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Emile Van Schaftingen - One of the best experts on this subject based on the ideXlab platform.
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Mammalian Phosphomannomutase PMM1 is the brain IMP-sensitive glucose-1,6-bisphosphatase
The Journal of biological chemistry, 2008Co-Authors: Maria Veiga-da-cunha, Gert Matthijs, Wendy Vleugels, Pushpa Maliekal, Emile Van SchaftingenAbstract:Glucose 1,6-bisphosphate (Glc-1,6-P(2)) concentration in brain is much higher than what is required for the functioning of phosphoglucomutase, suggesting that this compound has a role other than as a cofactor of phosphomutases. In cell-free systems, Glc-1,6-P(2) is formed from 1,3-bisphosphoglycerate and Glc-6-P by two related enzymes: PGM2L1 (phosphoglucomutase 2-like 1) and, to a lesser extent, PGM2 (phosphoglucomutase 2). It is hydrolyzed by the IMP-stimulated brain Glc-1,6-bisphosphatase of still unknown identity. Our aim was to test whether Glc-1,6-bisphosphatase corresponds to the Phosphomannomutase PMM1, an enzyme of mysterious physiological function sharing several properties with Glc-1,6-bisphosphatase. We show that IMP, but not other nucleotides, stimulated by >100-fold (K(a) approximately 20 mum) the intrinsic Glc-1,6-bisphosphatase activity of recombinant PMM1 while inhibiting its phosphoglucomutase activity. No such effects were observed with PMM2, an enzyme paralogous to PMM1 that physiologically acts as a Phosphomannomutase in mammals. Transfection of HEK293T cells with PGM2L1, but not the related enzyme PGM2, caused an approximately 20-fold increase in the concentration of Glc-1,6-P(2). Transfection with PMM1 caused a profound decrease (>5-fold) in Glc-1,6-P(2) in cells that were or were not cotransfected with PGM2L1. Furthermore, the concentration of Glc-1,6-P(2) in wild-type mouse brain decreased with time after ischemia, whereas it did not change in PMM1-deficient mouse brain. Taken together, these data show that PMM1 corresponds to the IMP-stimulated Glc-1,6-bisphosphatase and that this enzyme is responsible for the degradation of Glc-1,6-P(2) in brain. In addition, the role of PGM2L1 as the enzyme responsible for the synthesis of the elevated concentrations of Glc-1,6-P(2) in brain is established.
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Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of Phosphomannomutase 2.
FEBS letters, 1999Co-Authors: Michèle Pirard, Jaak Jaeken, Leen Heykants, Gert Matthijs, Els Schollen, Stephanie Grunewald, Emile Van SchaftingenAbstract:Seven mutant forms of human Phosphomannomutase 2 were produced in Escherichia coli and purified. These mutants had a Vmax of 0.2-50% of the wild enzyme and were unstable. The least active protein (R141H) bears a very frequent mutation, which has never been found in the homozygous state whereas the second least active protein (D188G) corresponds to a mutation associated with a particularly severe phenotype. We conclude that total lack of Phosphomannomutase 2 is incompatible with life. Another conclusion is that the elevated residual Phosphomannomutase activity found in fibroblasts of some patients is contributed by their mutated Phosphomannomutase 2.
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Kinetic properties and tissular distribution of mammalian Phosphomannomutase isozymes.
Biochemical Journal, 1999Co-Authors: Michel Pirard, Gert Matthijs, Els Schollen, Younes Achouri, Jean-françois Collet, Emile Van SchaftingenAbstract:Human tissues contain two types of Phosphomannomutase, PMM1 and PMM2. Mutations in the PMM2 gene are responsible for the most common form of carbohydrate-deficient glycoprotein syndrome [Matthijs, Schollen, Pardon, Veiga-da-Cunha, Jaeken, Cassiman and Van Schaftingen (1997) Nat. Genet. 19, 88-92]. The protein encoded by this gene has now been produced in Escherichia coli and purified to homogeneity, and its properties have been compared with those of recombinant human PMM1. PMM2 converts mannose 1-phosphate into mannose 6-phosphate about 20 times more rapidly than glucose 1-phosphate to glucose 6-phosphate, whereas PMM1 displays identical Vmax values with both substrates. The Ka values for both mannose 1,6-bisphosphate and glucose 1,6-bisphosphate are significantly lower in the case of PMM2 than in the case of PMM1. Like PMM1, PMM2 forms a phosphoenzyme with the chemical characteristics of an acyl-phosphate. PMM1 and PMM2 hydrolyse different hexose bisphosphates (glucose 1,6-bisphosphate, mannose 1,6-bisphosphate, fructose 1,6-bisphosphate) at maximal rates of approximately 3.5 and 0.3% of their PMM activity, respectively. Fructose 1,6-bisphosphate does not activate PMM2 but causes a time-dependent stimulation of PMM1 due to the progressive formation of mannose 1,6-bisphosphate from fructose 1,6-bisphosphate and mannose 1-phosphate. Experiments with specific antibodies, kinetic studies and Northern blots indicated that PMM2 is the only detectable isozyme in most rat tissues except brain and lung, where PMM1 accounts for about 66 and 13% of the total activities, respectively.
