bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2023–05–21
23 papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium
  1. Hemostatic defects in congenital disorders of glycosylation.
  2. Mannose treatment improves immune deficiency in mannose phosphate isomerase-congenital disorder of glycosylation: case report and review of literature.
  3. Congenital disorder of glycosylation - one size does not fit all: a parent's perspective.
  4. Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series.
  5. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.
  6. In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.
  7. A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.
  8. Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care.
  9. Pregnancy, Childbirth, Puerperium, Breastfeeding, and Sexuality in the World of Rare Diseases.
  10. RD-MON - Building a Rare Disease Monitor to Enhance Awareness for Patients with Rare Diseases in Intensive Care.
  11. Emerging roles and opportunities for rare disease patient advocacy groups.
  12. MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.
  13. Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells.
  14. Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
  15. Extracellular vesicles: a new communication paradigm of complement in neurological diseases.
  16. Single-cell and spatial transcriptomics: Advances in heart development and disease applications.
  17. High-Resolution and Multidimensional Phenotypes Can Complement Genomics Data to Diagnose Diseases in the Neonatal Population.
  18. Future of genetic therapies for rare genetic diseases: what to expect for the next 15 years?
  19. Morphological and genetic causes of fetal cardiomyopathies.
  20. Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation.
  21. Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
  22. Genetic disruption of mammalian endoplasmic reticulum-associated protein degradation: Human phenotypes and animal and cellular disease models.
  23. scBrainMap: a landscape for cell types and associated genetic markers in the brain.
  1. Res Pract Thromb Haemost. 2023 Mar;7(3): 100142
    Hemostatic defects in congenital disorders of glycosylation.
    Tiffany Pascreau, Claire Auditeau, Delphine Borgel.
      A "state of the Art" lecture titled "Hemostatic Defects in Congenital Disorders of Glycosylation" was presented at the ISTH 2022 congress. Congenital disorders of glycosylation (CDGs) are rare, inherited, metabolic diseases. The diagnosis of CDG is often challenging due to the broad variety of disorders, the variable level of severity, and phenotypic heterogeneity. Most CDGs are multisystem disorders, and neurologic involvement is frequent. Patients with CDG often present coagulation abnormalities characterized by low levels of procoagulant or anticoagulant factors. Antithrombin deficiency is frequently associated with factor XI deficiency and less frequently with a protein C, protein S, or factor IX deficiency. This coagulation profile differs from those observed in liver failure, disseminated intravascular coagulation, and vitamin K deficiency, and so, should prompt the physician to consider a diagnosis of CDG. Coagulopathy can lead to thrombotic and/or hemorrhagic complications. In patients with phosphomannomutase 2 deficiency (the most common CDG), thrombotic events are more frequent than hemorrhagic events. In other types of CDGs, both hemorrhagic and thrombotic events have been described. Overall, the hemostatic balance in these patients is precarious and necessitates close monitoring in a setting of acute illness with greater metabolic needs. Here, we review the most relevant hemostatic defects observed in CDG and their clinical implications. Finally, we summarize relevant new data on this topic presented at the ISTH 2022 congress.
    Keywords:  FIX; FXI; antithrombin; coagulation; congenital disorders of glycosylation; glycosylation; protein C; protein S
    DOI:  https://doi.org/10.1016/j.rpth.2023.100142
  2. Ther Adv Rare Dis. 2022 Jan-Dec;3:3 26330040221091283
    Mannose treatment improves immune deficiency in mannose phosphate isomerase-congenital disorder of glycosylation: case report and review of literature.
    Diederik De Graef, Jehan Mousa, Marta Biderman Waberski, Eva Morava.
      Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) is a CDG presenting with a clinically recognizable presentation, including early hypoglycemia, coagulation defects, and gastrointestinal and hepatic symptoms. We report on a female patient with biallelic pathogenic mutations in the MPI gene who presented with recurrent respiratory infections and abnormal IgM levels, but none of the classic symptoms associated with MPI-CDG. Oral mannose therapy led to a fast improvement in serum IgM levels and transferrin glycosylation in our patient. The patient did not experience severe infections after the initiation of treatment. We also reviewed the immune phenotype in patients so far reported with MPI-CDG.
    Keywords:  CDG; MPI; glycosylation; mannose; recurrent infections; therapy
    DOI:  https://doi.org/10.1177/26330040221091283
  3. Ther Adv Rare Dis. 2022 Jan-Dec;3:3 26330040221118099
    Congenital disorder of glycosylation - one size does not fit all: a parent's perspective.
    Konstantin Feinberg.
