GPI Mount Scopus — a variant of glucosephosphate isomerase deficiency

Shalev, Oded; Shalev, Ruth S.; Forman, Linda; Beutler, Ernest

doi:10.1007/bf01695868

Cited by 18 publications

(16 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reduced potency of GPI as a cytokine has been proposed to account for this (57). Alternatively, the marked hyperbilirubinemia and tissue hypoxia as a result of severe anemia have been implicated (58). Given the data presented here, we must also consider the effect of GPI deficiency on glycerolipid biosynthesis.…”

Section: Discussionmentioning

confidence: 87%

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

Haller

Smith

Liu

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Glycerolipids are structural components for membranes and serve in energy storage. We describe here the use of a photodynamic selection technique to generate a population of Chinese hamster ovary cells that display a global deficiency in glycerolipid biosynthesis. One isolate from this population, GroD1, displayed a profound reduction in the synthesis of phosphatidylcholine, phosphatidylethanolamine, and triglycerides but presented high levels of phosphatidic acid and normal levels of phosphatidylinositol synthesis. This was accompanied by a reduction in phosphatidate phosphatase 1 (PAP1) activity. Expression cloning and sequencing of the cDNA obtained from GroD1 revealed a point mutation, Gly-189 3 Glu, in glucose-6-phosphate isomerase (GPI), a glycolytic enzyme involved in an inherited disorder that results in anemia and neuromuscular symptoms in humans. GPI activity was reduced by 87% in GroD1. No significant differences were found in DNA synthesis, protein synthesis, and ATP levels, whereas glycerol 3-phosphate levels were increased in the mutant. Expression of wild-type hamster GPI restored GPI activity, glycerolipid biosynthesis, and PAP1 activity in GroD1. Two additional, independently isolated GPI-deficient mutants displayed similar phenotypes with respect to PAP1 activity and glycerolipid biosynthesis. These findings uncover a novel relationship between GPI, involved in carbohydrate metabolism, and PAP1, a lipogenic enzyme. These results may also help to explain neuromuscular symptoms associated with inherited GPI deficiency.

show abstract

Section: Discussionmentioning

confidence: 87%

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

Haller

Smith

Liu

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Patients with GPI deficiency present different degrees of non-spherocytic hemolytic anemia (NSHA). In some cases, these patients manifest neuromuscular dysfunctions characterized by muscle weakness and mental retardation [2, 38–43]. The molecular basis for these symptoms has not been established [2].…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-phosphate isomerase deficiency results in mTOR activation, failed translocation of lipin 1α to the nucleus and hypersensitivity to glucose: Implications for the inherited glycolytic disease

Haller

Krawczyk

Gostilovitch

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Inherited glucose-6-phosphate isomerase (GPI) deficiency is the second most frequent glycolytic erythroenzymopathy in humans. Patients present with non-spherocytic anemia of variable severity and with neuromuscular dysfunction. We previously described Chinese hamster (CHO) cell lines with mutations in GPI and loss of GPI activity. This resulted in a temperature sensitivity and severe reduction in the synthesis of glycerolipids due to a reduction in phosphatidate phosphatase (PAP). In the current article we attempt to describe the nature of this pleiotropic effect. We cloned and sequenced the CHO lipin 1 cDNA, a gene that codes for PAP activity. Overexpression of lipin 1 in the GPI-deficient cell line, GroD1 resulted in increased PAP activity, however it failed to restore glycerolipid biosynthesis. Fluorescent microscopy showed a failure of GPI-deficient cells to localize lipin 1α to the nucleus. We also found that glucose-6-phosphate levels in GroD1 cells were 10-fold over normal. Lowering glucose levels in the growth medium partially restored glycerolipid biosynthesis and nuclear localization of lipin 1α. Western blot analysis of the elements within the mTOR pathway, which influences lipin 1 activity, was consistent with an abnormal activation of this system. Combined, these data suggest that GPI deficiency results in an accumulation of glucose-6-phosphate, and possibly other glucose-derived metabolites, leading to activation of mTOR and sequestration of lipin 1 to the cytosol, preventing its proper functioning. These results shed light on the mechanism underlying the pathologies associated with inherited GPI deficiency and the variability in the severity of the symptoms observed in these patients.

