Muscle Glycogenosis Due to Phosphoglucomutase 1 Deficiency

Stojkovic, Tanya; Vissing, John; Petit, François; Piraud, Monique; Ørngreen, Mette Cathrine; Andersen, Grete; Claeys, Kristl G.; Wary, C.; Hogrel, Jean‐Yves; Laforêt, Pascal

doi:10.1056/nejmc0901158

Cited by 104 publications

(109 citation statements)

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“…Although the behavior of the protein produced in this recombinant system is not directly applicable to the situation in eukaryotic cells, such studies are essential for eliminating the complications of patient-derived data, such as heterozygosity and the presence of cellular homologs with PGM activity (1,3,4,17). Overall, our in vitro data support the view derived from previous in vivo studies (1,3) that folding defects and/or catalytic impairment may contribute to PGM1 deficiency, depending on the missense variant involved.…”

Section: Discussionsupporting

confidence: 80%

“…Expressed in tissues throughout the body, PGM1 is also required for protein N-glycosylation (1, 2) as glucose 1-phosphate is a precursor for the formation of nucleotide sugars used in glycan biosynthesis. Recent studies have identified PGM1 deficiency as a hereditary genetic disorder, with characteristics of both a glycogen storage disease (GSDXIV, MIM 612934) and a congenital disorder of glycosylation of types I and II (1,3,4). Affected individuals show multiple clinical phenotypes (3), including hepatopathy, dilated cardiomyopathy, hypoglycemia, muscle weakness, exercise intolerance, growth retardation, and congenital malformations of the head such as cleft palate.…”

mentioning

confidence: 99%

“…3. Recombinantly expressed, affinity purified proteins were used to eliminate the complications present in in vivo studies, including heterozygosity, use of cell extracts from varying tissue types, and the presence of homologous enzymes (1,3,4,17). Proteins were characterized for expression, solubility, conformational flexibility, and stability.…”

mentioning

confidence: 99%

“…PGM1 deficiency is autosomal recessive in inheritance, and associated with various types of mutations, including frame shifts, aberrant splicing, and missense variants (1)(2)(3)(4)(5). In the latter category, 13 different mutations were identified (3), affecting 12 residue positions in the protein.…”

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confidence: 99%

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Compromised Catalysis and Potential Folding Defects in in Vitro Studies of Missense Mutants Associated with Hereditary Phosphoglucomutase 1 Deficiency

Lee

Stiers

Kain

et al. 2014

Journal of Biological Chemistry

119

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Compromised Catalysis and Potential Folding Defects in in Vitro Studies of Missense Mutants Associated with Hereditary Phosphoglucomutase 1 Deficiency

Lee

Stiers

Kain

et al. 2014

Journal of Biological Chemistry

119

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“…Deficiency of this enzyme, now characterized clinically by hypoglycaemia, liver disease, cardiomyopathy, short stature, cleft palate and normal intelligence, has previously been associated with a primary muscle disease, Glycogen Storage Disease, XIV (Morava 2014). There are a limited number of patients reported in the literature; one of the first reported suffered from exercise-induced rhabdomyolysis and muscular glycogenosis (Stojkovic et al 2009;Timal et al 2012;Morava 2014). The disruption of this pathway (caused by reduced PGM1) results in dysregulation of glycolysis and disruption of the galactose metabolism pathway.…”

Section: Galactosaemia and Cdg: Dietary Treatment Approachesmentioning

confidence: 99%

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

et al. 2016

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Classical galactosaemia is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12). The disease is life threatening if left untreated in neonates and the only available treatment option is a long-term galactose restricted diet. While this is lifesaving in the neonate, complications persist in treated individuals, and the cause of these, despite early initiation of treatment, and shared GALT genotypes remain poorly understood. Systemic abnormal glycosylation has been proposed to contribute substantially to the ongoing pathophysiology. The gross N-glycosylation assembly defects observed in the untreated neonate correct over time with treatment. However, N-glycosylation processing defects persist in treated children and adults.Congenital disorders of glycosylation (CDG) are a large group of over 100 inherited disorders affecting largely N-and O-glycosylation.In this review, we compare the clinical features observed in galactosaemia with a number of predominant CDG conditions.We also summarize the N-glycosylation abnormalities, which we have described in galactosaemia adult and paediatric patients, using an automated high-throughput HILIC-UPLC analysis of galactose incorporation into serum IgG with analysis of the corresponding N-glycan gene expression patterns and the affected pathways.

