bims-meglyc 2023-02-12 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–02–12
fiveteen papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.
Glycoproteomics in Cerebrospinal Fluid Reveals Brain-Specific Glycosylation Changes.
Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD.
Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.
Cysteine Pathogenic Variants of PMM2 Are Sensitive to Environmental Stress with Loss of Structural Stability.
Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.
Diagnostic delay in rare diseases.
Advances in gene therapy hold promise for treating hereditary hearing loss.
NOX Dependent ROS Generation and Cell Metabolism.
Novel Molecular Therapies and Genetic Landscape in Selected Rare Diseases with Hematologic Manifestations: A Review of the Literature.
Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency.
Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.
Stem Cell-Based Organoid Models of Neurodevelopmental Disorders.
Literature Review on Health Emigration in Rare Diseases-A Machine Learning Perspective.
Critical considerations in N-glycoproteomics.

Child Neurol Open. 2023 Jan-Dec;10:10 2329048X231153781

A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy.

Daniel James Clark, Thomas Murray, Michael Drees, Neil Kulkarni.

  ALG6-CDG is a rare, but second most common, type 1 congenital disorder of glycosylation (CDG) caused by a defect in the α-1-3-glucosyltransferase (ALG6) enzyme in the N-glycan assembly pathway. Many mutations have been identified and inherited in an autosomal recessive pattern. There are less than 100 ALG6-CDG cases reported, all sharing the phenotype of hypotonia and developmental delay. The majority (perhaps >70%) have seizures, but a minority have intractable epilepsy or epileptic encephalopathy. We report the clinical course, EEG findings, and neuroimaging of a child found to have compound heterozygous alleles c.257 + 5G > A and c.680G > A (p.G227E) who developed explosive onset of intractable epilepsy and epileptic encephalopathy. Initially, CDG was not suspected due to its rarity and lack of multi-organ system involvement, but rapid whole exam sequence (8-day turnaround) revealed the specific diagnosis quickly.

Keywords:  EEG; congenital disorders of glycosylation; developmental delay; epilepsy; epileptic encephalopathy; inborn errors of metabolism

DOI:  https://doi.org/10.1177/2329048X231153781
Int J Mol Sci. 2023 Jan 18. pii: 1937. [Epub ahead of print]24(3):

Glycoproteomics in Cerebrospinal Fluid Reveals Brain-Specific Glycosylation Changes.

Melissa Baerenfaenger, Merel A Post, Pieter Langerhorst, Karin Huijben, Fokje Zijlstra, Joannes F M Jacobs, Marcel M Verbeek, Hans J C T Wessels, Dirk J Lefeber.

  The glycosylation of proteins plays an important role in neurological development and disease. Glycoproteomic studies on cerebrospinal fluid (CSF) are a valuable tool to gain insight into brain glycosylation and its changes in disease. However, it is important to consider that most proteins in CSFs originate from the blood and enter the CSF across the blood-CSF barrier, thus not reflecting the glycosylation status of the brain. Here, we apply a glycoproteomics method to human CSF, focusing on differences between brain- and blood-derived proteins. To facilitate the analysis of the glycan site occupancy, we refrain from glycopeptide enrichment. In healthy individuals, we describe the presence of heterogeneous brain-type N-glycans on prostaglandin H2-D isomerase alongside the dominant plasma-type N-glycans for proteins such as transferrin or haptoglobin, showing the tissue specificity of protein glycosylation. We apply our methodology to patients diagnosed with various genetic glycosylation disorders who have neurological impairments. In patients with severe glycosylation alterations, we observe that heavily truncated glycans and a complete loss of glycans are more pronounced in brain-derived proteins. We speculate that a similar effect can be observed in other neurological diseases where a focus on brain-derived proteins in the CSF could be similarly beneficial to gain insight into disease-related changes.

Keywords:  biomarkers; brain-type glycosylation; cerebrospinal fluid; glycoproteomics; neurodegenerative disease

DOI:  https://doi.org/10.3390/ijms24031937
Int J Mol Sci. 2023 Jan 21. pii: 2142. [Epub ahead of print]24(3):

Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD.

Ziyan Xie, Ting Xie, Jieying Liu, Qian Zhang, Xinhua Xiao.

  O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders.

Keywords:  NAFLD; O-GlcNAc; diabetes; insulin resistance; liver metabolism; post-translational modification

DOI:  https://doi.org/10.3390/ijms24032142
Am J Med Genet C Semin Med Genet. 2023 Feb 04.

Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Julie Lekstrom-Himes, P J Brooks, Dwight D Koeberl, Amy Brower, Aaron Goldenberg, Robert C Green, Jill A Morris, Joseph J Orsini, Timothy W Yu, Erika F Augustine.

Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional "one disease at a time" preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.

DOI: https://doi.org/10.1002/ajmg.c.32031
Oxid Med Cell Longev. 2023 ;2023 5964723

Cysteine Pathogenic Variants of PMM2 Are Sensitive to Environmental Stress with Loss of Structural Stability.

Fan Yu, Li Lin, Jingmiao Sun, Jicheng Pan, Yixin Liao, Yunfan Pan, Guannan Bai, Liangjian Ma, Jianhua Mao, Lidan Hu.

Congenital disorders of glycosylation (CDG) are severe metabolic disorders caused by an imbalance in the glycosylation pathway. Phosphomannomutase2 (PMM2-CDG), the most prevalent CDG, is mainly due to the disorder of PMM2. Pathogenic variants in cysteine have been found in various diseases, and cysteine residues have a potential as therapeutic targets. PMM2 harbor six cysteines; the variants Cys9Tyr (C9Y) and Cys241Ser (C241S) of PMM2 have been identified to associate with CDG, but the underlying molecular mechanisms remain uncharacterized. Here, we purified PMM2 wild type (WT), C9Y, and C241S to investigate their structural characteristics and biophysical properties by spectroscopic experiments under physiological temperature and environmental stress. Notably, the variants led to drastic changes in the protein properties and were prone to aggregate at physiological temperature. Meanwhile, PMM2 was sensitive to oxidative stress, and the cysteine pathogenic variants led to obvious aggregate formation and a higher cellular apoptosis ratio under oxidative stress. Molecular dynamic simulations indicated that the pathogenic variants changed the core domain of homomeric PMM2 and subunit binding free energy. Moreover, we tested the potential drug targeting PMM2-celastrol in cell level and explained the result by molecular docking simulation. In this study, we delineated the pathological mechanism of the cysteine substitution in PMM2, which addressed the vital role of cysteine in PMM2 and provided novel insights into prevention and treatment strategies for PMM2-CDG.

DOI: https://doi.org/10.1155/2023/5964723
Res Sq. 2023 Jan 25. pii: rs.3.rs-2448086. [Epub ahead of print]

Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.

Hossein Ardehali, Yuki Tatekoshi, Jason Shapiro, Mingyang Liu, George Bianco, Ayumi Tatekoshi, Adam De Jesus, Navid Koleini, J Andrew Wasserstrom, Wolfgang Dillmann, Samuel Weinberg.

Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but the underlying pathophysiology is not well-understood and treatment options are limited. Hexokinase-1 (HK1) mitochondrial-binding and protein O-GlcNAcylation are both altered in conditions with risk factors for HFpEF. Here we report a novel mouse model of HFpEF and show that HK1 mitochondrial-binding in endothelial cells (EC) is critical for the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 in ECs from HFpEF mice. Mice with deletion of the mitochondrial-binding-domain of HK1 spontaneously develop HFpEF, and their ECs display impaired angiogenic potential. Mitochondrial-bound HK1 associates with dolichyl-diphosphooligosaccharide-protein-glycosyltransferase (DDOST) and its mitochondrial dislocation decreases protein N-glycosylation. We also show that the spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine-transferase (OGT) increases protein O-GlcNAcylation by shifting the balance of the hexosamine-biosynthetic-pathway intermediate supply into the O-GlcNAcylation machinery. Pharmacological inhibition of OGT or EC-specific overexpression of O-GlcNAcase reverses angiogenic defects in ECs and the HFpEF phenotype, indicating that increased protein O-GlcNAcylation is responsible for the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation in ECs, and provides a potential new therapy for this disorder.

DOI: https://doi.org/10.21203/rs.3.rs-2448086/v1
Arch Argent Pediatr. 2023 Mar 02. e202202946

Diagnostic delay in rare diseases.

Verónica Aguerre.

DOI: https://doi.org/10.5546/aap.2022-02946.eng
Mol Ther. 2023 Feb 07. pii: S1525-0016(23)00064-3. [Epub ahead of print]

Advances in gene therapy hold promise for treating hereditary hearing loss.

Luoying Jiang, Daqi Wang, Yingzi He, Yilai Shu.

