bims-meglyc 2023-05-28 papers

on Metabolic disorders affecting glycosylation

Issue of 2023‒05‒28
eleven papers selected by
Silvia Radenkovic
Frontiers in Congenital Disorders of Glycosylation Consortium

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.
Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation.
Germline C1GALT1C1 mutation causes a multisystem chaperonopathy.
Precision medicine in rare diseases: What is next?
Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies.
CRISPR-based functional genomics screening in human-pluripotent-stem-cell-derived cell types.
The future of commercial genetic testing.
Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment.
Ogt deficiency induces abnormal cerebellar function and behavioral deficits of adult mice through modulating RhoA/ROCK signaling.
O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy.
Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects.

Int J Mol Sci. 2023 May 11. pii: 8632. [Epub ahead of print]24(10):

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.

Federica Conte, Juda-El Sam, Dirk J Lefeber, Robert Passier.

  Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

Keywords:  arrhythmogenic disorders; cardiomyopathies; congenital disorders of glycosylation; congenital heart disease; disorders of pentose phosphate pathway; disorders of sugar transporters; glycogen storage disorders; heart failure; inborn errors of metabolism; lysosomal storage disorders

DOI:  https://doi.org/10.3390/ijms24108632
Mol Genet Metab. 2023 May 09. pii: S1096-7192(23)00236-6. [Epub ahead of print]139(2): 107606

Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation.

Diederik De Graef, Anna N Ligezka, Joseph Rezents, Gina L Mazza, Graeme Preston, Kaitlin Schwartz, Wirginia Krzysciak, Christina Lam, Andrew C Edmondson, Christin Johnsen, Tamas Kozicz, Eva Morava.

  BACKGROUND: Given the lack of reliable data on the prevalence of bleeding abnormalities and thrombotic episodes in PMM2-CDG patients, and whether coagulation abnormalities change over time, we prospectively collected and reviewed natural history data. Patients with PMM2-CDG often have abnormal coagulation studies due to glycosylation abnormalities but the frequency of complications resulting from these has not been prospectively studied.METHODS: We studied fifty individuals enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study with molecularly confirmed diagnosis of PMM2-CDG. We collected data on prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, factor IX activity (FIX), factor XI activity (FXI), protein C activity (PC), protein S activity (PS) and antithrombin activity (AT).
RESULTS: Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI. AT deficiency was the most common abnormality in 83.3% of patients. AT activity was below 50% in 62.5% of all patients (normal range 80-130%). Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis. Stroke-like episodes (SLE) were reported in 18% of patients in our cohort. Based on the linear growth models, on average, patients did not show significant change in AT (n = 48; t(23.8) = 1.75, p = 0.09), FIX (n = 36; t(61) = 1.60, p = 0.12), FXI (n = 39; t(22.8) = 1.88, p = 0.07), PS (n = 25; t(28.8) = 1.08, p = 0.29), PC (n = 38; t(68) = 1.61, p = 0.11), INR (n = 44; t(184) = -1.06, p = 0.29), or PT (n = 43; t(192) = -0.69, p = 0.49) over time. AT activity positively correlated with FIX activity. PS activity was significantly lower in males.
CONCLUSION: Based on our natural history data and previous literature, we conclude that caution should be exercised when the AT levels are lower than 65%, as most thrombotic events occur in patients with AT below this level. All five, male PMM2-CDG patients in our cohort who developed thrombosis had abnormal AT levels, ranging between 19% and 63%. Thrombosis was associated with infection in all cases. We did not find significant change in AT levels over time. Several PMM2-CDG patients had an increased bleeding tendency. More long-term follow-up is necessary on coagulation abnormalities and the associated clinical symptoms to provide guidelines for therapy, patient management, and appropriate counseling.
SYNOPSIS: Most PMM2-CDG patients display chronic coagulation abnormalities without significant improvement, associated with a frequency of 16% clinical bleeding abnormalities, and 10% thrombotic episodes in patients with severe antithrombin deficiency.