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Carbohydrate-deficient glycoprotein syndrome type IA (Phosphomannomutase-deficiency)
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1999Co-Authors: H. Carchon, Emile Van Schaftingen, Gert Matthijs, Jaak JaekenAbstract:AbstractThe carbohydrate-deficient glycoprotein or CDG syndromes (OMIM 212065) are a recently delineated group of genetic, multisystem diseases with variable dysmorphic features. The known CDG syndromes are characterized by a partial deficiency of the N-linked glycans of secretory glycoproteins, lysosomal enzymes, and probably also membranous glycoproteins. Due to the deficiency of terminal N-acetylneuraminic acid or sialic acid, the glycan changes can be observed in serum transferrin or other glycoproteins using isoelectrofocusing with immunofixation as the most widely used diagnostic technique. Most patients show a serum sialotransferrin pattern characterized by increased di- and asialotransferrin bands (type I pattern). The majority of patients with type I are Phosphomannomutase deficient (type IA), while in a few other patients, deficiencies of phosphomannose isomerase (type IB) or endoplasmic reticulum glucosyltransferase (type IC) have been demonstrated. This review is an update on CDG syndrome type IA
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Prenatal diagnosis in CDG1 families: beware of heterogeneity
European Journal of Human Genetics, 1998Co-Authors: Gert Matthijs, Jaak Jaeken, Els Schollen, Jean-jacques Cassiman, Valérie Cormier-daire, Emile Van SchaftingenAbstract:Carbohydrate-deficient glycoprotein syndrome type I (CDG1) is an autosomal recessive, metabolic disorder with severe psychomotor retardation and a high mortality rate in early childhood. Most patients have a deficiency of Phosphomannomutase, due to mutations in PMM2 , a gene located on chromosome 16p13. Over a period of 18 months we offered prenatal diagnosis to eight families. In six cases and prior to the identification of the gene, the diagnosis was based on linkage analysis and Phosphomannomutase measurements. Subsequently direct mutation analysis has been used in two families. It is shown here that Phosphomannomutase activities are strongly reduced in cultured amniocytes and trophoblasts of affected foetuses. We refrained from offering prenatal testing in two other families, because either the disease did not link to chromosome 16 and/or normal Phosphomannomutase activities were measured in fibroblasts from the proband. This confirms earlier suggestions of heterogeneity for CDG1.
Jaak Jaeken - One of the best experts on this subject based on the ideXlab platform.
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Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of Phosphomannomutase 2.
FEBS letters, 1999Co-Authors: Michèle Pirard, Jaak Jaeken, Leen Heykants, Gert Matthijs, Els Schollen, Stephanie Grunewald, Emile Van SchaftingenAbstract:Seven mutant forms of human Phosphomannomutase 2 were produced in Escherichia coli and purified. These mutants had a Vmax of 0.2-50% of the wild enzyme and were unstable. The least active protein (R141H) bears a very frequent mutation, which has never been found in the homozygous state whereas the second least active protein (D188G) corresponds to a mutation associated with a particularly severe phenotype. We conclude that total lack of Phosphomannomutase 2 is incompatible with life. Another conclusion is that the elevated residual Phosphomannomutase activity found in fibroblasts of some patients is contributed by their mutated Phosphomannomutase 2.