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL)-an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and additionally, CRISPR/Cas tools have been attempted for HHL treatment. Therefore, in order to further advance the development of inner ear gene therapy and promote its broad application in other forms of genetic disease, it is imperative to review the progress of gene therapy for HHL. Herein, we address three main gene therapy strategies-gene replacement, gene suppression, and gene editing, summarizing which strategy is most appropriate for particular monogenic diseases based on different pathogenic mechanisms and then focusing on their successful applications for HHL in preclinical trials. Finally, we elaborate on the challenges and outlooks of gene therapy for HHL.

DOI: https://doi.org/10.1016/j.ymthe.2023.02.001
Int J Mol Sci. 2023 Jan 20. pii: 2086. [Epub ahead of print]24(3):

NOX Dependent ROS Generation and Cell Metabolism.

Tiziana Pecchillo Cimmino, Rosario Ammendola, Fabio Cattaneo, Gabriella Esposito.

  Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, the superoxide anion radical (O2·-) is a key redox signaling molecule prominently generated by the NADPH oxidase (NOX) enzyme family and by the mitochondrial electron transport chain. Notably, altered redox balance and deregulated redox signaling are recognized hallmarks of cancer and are involved in malignant progression and resistance to drugs treatment. Since oxidative stress and metabolism of cancer cells are strictly intertwined, in this review, we focus on the emerging roles of NOX enzymes as important modulators of metabolic reprogramming in cancer. The NOX family includes seven isoforms with different activation mechanisms, widely expressed in several tissues. In particular, we dissect the contribute of NOX1, NOX2, and NOX4 enzymes in the modulation of cellular metabolism and highlight their potential role as a new therapeutic target for tumor metabolism rewiring.

Keywords:  NADPH oxidase; NOX; ROS; cell metabolism; glycolytic enzymes; metabolic reprogramming; reactive oxygen species; redox metabolism

DOI:  https://doi.org/10.3390/ijms24032086
Cells. 2023 Jan 30. pii: 449. [Epub ahead of print]12(3):

Novel Molecular Therapies and Genetic Landscape in Selected Rare Diseases with Hematologic Manifestations: A Review of the Literature.

Gabriela Ręka, Martyna Stefaniak, Monika Lejman.

  Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, ADAMTS13, GBA1, and PIG-A genes, respectively). In Castleman disease, improper ETS1, PTPN6, TGFBR2, DNMT3A, and PDGFRB genes cause the appearance of symptoms. In histiocytosis, several mutation variants are described: BRAF, MAP2K1, MAP3K1, ARAF, ERBB3, NRAS, KRAS, PICK1, PIK3R2, and PIK3CA. Genes like HPLH1, PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4, ITK, CD27, MAGT1, LYST, AP3B1, and RAB27A are possible reasons for hemophagocytic lymphohistiocytosis. Among novel molecular medicines, tyrosine kinase inhibitors, mTOR inhibitors, BRAF inhibitors, interleukin 1 or 6 receptor antagonists, monoclonal antibodies, and JAK inhibitors are examples of drugs expanding therapeutic possibilities. An explanation of the molecular basis of rare diseases might lead to a better understanding of the pathogenesis and prognosis of the disease and may allow for the development of new molecularly targeted therapies.

Keywords:  genes; hematology; rare diseases; therapy

DOI:  https://doi.org/10.3390/cells12030449
bioRxiv. 2023 Jan 23. pii: 2023.01.23.523684. [Epub ahead of print]

Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency.

Ross C Bretherton, Isabella M Reichardt, Kristin A Zabrecky, Alex J Goldstein, Logan R J Bailey, Darrian Bugg, Timothy S McMillen, Kristina B Kooiker, Galina V Flint, Amy Martinson, Jagdambika Gunaje, Franziska Koser, Elizabeth Plaster, Wolfgang A Linke, Michael Regnier, Farid Moussavi-Harami, Nathan J Sniadecki, Cole A DeForest, Jennifer Davis.

Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)- the leading cause of heart failure 1,2 . Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis 3,4 . Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart's material properties is essential for the DCM phenotype. Here we report in a mouse model of inherited DCM that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38α in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary cardiomyocyte defect in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies.

DOI: https://doi.org/10.1101/2023.01.23.523684
J Lipid Atheroscler. 2023 Jan;12(1): 47-57

Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.

Seyed Amirhossein Tabatabaei Dakhili, Amanda A Greenwell, John R Ussher.