show abstract

“…In a bioassay it was shown that the dimer is responsible for catalytic activity (GPI) and the monomer for neurotrophic (NLK) activity (Mizrachi 1989). Besides our patient I (GPI Homburg), neurological symptoms have also been found in patients with the variants GPI Utrecht (Helleman and van Biervliet 1975), GPI Paris (Kahn et al 1978), GPI Mount Scopus (Shalev et al 1993), and with a GPI variant described by Zanella et al (1980). Until now, only GPI Mount Scopus has been characterized at the molecular level (Beutler et al 1997).…”

Section: Discussionmentioning

confidence: 74%

“…Similarly, the patients harbouring the other GPI mutations exhibit no neurological symptoms. In the case of GPI Mount Scopus (R347C) it was impossible to ascertain whether the sensineural deficits of the patient were directly related to the enzyme deficiency, or were secondary to neonatal hyperbilirubinaemia and tissue hypoxia due to profound anaemia (Shalev et al 1993). In contrast, our investigations revealed that the neuromuscular symptoms of patient I are directly related to enzyme deficiency (Schröter et al 1985).…”

Section: Discussionmentioning

confidence: 89%

“…GPI deficiency in humans is an autosomal recessive genetic disorder that has the typical manifestation of nonspherocytic haemolytic anaemia of variable clinical expression. It has been reported that severe GPI deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment (Whitelaw et al 1979;Schröter et al 1985;Eber et al 1986;Ravindranath et al 1987;Shalev et al 1993). Although several GPI variants in humans have been defined in terms of electrophoretic mobility, thermal stability, enzyme activity, and peptide mapping, at the nucleotide level only 22 point mutations have been described to date (reviewed in Beutler et al 1997;Huppke et al 1997).…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency

et al. 1998

View full text Add to dashboard Cite

Glucose-6-phosphate isomerase (GPI) deficiency, an autosomal recessive genetic disorder with the typical manifestation of nonspherocytic haemolytic anaemia, can be associated in some cases with neurological impairment. GPI has been found to be identical to neuroleukin (NLK), which has neurotrophic and lymphokine properties. To focus on the possible effects of GPI mutations on the central nervous system through an effect on neuroleukin activity, we analysed DNA isolated from two patients with severe GPI deficiency, one of them with additional neurological deficits, and their families. The neurologically affected patient (GPI Homburg) is compound heterozygous for a 59 A-->C (H20P) and a 1016 T-->C (L339P) exchange. Owing to the insertion of proline, the H20P and L339P mutations are likely to affect the folding and activity of the enzyme. In the second family studied, the two affected siblings showed no neurological symptoms. The identified mutations are 1166 A-->G (H389R) and 1549 C-->G (L517V), which are located at the subunit interface. We propose that mutations that lead to incorrect folding destroy both catalytic (GPI) and neurotrophic (NLK) activities, thereby leading to the observed clinical symptoms (GPI Homburg). Those alterations at the active site, however, that allow correct folding retain the neurotrophic properties of the molecule (GPI Calden).

show abstract

GPI Mount Scopus — a variant of glucosephosphate isomerase deficiency

Cited by 18 publications

References 28 publications

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase

Glucose-6-phosphate isomerase deficiency results in mTOR activation, failed translocation of lipin 1α to the nucleus and hypersensitivity to glucose: Implications for the inherited glycolytic disease

Molecular basis of neurological dysfunction coupled with haemolytic anaemia in human glucose-6-phosphate isomerase (GPI) deficiency

Contact Info

Product

Resources

About