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Carbohydrate-deficient glycoprotein syndrome type IA (Phosphomannomutase-deficiency)
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1999Co-Authors: H. Carchon, Emile Van Schaftingen, Gert Matthijs, Jaak JaekenAbstract:AbstractThe carbohydrate-deficient glycoprotein or CDG syndromes (OMIM 212065) are a recently delineated group of genetic, multisystem diseases with variable dysmorphic features. The known CDG syndromes are characterized by a partial deficiency of the N-linked glycans of secretory glycoproteins, lysosomal enzymes, and probably also membranous glycoproteins. Due to the deficiency of terminal N-acetylneuraminic acid or sialic acid, the glycan changes can be observed in serum transferrin or other glycoproteins using isoelectrofocusing with immunofixation as the most widely used diagnostic technique. Most patients show a serum sialotransferrin pattern characterized by increased di- and asialotransferrin bands (type I pattern). The majority of patients with type I are Phosphomannomutase deficient (type IA), while in a few other patients, deficiencies of phosphomannose isomerase (type IB) or endoplasmic reticulum glucosyltransferase (type IC) have been demonstrated. This review is an update on CDG syndrome type IA
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Prenatal diagnosis in CDG1 families: beware of heterogeneity
European Journal of Human Genetics, 1998Co-Authors: Gert Matthijs, Jaak Jaeken, Els Schollen, Jean-jacques Cassiman, Valérie Cormier-daire, Emile Van SchaftingenAbstract:Carbohydrate-deficient glycoprotein syndrome type I (CDG1) is an autosomal recessive, metabolic disorder with severe psychomotor retardation and a high mortality rate in early childhood. Most patients have a deficiency of Phosphomannomutase, due to mutations in PMM2 , a gene located on chromosome 16p13. Over a period of 18 months we offered prenatal diagnosis to eight families. In six cases and prior to the identification of the gene, the diagnosis was based on linkage analysis and Phosphomannomutase measurements. Subsequently direct mutation analysis has been used in two families. It is shown here that Phosphomannomutase activities are strongly reduced in cultured amniocytes and trophoblasts of affected foetuses. We refrained from offering prenatal testing in two other families, because either the disease did not link to chromosome 16 and/or normal Phosphomannomutase activities were measured in fibroblasts from the proband. This confirms earlier suggestions of heterogeneity for CDG1.
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Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance.
Pediatric research, 1996Co-Authors: Jaak Jaeken, Maciej Adamowicz, Michel Pirard, Ewa Pronicka, Emile Van SchaftingenAbstract: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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Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.
FEBS letters, 1995Co-Authors: Emile Van Schaftingen, Jaak JaekenAbstract: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.
Gert Matthijs - One of the best experts on this subject based on the ideXlab platform.
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Mammalian Phosphomannomutase PMM1 is the brain IMP-sensitive glucose-1,6-bisphosphatase
The Journal of biological chemistry, 2008Co-Authors: Maria Veiga-da-cunha, Gert Matthijs, Wendy Vleugels, Pushpa Maliekal, Emile Van SchaftingenAbstract:Glucose 1,6-bisphosphate (Glc-1,6-P(2)) concentration in brain is much higher than what is required for the functioning of phosphoglucomutase, suggesting that this compound has a role other than as a cofactor of phosphomutases. In cell-free systems, Glc-1,6-P(2) is formed from 1,3-bisphosphoglycerate and Glc-6-P by two related enzymes: PGM2L1 (phosphoglucomutase 2-like 1) and, to a lesser extent, PGM2 (phosphoglucomutase 2). It is hydrolyzed by the IMP-stimulated brain Glc-1,6-bisphosphatase of still unknown identity. Our aim was to test whether Glc-1,6-bisphosphatase corresponds to the Phosphomannomutase PMM1, an enzyme of mysterious physiological function sharing several properties with Glc-1,6-bisphosphatase. We show that IMP, but not other nucleotides, stimulated by >100-fold (K(a) approximately 20 mum) the intrinsic Glc-1,6-bisphosphatase activity of recombinant PMM1 while inhibiting its phosphoglucomutase activity. No such effects were observed with PMM2, an enzyme paralogous to PMM1 that physiologically acts as a Phosphomannomutase in mammals. Transfection of HEK293T cells with PGM2L1, but not the related enzyme PGM2, caused an approximately 20-fold increase in the concentration of Glc-1,6-P(2). Transfection with PMM1 caused a profound decrease (>5-fold) in Glc-1,6-P(2) in cells that were or were not cotransfected with PGM2L1. Furthermore, the concentration of Glc-1,6-P(2) in wild-type mouse brain decreased with time after ischemia, whereas it did not change in PMM1-deficient mouse brain. Taken together, these data show that PMM1 corresponds to the IMP-stimulated Glc-1,6-bisphosphatase and that this enzyme is responsible for the degradation of Glc-1,6-P(2) in brain. In addition, the role of PGM2L1 as the enzyme responsible for the synthesis of the elevated concentrations of Glc-1,6-P(2) in brain is established.
