bims-meglyc 2023-04-16 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–04–16
eight papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG.
Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.
Relevance of Sugar Transport across the Cell Membrane.
N-glycoproteomics of brain synapses and synaptic vesicles.
The Liver and Glycogen: In Sickness and in Health.
Recent Progress on Fructose Metabolism-Chrebp, Fructolysis, and Polyol Pathway.
Rapid Whole Genome Sequencing for Diagnosis of Single Locus Genetic Diseases in Critically Ill Children.
Cancer Spheroids and Organoids as Novel Tools for Research and Therapy: State of the Art and Challenges to Guide Precision Medicine.

J Pediatr Endocrinol Metab. 2023 Apr 13.

Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG.

Merve Yoldas Celik, Havva Yazici, Fehime Erdem, Ayse Yuksel Yanbolu, Ayca Aykut, Asude Durmaz, Selcan Zeybek, Ebru Canda, Sema Kalkan Ucar, Mahmut Coker.

   OBJECTIVES: Congenital Glycosylation Disorders (CDG) are a large group of inherited metabolic diseases with multi-organ involvement. Herein, we aimed to expand the clinical characteristics of patients with CDG based on our experience with diagnoses and follow-up of CDG patients from different subtypes.
METHODS: The clinical and laboratory findings from the last 15 years were reviewed retrospectively in Ege University Child Metabolism and Nutrition Department.
RESULTS: There were 8 (57.2 %) females and 6 (42.8 %) males. Diagnoses of the patients were PMM2-CDG (n=4), PGM1-CDG (n=2), DPAGT1-CDG (n=2), SRD5A3-CDG (n=2), MPI-CDG (n=1), POMT2-CDG (n=1), B3GALNT2-CDG (n=1), DPM1-CDG (n=1). The clinical findings of the patients were dysmorphia (85.7 %), developmental delay (85.7 %), intellectual disability (85.7 %), ocular abnormalities (64.2 %), skeletal malformations (64.2 %), failure to thrive (57.1 %), microcephaly (57.1 %), hepatomegaly (35.7 %), hearing loss (35.7 %), seizures (28.5 %), gastrointestinal symptoms (21.4 %), endocrine abnormalities (21.4 %), and cardiac abnormalities (7.1 %). Laboratory findings were abnormal TIEF (92.8 %), abnormal liver enzymes (64.2 %), decreased protein C (64.2 %), decreased antithrombin III (64.2 %), decreased protein S (42.8 %), hypogammaglobulinemia (35.7 %), cerebellar hypoplasia (28.5 %), CK elevation (7.1 %), and hypoglycemia (7.1 %).
CONCLUSIONS: This study contributes to the literature by sharing our ultra-rare DPM1-CDG case with less than 20 cases in the literature and expanding the clinical and molecular characteristics of other CDG patients. Hyperinsulinemic hypoglycemia, short stature, hypothyroidism, growth hormone deficiency, hypogammaglobulinemia, pericardial effusion, elevated CK, congenital myasthenia, and anorectal malformation were unique findings that were observed. Cerebello-ocular findings accompanying multi-organ involvement were an essential clue for a possible CDG.

Keywords:  B3GALNT2; CDG; DPAGT1; DPM1; POMT2; SRD5A3

DOI:  https://doi.org/10.1515/jpem-2022-0641
Front Genet. 2023 ;14 1148067

Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.

Akito Shindo, Kazutaka Ueda, Shun Minatsuki, Yukiteru Nakayama, Satoshi Hatsuse, Kanna Fujita, Seitaro Nomura, Masaru Hatano, Norifumi Takeda, Hiroshi Akazawa, Issei Komuro.

  Glycogen storage disease type III (GSD-III) is an autosomal recessive metabolic disorder caused by mutations in the AGL gene, and may develop various types of pulmonary hypertension (PH). Here, we report a case of 24-year-old man with GSD-IIIb with two novel null variants in AGL (c.2308 + 2T>C and c.3045_3048dupTACC). He developed multi-drug-resistant pulmonary veno-occlusive disease (PVOD) and was registered as a candidate for lung transplantation. No pathogenic variants were detected in previously known causative genes for pulmonary hypertension and the underlying mechanism of coincidence of two rare diseases was unknown. We discuss the association of the loss of glycogen-debranching enzyme with incident PVOD.