Keywords:  Abnormal coagulation; Antithrombin; Bleeding; CDG; Factor XI; Glycosylation; Thrombosis

DOI:  https://doi.org/10.1016/j.ymgme.2023.107606
Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2211087120

Germline C1GALT1C1 mutation causes a multisystem chaperonopathy.

Florian Erger, Rajindra P Aryal, Björn Reusch, Yasuyuki Matsumoto, Robert Meyer, Junwei Zeng, Cordula Knopp, Maxence Noel, Lukas Muerner, Andrea Wenzel, Stefan Kohl, Nikolai Tschernoster, Gunter Rappl, Isabelle Rouvet, Jutta Schröder-Braunstein, Felix S Seibert, Holger Thiele, Martin G Häusler, Lutz T Weber, Maike Büttner-Herold, Miriam Elbracht, Sandra F Cummings, Janine Altmüller, Sandra Habbig, Richard D Cummings, Bodo B Beck.

  Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, causing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase (C1GALT1), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1. Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1. They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant occurs within the transmembrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.

Keywords:  C1GALT1C1; COSMC-CDG; Cosmc; O-glycosylation; Tn-antigen

DOI:  https://doi.org/10.1073/pnas.2211087120
J Intern Med. 2023 May 21.

Precision medicine in rare diseases: What is next?

Bianca Tesi, Catherine Boileau, Kym M Boycott, Guillaume Canaud, Mark Caulfield, Daniela Choukair, Sue Hill, Malte Spielmann, Anna Wedell, Valtteri Wirta, Ann Nordgren, Anna Lindstrand.

  Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in non-coding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step towards precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments. This article is protected by copyright. All rights reserved.

Keywords:  data sharing; gene therapy; genome sequencing; molecular diagnosis; precision medicine; rare diseases

DOI:  https://doi.org/10.1111/joim.13655
Biomedicines. 2023 May 22. pii: 1500. [Epub ahead of print]11(5):

Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies.

Yafei Huang, Bingying Zhou.

  Mitochondria are the main site of intracellular synthesis of ATP, which provides energy for various physiological activities of the cell. Cardiomyocytes have a high density of mitochondria and mitochondrial damage is present in a variety of cardiovascular diseases. In this paper, we describe mitochondrial damage in mitochondrial cardiomyopathy, congenital heart disease, coronary heart disease, myocardial ischemia-reperfusion injury, heart failure, and drug-induced cardiotoxicity, in the context of the key roles of mitochondria in cardiac development and homeostasis. Finally, we discuss the main current therapeutic strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction, including pharmacological strategies, gene therapy, mitochondrial replacement therapy, and mitochondrial transplantation. It is hoped that this will provide new ideas for the treatment of cardiovascular diseases.

Keywords:  cardiomyocytes; cardiovascular diseases; mitochondria; mitochondrial dysfunction; therapeutic strategies targeting mitochondria

DOI:  https://doi.org/10.3390/biomedicines11051500
Cell Genom. 2023 May 10. 3(5): 100300

CRISPR-based functional genomics screening in human-pluripotent-stem-cell-derived cell types.

Kun Li, Miao Ouyang, Jiangshan Zhan, Ruilin Tian.

  While our knowledge of gene expression in different human cell types is rapidly expanding with advances in transcriptomic profiling technologies, the next challenge is to understand gene function in each cell type. CRISPR-Cas9-based functional genomics screening offers a powerful approach to determine gene function in a high-throughput manner. With the maturation of stem cell technology, a variety of human cell types can be derived from human pluripotent stem cells (hPSCs). Recently, the integration of CRISPR screening with hPSC differentiation technologies opens up unprecedented opportunities to systematically examine gene function in different human cell types and identify mechanisms and therapeutic targets for human diseases. This review highlights recent progress in the development and applications of CRISPR-Cas9-based functional genomics screening in hPSC-derived cell types, discusses current challenges and limitations, and outlines future directions for this emerging field.