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cerebellar ataxia and congenital disorder of glycosylation ia cdg ia with normal routine cdg screening
Journal of Neurology, 2007Co-Authors: Sascha Vermeer, Eva Morava, Ron A. Wevers, Gert Matthijs, H Kremer, Q H Leijten, H Scheffer, N A V M Knoers, Dirk LefeberAbstract:Cerebellar ataxia can have many genetic causes among which are the congenital disorders of glycosylation type I (CDG-I). In this group of disorders, a multisystem phenotype is generally observed including the involvement of many organs, the endocrine, hematologic and central nervous systems. A few cases of CDG-Ia have been reported with a milder presentation, namely cerebellar hypoplasia as an isolated abnormality. To identify patients with a glycosylation disorder, isofocusing of plasma transferrin is routinely performed. Here, we describe two CDG-Ia patients,who presented with mainly ataxia and cerebellar hypoplasia and with a normal or only slightly abnormal transferrin isofocusing result. Surprisingly, the activity of the corresponding enzyme Phosphomannomutase was clearly deficient in both leucocytes and fibroblasts. Therefore, in patients presenting with apparently recessive inherited ataxia caused by cerebellar hypoplasia and an unknown genetic aetiology after proper diagnostic work-up, we recommend the measurement of Phosphomannomutase activity when transferrin isofocusing is normal or inconclusive.
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Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients
Molecular genetics and metabolism, 2007Co-Authors: Els Schollen, Maciej Adamowicz, Ron A. Wevers, Ewa Pronicka, Paz Briones, Liesbeth Keldermans, François Foulquier, Amparo Chabas, Felix Sánchez-valverde, Gert MatthijsAbstract:Congenital disorders of glycosylation type Ia (CDG-Ia) is a recessive metabolic disorder caused by mutations in the PMM2 gene and characterized by a defect in the synthesis of N-glycans. The clinical presentation ranges from very severe multi-organ failure to mild neurological problems. A plethora of PMM2 mutations has been described and the vast majority are missense mutations. This selection reflects the requirement of a minimal Phosphomannomutase activity to be compatible with life. We describe the characterization of two unusual truncating mutations in two CDG-Ia patients. The first patient is compound heterozygous for the PMM2 mutation p.V231M (c.691G>A) and a deep intronic point mutation (c.639-15.479C>T). The latter variant activates a cryptic splice site which results in an in-frame insertion of a pseudoexon of 123 bp between exon 7 and 8. The second patient is compound heterozygous for the mutation p.V44A (c.131T>C) and an Alu retrotransposition mediated complex deletion of approximately 28 kb encompassing exon 8. These types of mutations have not been described before in CDG-Ia patients. Their detection stresses the importance to combine PMM2 mutation screening on genomic DNA with analysis of the transcripts and/or with the enzymatic analysis of the Phosphomannomutase activity. Next to the exonic deletions, which already receive more attention than before, it is likely that deep intronic mutations represent an increasingly important category of mutations.
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Targeted disruption of the mouse Phosphomannomutase 2 gene causes early embryonic lethality
Molecular and cellular biology, 2006Co-Authors: Christian Thiel, Gert Matthijs, Torben Lübke, Kurt Von Figura, Christian KornerAbstract:Mutations in the cytosolic enzyme Phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the Pmm2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the Pmm2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that Pmm2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female Pmm2-null allele is impaired.