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Glycogen Storage Diseases

Cox

2017

Encyclopedia of Life Sciences

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Glycogen is a dense repository of energy which is present mostly in animal tissues; with its highly arborised structure, the glycogen dendrimer is a source of readily accessible glucose units at low osmotic cost. Access to, and accretion of glycogen is subject to fine metabolic and hormonal regulation; indeed, glycogen biosynthesis is driven by high‐energy phosphate‐bond energy, requiring also the participation of several unique protein complexes. Seminal research by Carl and Gerty Cori into the pathophysiology of glycogen metabolism opened up scientific universe of hormonal signalling, phosphorylation control and second messengers. That the glycogen storage disorder, Pompe disease, proved to be an inborn error affecting lysosome function demonstrated the crucial importance of lysosomal autophagy in cellular housekeeping. The polyglucosan body diseases, characterised by insoluble starch‐like deposits, reveal the critical role of macromolecular remodelling for the symmetrical compaction of branched glycogen structures to ensure that safe storage in the cytoplasm is combined with rapid metabolic access. Inherited defects in proteins which regulate glycogen metabolism, those which enact glycogenolysis and glycogen synthesis cause pathological glycogen accumulation – or prevent its formation. Defects in glycolysis also have consequential metabolic effects on glycogen storage. Latterly, at least eight human loci which harbour mutations associated with polyglucosan and Lafora body disease have been reported in these clinically diverse, but fatal, multisystem disorders. The principal defects identify pathways responsible for the unique control of glycogen metabolism in neurons; other conditions point to coregulation of glycogen metabolism and control of immune and inflammatory responses. Glycogen is an essential macromolecule, the adaptive advantages of which come at a cost. Disorders affecting the dynamic metabolism, regulation and maintenance of this vital energy source offer unique insights into a vast interactive network of molecular cell physiology. Key Concepts Glycogen is an essential intracellular macromolecule; its highly branched but compacted polymeric structure facilitates the rapid availability of glucose units for metabolic utilisation. With ≈55 000 linked glucose units, mature glycogen is a highly ordered sphere with a low intrinsic osmotic burden (molecular mass ≈ 10 7 Da). Glycogen is near ubiquitous in cells including neurons; but it is most abundant in muscle tissue, including cardiac muscle, and in the liver. Skeletal muscle provides the greatest net repository of glycogen for short‐lived bursts of ATP generation but the concentration in liver tissue is several‐fold greater. Liver glycogen is principally used to maintain interprandial glucose homeostasis. Appropriate molecular compaction of its symmetrical, highly branched structure maintains the solubility of glycogen in the cytoplasm – it also promotes access of metabolic enzymes, including complex protein assemblies which regulate the supply of glucose energy from its breakdown. To maintain optimal functional integrity, the branched structure of glycogen is constitutively remodelled by autophagy in the lysosomal compartment. With a short half‐life, glycogen undergoes dynamic interactions; its synthesis and degradation are subject to fine metabolic control. Inborn errors of biosynthesis and catabolism, including disorders of glycolysis, not only affect the abundance and availability of metabolic glucose released from intracellular glycogen but can also lead to altered glycogen storage and its macromolecular structure. Defects in proteins that regulate glycogen metabolism and transport, as well as those which catalyse its biosynthesis and breakdown, cause pathological – or defective – accumulation of glycogen in diverse tissues. Failure to synthesise glycogen and defective glycogenolysis lead to complex metabolic disturbances characterised by interprandial hypoglycaemia; accumulation of aberrant glycogen structures has additional pathological effects due to cellular toxicity. Glycogen storage disorders reveal much about the physiological biochemistry of glycogen and regulatory processes in the dynamic control of energy metabolism – including the special case of neuronal tissue.

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Muscle Glycogenosis Due to Phosphoglucomutase 1 Deficiency

Cited by 104 publications

References 3 publications

Compromised Catalysis and Potential Folding Defects in in Vitro Studies of Missense Mutants Associated with Hereditary Phosphoglucomutase 1 Deficiency

Compromised Catalysis and Potential Folding Defects in in Vitro Studies of Missense Mutants Associated with Hereditary Phosphoglucomutase 1 Deficiency

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

Glycogen Storage Diseases

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