Keywords:  AGL; PVOD; glycogen storage disease; pulmonary hypertension; pulmonary veno-occlusive disease

DOI:  https://doi.org/10.3389/fgene.2023.1148067
Int J Mol Sci. 2023 Mar 23. pii: 6085. [Epub ahead of print]24(7):

Relevance of Sugar Transport across the Cell Membrane.

Roxana Carbó, Emma Rodríguez.

  Sugar transport through the plasma membrane is one of the most critical events in the cellular transport of nutrients; for example, glucose has a central role in cellular metabolism and homeostasis. The way sugars enter the cell involves complex systems. Diverse protein systems participate in the membrane traffic of the sugars from the extracellular side to the cytoplasmic side. This diversity makes the phenomenon highly regulated and modulated to satisfy the different needs of each cell line. The beautiful thing about this process is how evolutionary processes have diversified a single function: to move glucose into the cell. The deregulation of these entrance systems causes some diseases. Hence, it is necessary to study them and search for a way to correct the alterations and utilize these mechanisms to promote health. This review will highlight the various mechanisms for importing the valuable sugars needed to create cellular homeostasis and survival in all kinds of cells.

Keywords:  sugar transporters; therapeutics; transmembrane communication; transport-derived diseases

DOI:  https://doi.org/10.3390/ijms24076085
Cell Rep. 2023 Apr 09. pii: S2211-1247(23)00379-0. [Epub ahead of print]42(4): 112368

N-glycoproteomics of brain synapses and synaptic vesicles.

Mazdak M Bradberry, Trenton M Peters-Clarke, Evgenia Shishkova, Edwin R Chapman, Joshua J Coon.

  At mammalian neuronal synapses, synaptic vesicle (SV) glycoproteins are essential for robust neurotransmission. Asparagine (N)-linked glycosylation is required for delivery of the major SV glycoproteins synaptophysin and SV2A to SVs. Despite this key role for N-glycosylation, the molecular compositions of SV N-glycans are largely unknown. In this study, we combined organelle isolation techniques and high-resolution mass spectrometry to characterize N-glycosylation at synapses and SVs from mouse brain. Detecting over 2,500 unique glycopeptides, we found that SVs harbor a distinct population of oligomannose and highly fucosylated N-glycans. Using complementary fluorescence methods, we identify at least one highly fucosylated N-glycan enriched in SVs compared with synaptosomes. High fucosylation was characteristic of SV proteins, plasma membrane proteins, and cell adhesion molecules with key roles in synaptic function and development. Our results define the N-glycoproteome of a specialized neuronal organelle and inform timely questions in the glycobiology of synaptic pruning and neuroinflammation.

Keywords:  CP: Neuroscience; N-glycan; congenital disorders of glycosylation; fucose; glycosylation; membrane trafficking; plasma membrane; synapse; synaptic vesicle

DOI:  https://doi.org/10.1016/j.celrep.2023.112368
Int J Mol Sci. 2023 Mar 24. pii: 6133. [Epub ahead of print]24(7):

The Liver and Glycogen: In Sickness and in Health.

Gwyneth S T Soon, Michael Torbenson.

  The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

Keywords:  Mauriac syndrome; clear cell hepatocellular carcinoma; glycogenic hepatopathy; hepatic glycogenosis; pathology; pseudoground glass

DOI:  https://doi.org/10.3390/ijms24076133
Nutrients. 2023 Apr 05. pii: 1778. [Epub ahead of print]15(7):

Recent Progress on Fructose Metabolism-Chrebp, Fructolysis, and Polyol Pathway.

Katsumi Iizuka.