Keywords:  CRISPR technology; cell differentiation; functional genomics; genetic screens; human pluripotent stem cells

DOI:  https://doi.org/10.1016/j.xgen.2023.100300
Curr Opin Pediatr. 2023 May 24.

The future of commercial genetic testing.

Benjamin D Solomon.

PURPOSE OF REVIEW: There are thousands of different clinical genetic tests currently available. Genetic testing and its applications continue to change rapidly for multiple reasons. These reasons include technological advances, accruing evidence about the impact and effects of testing, and many complex financial and regulatory factors.RECENT FINDINGS: This article considers a number of key issues and axes related to the current and future state of clinical genetic testing, including targeted versus broad testing, simple/Mendelian versus polygenic and multifactorial testing models, genetic testing for individuals with high suspicion of genetic conditions versus ascertainment through population screening, the rise of artificial intelligence in multiple aspects of the genetic testing process, and how developments such as rapid genetic testing and the growing availability of new therapies for genetic conditions may affect the field.
SUMMARY: Genetic testing is expanding and evolving, including into new clinical applications. Developments in the field of genetics will likely result in genetic testing becoming increasingly in the purview of a very broad range of clinicians, including general paediatricians as well as paediatric subspecialists.

DOI: https://doi.org/10.1097/MOP.0000000000001260
Int J Mol Sci. 2023 May 22. pii: 9064. [Epub ahead of print]24(10):

Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment.

Lidia Larizza, Maria Vittoria Cubellis.

Rare Diseases (RD) do not have an exact definition since local authorities define the criteria in different ways, from fewer than 5 people in 10,000, according to the European Union, to the standard world average of 40 cases per 100,000 people [...].

DOI: https://doi.org/10.3390/ijms24109064
J Neurosci. 2023 May 22. pii: JN-RM-1962-22. [Epub ahead of print]

Ogt deficiency induces abnormal cerebellar function and behavioral deficits of adult mice through modulating RhoA/ROCK signaling.

Jinyu Zhang, Kaiyan Wei, Wenzheng Qu, Mengxuan Wang, Qiang Zhu, Xiaoxue Dong, Xiaoli Huang, Wen Yi, Shunliang Xu, Xuekun Li.

Previous studies have shown the essential roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function and neurological diseases. However, the function of Ogt and O-GlcNAcylation in the adult cerebellum has not been well elucidated. Here, we have found that cerebellum has the highest level of O-GlcNAcylation relative to cortex and hippocampus of adult male mice. Specific deletion of Ogt in granule neuronal precursors (GNPs) induces abnormal morphology and decreased size of the cerebellum in adult male Ogt deficient (cKO) mice. Adult male cKO mice show the reduced density and aberrant distribution of cerebellar granule cells (CGCs), the disrupted arrangement of Bergman glia and Purkinje cells. In addition, adult male cKO mice exhibit aberrant synaptic connection, impaired motor coordination, and learning and memory abilities. Mechanistically, we have identified G protein subunit alpha 12 (Gα12) is modified by Ogt-mediated O-GlcNAcylation. O-GlcNAcylation of Gα12 facilitates its binding to Rho guanine nucleotide exchange factor 12 (Arhgef12) and consequently activates RhoA/ROCK signaling. RhoA/ROCK pathway activator LPA can rescue the developmental deficits of Ogt deficient CGCs. Therefore, our study has revealed the critical function and related mechanisms of Ogt and O-GlcNAcylation in the cerebellum of adult male mice.SIGNIFICANCE STATEMENT:Cerebellar function are regulated by diverse mechanisms. To unveil novel mechanisms is critical for understanding the cerebellar function and the clinical therapy of cerebellum-related diseases. In the present study, we have shown that O-GlcNAc transferase gene (Ogt) deletion induces abnormal cerebellar morphology, synaptic connection, and behavioral deficits of adult male mice. Mechanistically, Ogt catalyzes O-GlcNAcylation of Gα12, which promotes the binding to Arhgef12, and regulates RhoA/ROCK signaling pathway. Our study has uncovered the important roles of Ogt and O-GlcNAcylation in regulating cerebellar function and cerebellum-related behavior. Our results suggest that Ogt and O-GlcNAcylation could be potential targets for some cerebellum-related diseases.

