PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose

Voermans, Nicol C.; Preisler, Nicolai; Madsen, Karen L.; Janssen, Mirian C. H.; Küsters, Benno; Bakar, Nurulamin Abu; Conte, Federica; Lamberti, V.M.L.; Nusman, F.; Engelen, B.G.M. van; Scherpenzeel, Monique van; Vissing, John; Lefeber, Dirk

doi:10.1016/j.nmd.2017.01.014

Cited by 35 publications

(62 citation statements)

References 6 publications

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“…Affected patients show multiple disease phenotypes, including dilated cardiomyopathy, exercise intolerance, and hepatopathy. Previous case reports in PGM1-CDG patients receiving oral D-galactose showed clinical improvement [ 14 ]. Thus, we next tested whether oral galactose supplementation could reverse low PGM1-promoted HCC progression.…”

Section: Resultsmentioning

confidence: 94%

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

et al. 2018

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Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression.

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Section: Resultsmentioning

confidence: 94%

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

et al. 2018

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“…Phosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose‐1 phosphate (Glc‐1P) and glucose‐6 phosphate (Glc‐6P) and therefore, it plays a fundamental role in glycolysis, glycogenesis, and glycogenolysis . Consequently, inherited deficiency of PGM1 in humans has previously been identified as glycogen storage disorder Type 14, which resulted from deleterious recessive variants in the PGM1 genes . Yet, PGM1 deficiency is increasingly recognized as a congenital disorder of glycosylation (CDG), where reduced N ‐linked glycosylation in the endoplasmic reticulum and Golgi is observed, resulting in both missing and truncated glycans (mixed type I and type II glycosylation defects) …”

Section: Introductionmentioning

confidence: 99%

“…1 Consequently, inherited deficiency of PGM1 in humans has previously been identified as glycogen storage disorder Type 14, which resulted from deleterious recessive variants in the PGM1 genes. 2,3 Yet, PGM1 deficiency is increasingly recognized as a congenital disorder of glycosylation (CDG), where reduced N-linked glycosylation in the endoplasmic reticulum and Golgi is observed, resulting in both missing and truncated glycans (mixed type I and type II glycosylation defects). 2,[4][5][6] At birth, affected patients have frequent malformations in the spectrum of bifid uvula, cleft palate, and Pierre-Robin sequence.…”

Section: Introductionmentioning

confidence: 99%

A novel phosphoglucomutase‐deficient mouse model reveals aberrant glycosylation and early embryonic lethality

Balakrishnan

Verheijen

Lupo

et al. 2019

J of Inher Metab Disea

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Patients with phosphoglucomutase (PGM1) deficiency, a congenital disorder of glycosylation (CDG) suffer from multiple disease phenotypes. Midline cleft defects are present at birth. Overtime, additional clinical phenotypes, which include severe hypoglycemia, hepatopathy, growth retardation, hormonal deficiencies, hemostatic anomalies, frequently lethal, early‐onset of dilated cardiomyopathy and myopathy emerge, reflecting the central roles of the enzyme in (glycogen) metabolism and glycosylation. To delineate the pathophysiology of the tissue‐specific disease phenotypes, we constructed a constitutive Pgm2 (mouse ortholog of human PGM1)‐knockout (KO) mouse model using CRISPR‐Cas9 technology. After multiple crosses between heterozygous parents, we were unable to identify homozygous life births in 78 newborn pups (P = 1.59897E‐06), suggesting an embryonic lethality phenotype in the homozygotes. Ultrasound studies of the course of pregnancy confirmed Pgm2‐deficient pups succumb before E9.5. Oral galactose supplementation (9 mg/mL drinking water) did not rescue the lethality. Biochemical studies of tissues and skin fibroblasts harvested from heterozygous animals confirmed reduced Pgm2 enzyme activity and abundance, but no change in glycogen content. However, glycomics analyses in serum revealed an abnormal glycosylation pattern in the Pgm2+/− animals, similar to that seen in PGM1‐CDG.

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“…A unique combination of CDG-I (lack of complete glycans) and CDG-II (truncated glycans especially lacking Gal residue) in PGM1-CDG is easily seen by intact transferrin glycoprofiling. Moreover, it is also used to follow-up the biochemical improvement of several patients that underwent an oral D-galactose supplementation (Voermans et al 2017 , Wong et al 2017 ). It has become the primary diagnostic test for CDG, also including fast identification of B4GALT1-CDG, MGAT2-CDG, SLC35A1-CDG, and SLC35A2-CDG (van Scherpenzeel et al 2015 ).…”

Section: Application Of Clinical Glycomics For Cdg Diagnosticsmentioning

confidence: 99%

Clinical glycomics for the diagnosis of congenital disorders of glycosylation

Bakar

Lefeber

Scherpenzeel

2018

J of Inher Metab Disea

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Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different glycomics methodologies ranging from gel electrophoresis to mass spectrometry (MS) and from free glycans to intact glycoproteins. The role of glycomics in the diagnosis of congenital disorders of glycosylation (CDG) is presented, including a diagnostic flow chart and an overview of glycomics data of known CDG subtypes. The review ends with some future perspectives, showing upcoming technologies as system wide mapping of the N- and O-glycoproteome, intact glycoprotein profiling and analysis of sugar metabolism. These new advances will provide additional insights and opportunities to develop personalized therapy. This is especially true for inborn errors of metabolism, which are amenable to causal therapy, because interventions through supplementation therapy can directly target the pathogenesis at the molecular level.

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PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose

Cited by 35 publications

References 6 publications

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking

A novel phosphoglucomutase‐deficient mouse model reveals aberrant glycosylation and early embryonic lethality

Clinical glycomics for the diagnosis of congenital disorders of glycosylation

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