  Excess fructose intake is associated with obesity, fatty liver, tooth decay, cancer, and cardiovascular diseases. Even after the ingestion of fructose, fructose concentration in the portal blood is never high; fructose is further metabolized in the liver, and the blood fructose concentration is 1/100th of the glucose concentration. It was previously thought that fructose was metabolized in the liver and not in the small intestine, but it has been reported that metabolism in the small intestine also plays an important role in fructose metabolism. Glut5 knockout mice exhibit poor fructose absorption. In addition, endogenous fructose production via the polyol pathway has also received attention; gene deletion of aldose reductase (Ar), ketohexokinase (Khk), and triokinase (Tkfc) has been found to prevent the development of fructose-induced liver lipidosis. Carbohydrate response element-binding protein (Chrebp) regulates the expression of Glut5, Khk, aldolase b, and Tkfc. We review fructose metabolism with a focus on the roles of the glucose-activating transcription factor Chrebp, fructolysis, and the polyol pathway.

Keywords:  Aldob; Chrebp; Glut5; Khk; Tkfc; aldolase b; carbohydrate response element-binding protein; glucose transporter 5; ketohexokinase; triokinase/FMN cyclase

DOI:  https://doi.org/10.3390/nu15071778
Methods Mol Biol. 2023 ;2621 217-239

Rapid Whole Genome Sequencing for Diagnosis of Single Locus Genetic Diseases in Critically Ill Children.

Mallory J Owen, Sergey Batalov, Katarzyna A Ellsworth, Meredith Wright, Sylvia Breeding, Kwon Hugh, Stephen F Kingsmore, Yan Ding.

  Upon admission to intensive care units (ICU), the differential diagnosis of almost all infants with diseases of unclear etiology includes single locus genetic diseases. Rapid whole genome sequencing (rWGS), including sample preparation, short-read sequencing-by-synthesis, informatics pipelining, and semiautomated interpretation, can now identify nucleotide and structural variants associated with most genetic diseases with robust analytic and diagnostic performance in as little as 13.5 h. Early diagnosis of genetic diseases transforms medical and surgical management of infants in ICUs, minimizing both the duration of empiric treatment and the delay to start of specific treatment. Both positive and negative rWGS tests have clinical utility and can improve outcomes. Since first described 10 years ago, rWGS has evolved considerably. Here we describe our current methods for routine diagnostic testing for genetic diseases by rWGS in as little as 18 h.

Keywords:  Genetic disease; Genomic medicine; Infant; Intensive care; Next-generation sequencing; Rapid precision medicine; Whole genome sequencing

DOI:  https://doi.org/10.1007/978-1-0716-2950-5_12
Cells. 2023 Mar 24. pii: 1001. [Epub ahead of print]12(7):

Cancer Spheroids and Organoids as Novel Tools for Research and Therapy: State of the Art and Challenges to Guide Precision Medicine.

Sanae El Harane, Bochra Zidi, Nadia El Harane, Karl-Heinz Krause, Thomas Matthes, Olivier Preynat-Seauve.

  Spheroids and organoids are important novel players in medical and life science research. They are gradually replacing two-dimensional (2D) cell cultures. Indeed, three-dimensional (3D) cultures are closer to the in vivo reality and open promising perspectives for academic research, drug screening, and personalized medicine. A large variety of cells and tissues, including tumor cells, can be the starting material for the generation of 3D cultures, including primary tissues, stem cells, or cell lines. A panoply of methods has been developed to generate 3D structures, including spontaneous or forced cell aggregation, air-liquid interface conditions, low cell attachment supports, magnetic levitation, and scaffold-based technologies. The choice of the most appropriate method depends on (i) the origin of the tissue, (ii) the presence or absence of a disease, and (iii) the intended application. This review summarizes methods and approaches for the generation of cancer spheroids and organoids, including their advantages and limitations. We also highlight some of the challenges and unresolved issues in the field of cancer spheroids and organoids, and discuss possible therapeutic applications.

Keywords:  3D cell culture; cell and gene therapy; drug screening; immunotherapy; personalized medicine; tissue engineering

DOI:  https://doi.org/10.3390/cells12071001