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Tissue distribution of the murine Phosphomannomutases Pmm1 and Pmm2 during brain development
The European journal of neuroscience, 2005Co-Authors: Kathy Cromphout, Jacques Jaeken, S Grünewald, Jean-françois Collet, Liesbeth Keldermans, An Snellinx, N De Geest, Raphael Sciot, E Vanschaftingen, Gert MatthijsAbstract:The most common type of the congenital disorders of glycosylation, CDG-Ia, is caused by mutations in the human PMM2 gene, reducing Phosphomannomutase (PMM) activity. The PMM2 mutations mainly lead to neurological symptoms, while other tissues are only variably affected. Another Phosphomannomutase, PMM1, is present at high levels in the brain. This raises the question why PMM1 does not compensate for the reduced PMM2 activity during CDG-Ia pathogenesis. We compared the expression profile of the murine Pmm1 and Pmm2 mRNA and protein in prenatal and postnatal mouse brain at the histological level. We observed a considerable expression of both Pmms in different regions of the embryonic and adult mouse brain. Surprisingly, the expression patterns were largely overlapping. This data indicates that expression differences on the cellular and tissue level are an unlikely explanation for the absence of functional compensation. These results suggest that Pmm1 in vivo does not exert the Phosphomannomutase-like activity seen in biochemical assays, but either acts on as yet unidentified specific substrates or fulfils entirely different functions.
Christian Korner - One of the best experts on this subject based on the ideXlab platform.
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Lack of Phosphomannomutase 2 affects Xenopus laevis morphogenesis and the non-canonical Wnt5a/Ror2 signalling
Journal of Inherited Metabolic Disease, 2015Co-Authors: Nastassja Himmelreich, Christian Korner, Lilian T. Kaufmann, Herbert Steinbeisser, Christian ThielAbstract:Reduced Phosphomannomutase 2 activity in man leads to hypoglycosylation of glycoconjugates causing PMM2-CDG, the most common type of congenital disorders of glycosylation. Here we show that an antisense morpholino-mediated knockdown of the Xenopus laevis Phosphomannomutase 2 gene provoked a general underglycosylation in frog embryos, which led to an altered phenotype and reduced glycosylation of Wnt5a as member of the non-canonical Wnt signalling. Loss of function experiments in hemi-sectioned embryos proved that due to the Phosphomannomutase 2 knockdown expression of the Wnt5a/Ror2 target gene paraxial protocadherin was significantly decreased. Regarding the expression of paraxial protocadherin , a gain of function could only be achieved by injections of w nt5a and ror2 in dorsal neighbouring blastomeres, while a parallel injection of Phosphomannomutase 2 morpholino led to a significant reduced level of expression. Our data show for the first time that a knockdown of Phosphomannomutase 2 influences in vivo the non-canonical Wnt signalling during early embryogenesis.
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lack of Phosphomannomutase 2 affects xenopus laevis morphogenesis and the non canonical wnt5a ror2 signalling
Journal of Inherited Metabolic Disease, 2015Co-Authors: Nastassja Himmelreich, Christian Korner, Lilian T. Kaufmann, Herbert Steinbeisser, Christian ThielAbstract:Reduced Phosphomannomutase 2 activity in man leads to hypoglycosylation of glycoconjugates causing PMM2-CDG, the most common type of congenital disorders of glycosylation. Here we show that an antisense morpholino-mediated knockdown of the Xenopus laevis Phosphomannomutase 2 gene provoked a general underglycosylation in frog embryos, which led to an altered phenotype and reduced glycosylation of Wnt5a as member of the non-canonical Wnt signalling. Loss of function experiments in hemi-sectioned embryos proved that due to the Phosphomannomutase 2 knockdown expression of the Wnt5a/Ror2 target gene paraxial protocadherin was significantly decreased. Regarding the expression of paraxial protocadherin, a gain of function could only be achieved by injections of wnt5a and ror2 in dorsal neighbouring blastomeres, while a parallel injection of Phosphomannomutase 2 morpholino led to a significant reduced level of expression. Our data show for the first time that a knockdown of Phosphomannomutase 2 influences in vivo the non-canonical Wnt signalling during early embryogenesis.
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Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice.
Nature medicine, 2011Co-Authors: Anette Schneider, Jan Rindermann, Charles Derossi, Diana Popovici, Hermann Josef Gröne, Georg F Hoffmann, Christian Thiel, Christian KornerAbstract:Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes Phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
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Targeted disruption of the mouse Phosphomannomutase 2 gene causes early embryonic lethality
Molecular and cellular biology, 2006Co-Authors: Christian Thiel, Gert Matthijs, Torben Lübke, Kurt Von Figura, Christian KornerAbstract:Mutations in the cytosolic enzyme Phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the Pmm2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the Pmm2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that Pmm2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female Pmm2-null allele is impaired.