DOI: https://doi.org/10.1523/JNEUROSCI.1962-22.2023
Front Neurosci. 2023 ;17 1137847

O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy.

Hsueh-Fu Wu, Chia-Wei Huang, Jennifer Art, Hong-Xiang Liu, Gerald W Hart, Nadja Zeltner.

  O-GlcNAcylation is a post-translational modification (PTM) that regulates a wide range of cellular functions and has been associated with multiple metabolic diseases in various organs. The sympathetic nervous system (SNS) is the efferent portion of the autonomic nervous system that regulates metabolism of almost all organs in the body. How much the development and functionality of the SNS are influenced by O-GlcNAcylation, as well as how such regulation could contribute to sympathetic neuron (symN)-related neuropathy in diseased states, remains unknown. Here, we assessed the level of protein O-GlcNAcylation at various stages of symN development, using a human pluripotent stem cell (hPSC)-based symN differentiation paradigm. We found that pharmacological disruption of O-GlcNAcylation impaired both the growth and survival of hPSC-derived symNs. In the high glucose condition that mimics hyperglycemia, hPSC-derived symNs were hyperactive, and their regenerative capacity was impaired, which resembled typical neuronal defects in patients and animal models of diabetes mellitus. Using this model of sympathetic neuropathy, we discovered that O-GlcNAcylation increased in symNs under high glucose, which lead to hyperactivity. Pharmacological inhibition of O-GlcNAcylation rescued high glucose-induced symN hyperactivity and cell stress. This framework provides the first insight into the roles of O-GlcNAcylation in both healthy and diseased human symNs and may be used as a platform for therapeutic studies.

Keywords:  O-GlcNAcylation; autonomic nervous system; diabetes; human pluripotent stem cells; hyperglycemia; peripheral nervous system; peripheral neuropathy; sympathetic neuron

DOI:  https://doi.org/10.3389/fnins.2023.1137847
J Pediatr. 2023 May 19. pii: S0022-3476(23)00343-8. [Epub ahead of print] 113495

Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects.

Matthew D Durbin, Korre Fairman, Lindsey R Helvaty, Manyan Huang, Ming Li, Daniel Abreu, Gabrielle C Geddes, Benjamin M Helm, Benjamin J Landis, Alexis McEntire, Dana K Mitchell, Stephanie M Ware.

  OBJECTIVE: To evaluate genetic evaluation practices in newborns with the most common birth defect, congenital heart defects (CHD), we determine the prevalence and the yield of genetic evaluation across time and across patient subtypes, before and after implementation of institutional genetic testing guidelines.STUDY DESIGN: Retrospective cross-sectional study of 664 hospitalized newborns with CHD using multivariate analyses of genetic evaluation practices across time and patient subtypes.
RESULTS: Genetic testing guidelines for hospitalized newborns with CHD were implemented in 2014, and subsequently genetic testing increased (40% in 2013 and 75% in 2018, odds ratio: 5.02, 95% CI: [2.84, 8.88], p<0.001) as did medical geneticists' involvement (24% in 2013 and 64% in 2018, p<0.001). In 2018 there was an increased use of chromosomal microarray (p<0.001), gene panels (p=0.016), and exome sequencing (p=0.001). The testing yield was high (42%) and consistent across years and patient subtypes analyzed. Increased testing prevalence (p<0.001) concomitant with consistent testing yield (p=0.139) added an estimated 10 additional genetic diagnoses per year, reflecting a 29% increase.
CONCLUSION: In patients with CHD, yield of genetic testing was high. After implementing guidelines, genetic testing increased significantly and shifted to newer sequence-based methods. Increased use of genetic testing identified more patients with clinically important results with potential to impact patient care.

Keywords:  Congenital heart disease; cardiovascular genetics; genetic testing

DOI:  https://doi.org/10.1016/j.jpeds.2023.113495