  Diabetic cardiomyopathy was originally described as the presence of ventricular dysfunction in the absence of coronary artery disease and/or hypertension. It is characterized by diastolic dysfunction and is more prevalent in people with diabetes than originally realized, leading to the suggestion in the field that it simply be referred to as diabetic heart disease. While there are currently no approved therapies for diabetic heart disease, a multitude of studies clearly demonstrate that it is characterized by several disturbances in myocardial energy metabolism. One of the most prominent changes in myocardial energy metabolism in diabetes is a robust impairment in glucose oxidation. Herein we will describe the mechanisms responsible for the diabetes-induced decline in myocardial glucose oxidation, and the pharmacological approaches that have been pursued to correct this metabolic disorder. With surmounting evidence that stimulating myocardial glucose oxidation can alleviate diastolic dysfunction and other pathologies associated with diabetic heart disease, this may also represent a novel strategy for decreasing the prevalence of heart failure with preserved ejection fraction in the diabetic population.

Keywords:  Cardiac energetics; Diabetic cardiomyopathies; Diabetic heart disease; Diastolic dysfunction; Glucose oxidation; Pyruvate dehydrogenase

DOI:  https://doi.org/10.12997/jla.2023.12.1.47
Biol Psychiatry. 2023 Jan 24. pii: S0006-3223(23)00039-2. [Epub ahead of print]

Stem Cell-Based Organoid Models of Neurodevelopmental Disorders.

Lu Wang, Charlotte Owusu-Hammond, David Sievert, Joseph G Gleeson.

  The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.

Keywords:  Assembloid; Autism; Brain organoid; Dominant; Epilepsy; Gene-environment-interaction; Genotype-phenotype; Microcephaly; Mosaic; Mutation; Neural rosette; Recessive

DOI:  https://doi.org/10.1016/j.biopsych.2023.01.012
Int J Environ Res Public Health. 2023 Jan 30. pii: 2483. [Epub ahead of print]20(3):

Literature Review on Health Emigration in Rare Diseases-A Machine Learning Perspective.

Małgorzata Skweres-Kuchta, Iwona Czerska, Elżbieta Szaruga.

  The article deals with one of the effects of health inequalities and gaps in access to treatments for rare diseases, namely health-driven emigration. The purpose of the paper is to systematize knowledge about the phenomenon of health emigration observed among families affected by rare diseases, for which reimbursed treatment is available, but only in selected countries. The topic proved to be niche; the issue of "health emigration in rare diseases" is an area for exploration. Therefore, the further analysis used text mining and machine learning methods based on a database selected based on keywords related to this issue. The results made it possible to systematize the guesses made by researchers in management and economic fields, to identify the most common keywords and thematic clusters around the perspective of the patient, drug manufacturer and treatment reimbursement decision-maker, and the perspective integrating all the others. Since the topic of health emigration was not directly addressed in the selected sources, the authors attempted to define the related concepts and discussed the importance of this phenomenon in managing the support system in rare diseases. Thus, they indicated directions for further research in this area.

Keywords:  access gap; discrimination in access to therapy; health emigration; orphan drug; rare disease

DOI:  https://doi.org/10.3390/ijerph20032483
Curr Opin Chem Biol. 2023 Feb 07. pii: S1367-5931(23)00010-8. [Epub ahead of print]73 102272

Critical considerations in N-glycoproteomics.

The Huong Chau, Anastasia Chernykh, Rebeca Kawahara, Morten Thaysen-Andersen.

  N-Glycoproteomics, the system-wide study of glycans asparagine-linked to protein carriers, holds a unique and still largely untapped potential to provide deep insights into the complexity and dynamics of the heterogeneous N-glycoproteome. Despite the advent of innovative analytical and informatics tools aiding the analysis, N-glycoproteomics remains challenging and consequently largely restricted to specialised laboratories. Aiming to stimulate discussions of method harmonisation, data standardisation and reporting guidelines to make N-glycoproteomics more reproducible and accessible to the community, we here discuss critical considerations related to the design and execution of N-glycoproteomics experiments and highlight good practices in N-glycopeptide data collection, analysis, interpretation and sharing. Giving the rapid maturation and, expectedly, a wide-spread implementation of N-glycoproteomics capabilities across the community in future years, this piece aims to point out common pitfalls, to encourage good data sharing and documentation practices, and to highlight practical solutions and strategies to enhance the insight into the N-glycoproteome.

Keywords:  Data sharing; Glycoproteome; Glycoproteomics; N-Glycopeptide; N-Glycosylation; Standardisation

DOI:  https://doi.org/10.1016/j.cbpa.2023.102272