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carbohydrate deficient glycoprotein syndrome type v deficiency of dolichyl p glc man9glcnac2 pp dolichyl glucosyltransferase
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Christian Korner, Roland Knauer, U Holzbach, F Hanefeld, Ludwig Lehle, Kurt Von FiguraAbstract:Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V). Clinically this type resembles the classical type Ia of CDGS caused by the deficiency of Phosphomannomutase. As a result of the glucosyltransferase deficiency in CDGS type V nonglucosylated lipid-linked oligosaccharides accumulate. The defect is leaky and glucosylated oligosaccharides are found on nascent glycoproteins. The limited availability of glucosylated lipid-linked oligosaccharides explains the incomplete usage of N-glycosylation sites in glycoproteins. This finding is reflected in the presence of transferrin forms in serum that lack one or both of the two N-linked oligosaccharides and the reduction of mannose incorporation to about one-third of control in glycoproteins of fibroblasts.
Christian Thiel - One of the best experts on this subject based on the ideXlab platform.
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Lack of Phosphomannomutase 2 affects Xenopus laevis morphogenesis and the non-canonical Wnt5a/Ror2 signalling
Journal of Inherited Metabolic Disease, 2015Co-Authors: Nastassja Himmelreich, Christian Korner, Lilian T. Kaufmann, Herbert Steinbeisser, Christian ThielAbstract:Reduced Phosphomannomutase 2 activity in man leads to hypoglycosylation of glycoconjugates causing PMM2-CDG, the most common type of congenital disorders of glycosylation. Here we show that an antisense morpholino-mediated knockdown of the Xenopus laevis Phosphomannomutase 2 gene provoked a general underglycosylation in frog embryos, which led to an altered phenotype and reduced glycosylation of Wnt5a as member of the non-canonical Wnt signalling. Loss of function experiments in hemi-sectioned embryos proved that due to the Phosphomannomutase 2 knockdown expression of the Wnt5a/Ror2 target gene paraxial protocadherin was significantly decreased. Regarding the expression of paraxial protocadherin , a gain of function could only be achieved by injections of w nt5a and ror2 in dorsal neighbouring blastomeres, while a parallel injection of Phosphomannomutase 2 morpholino led to a significant reduced level of expression. Our data show for the first time that a knockdown of Phosphomannomutase 2 influences in vivo the non-canonical Wnt signalling during early embryogenesis.
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lack of Phosphomannomutase 2 affects xenopus laevis morphogenesis and the non canonical wnt5a ror2 signalling
Journal of Inherited Metabolic Disease, 2015Co-Authors: Nastassja Himmelreich, Christian Korner, Lilian T. Kaufmann, Herbert Steinbeisser, Christian ThielAbstract:Reduced Phosphomannomutase 2 activity in man leads to hypoglycosylation of glycoconjugates causing PMM2-CDG, the most common type of congenital disorders of glycosylation. Here we show that an antisense morpholino-mediated knockdown of the Xenopus laevis Phosphomannomutase 2 gene provoked a general underglycosylation in frog embryos, which led to an altered phenotype and reduced glycosylation of Wnt5a as member of the non-canonical Wnt signalling. Loss of function experiments in hemi-sectioned embryos proved that due to the Phosphomannomutase 2 knockdown expression of the Wnt5a/Ror2 target gene paraxial protocadherin was significantly decreased. Regarding the expression of paraxial protocadherin, a gain of function could only be achieved by injections of wnt5a and ror2 in dorsal neighbouring blastomeres, while a parallel injection of Phosphomannomutase 2 morpholino led to a significant reduced level of expression. Our data show for the first time that a knockdown of Phosphomannomutase 2 influences in vivo the non-canonical Wnt signalling during early embryogenesis.
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Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice.
Nature medicine, 2011Co-Authors: Anette Schneider, Jan Rindermann, Charles Derossi, Diana Popovici, Hermann Josef Gröne, Georg F Hoffmann, Christian Thiel, Christian KornerAbstract:Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes Phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
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Targeted disruption of the mouse Phosphomannomutase 2 gene causes early embryonic lethality
Molecular and cellular biology, 2006Co-Authors: Christian Thiel, Gert Matthijs, Torben Lübke, Kurt Von Figura, Christian KornerAbstract:Mutations in the cytosolic enzyme Phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the Pmm2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the Pmm2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that Pmm2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female Pmm2-null allele is impaired.