residue Asp(21) suggests that alpha-phosphomannomutase (alpha-PMM) uses a different method of protecting the aspartylphosphate from hydrolysis than the HADSF member beta-phosphoglucomutase. It is hypothesized that the electrostatic repulsion of positive charges at the interface of the cap and core domains stabilizes alpha-PMM1 in the open conformation and that the negatively charged substrate binds to the cap, thereby facilitating its closure over the core domain. The two isozymes, alpha-PMM1 and alpha-PMM2, are shown to have a conserved active-site structure and to display similar kinetic properties. Analysis of the known mutation sites in the context of the structures reveals the genotype-phenotype relationship underlying CDG-1a.
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PMID:The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a. 1654 Apr 64

Congenital Disorders of Glycosylation (CDG) are a group of recessive genetic disorders characterized by hypoglycosylation of glycoproteins. CDG-Ia, the most common type, is caused by mutations in the PMM2 gene, coding for a phosphomannomutase (PMM2; EC 5.4.2.8). The mutational spectrum of PMM2 comprises more than 80 different mutations but one of them, R141H, is particularly interesting due to its high frequency among CDG-Ia patients worldwide. In contrast, other mutations are ethnically or geographically restricted, such as D65Y which is only found in patients of Iberian ancestry. In the present study a population genetic approach was used in an attempt to clarify the origins of two important disease causing mutations: R141H and D65Y. Based on SNP and STR genotypic analysis, we ascertained an association between the R141H substitution and a particular haplotype, suggesting a common origin for all the mutated chromosomes. Similar results were found for D65Y, although the associated haplotype was different from that of R141H, suggesting independent origins for these two mutations. Our results enable us to infer an Iberian origin for the D65Y mutation.
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PMID:Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2. 1716 82


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