      This article is written by the parent of a child living with PMM2-congenital disorder of glycosylation (abbreviated to PMM2-CDG). It provides a parental perspective of the journey taken from diagnosis to present day and details the effect of off-label treatment with epalrestat.
    Keywords:  PMM2; cerebellum; congenital disorder of glycosylation; epalrestat; protein glycosylation
    DOI:  https://doi.org/10.1177/26330040221118099
  4. Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040221150269
    Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series.
    Silvia Radenkovic, Christin Johnsen, Andreas Schulze, Gurnoor Lail, Laura Guilder, Kaitlin Schwartz, Matthew Schultz, Saadet Mercimek-Andrews, Suzanne Boyer, Eva Morava.
      Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme. Like other CDGs, PGM1-CDG has a multisystemic presentation. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycemia, and cardiac involvement. Phenotypic severity can vary, though cardiac presentation is usually part of the most severe phenotype, often resulting in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose (D-gal) supplementation, which significantly improves many aspects of the disorder. Here, we describe five PGM1-CDG patients treated with D-gal and report both on novel clinical symptoms in PGM1-CDG as well as the effects of the D-gal treatment. D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients. Furthermore, there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two, while hypoglycemia resolved in two patients. One patient discontinued the treatment due to urinary frequency and lack of clinical improvement. Furthermore, one patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses of therapy. D-gal also failed to improve the cardiac function, which was initially abnormal in three patients, and remains the biggest challenge in treating PGM1-CDG. Together, our findings expand the phenotype of PGM1-CDG and underline the importance of developing novel therapies that would specifically treat the cardiac phenotype in PGM1-CDG.
    Keywords:  D-galactose therapy; PGM1 deficiency; PGM1-CDG; cardiac phenotype; case series; congenital disorder of glycosylation
    DOI:  https://doi.org/10.1177/26330040221150269
  5. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2302584120
    The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.
    Ida Signe Bohse Larsen, Lorenzo Povolo, Luping Zhou, Weihua Tian, Kasper Johansen Mygind, John Hintze, Chen Jiang, Verity Hartill, Katrina Prescott, Colin A Johnson, Sureni V Mullegama, Allyn McConkie-Rosell, Marie McDonald, Lars Hansen, Sergey Y Vakhrushev, Katrine T Schjoldager, Henrik Clausen, Thomas Worzfeld, Hiren J Joshi, Adnan Halim.
      Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
    Keywords:  O-mannosylation; congenital disorders of glycosylation; glycoproteomics; glycosylation; plexin
    DOI:  https://doi.org/10.1073/pnas.2302584120
  6. Int J Mol Sci. 2023 May 04. pii: 8247. [Epub ahead of print]24(9):
    In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.
    Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G P van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P Mahalleh-Yousefi, Merel A Post, Karin Huijben, Daan M Panneman, Richard J T Rodenburg, Nicol C Voermans, Alejandro Garanto, Werner J H Koopman, Hans J C T Wessels, Marek J Noga, Dirk J Lefeber.
      Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.
    Keywords:  PGM1 congenital disorder of glycosylation; PGM1 deficiency; in vitro muscle model; muscle energy homeostasis; muscle metabolic plasticity; phosphoglucomutase 1
    DOI:  https://doi.org/10.3390/ijms24098247
  7. Mol Genet Genomic Med. 2023 May 19. e2197
    A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.
    Yan Xue, Yiran Zhao, Bo Wu, Jianbo Shu, Dandan Yan, Dong Li, Xiaoli Yu, Chunquan Cai.
       BACKGROUND: The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of β1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation.
    METHOD: Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants.
    RESULTS: The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations.
    CONCLUSIONS: The case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.
    Keywords:  ALG1 gene; ALG1-CDG; congenital disorder of glycosylation; epileptic seizures; variant
    DOI:  https://doi.org/10.1002/mgg3.2197
  8. Am J Bioeth. 2023 May 19. 1-10
    Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care.
    Meghan C Halley, Colin M E Halverson, Holly K Tabor, Aaron J Goldenberg.
      Rare genetic diseases collectively impact millions of individuals in the United States. These patients and their families share many challenges including delayed diagnosis, lack of knowledgeable providers, and limited economic incentives to develop new therapies for small patient groups. As such, rare disease patients and families often must rely on advocacy, including both self-advocacy to access clinical care and public advocacy to advance research. However, these demands raise serious concerns for equity, as both care and research for a given disease can depend on the education, financial resources, and social capital available to the patients in a given community. In this article, we utilize three case examples to illustrate ethical challenges at the intersection of rare diseases, advocacy and justice, including how reliance on advocacy in rare disease may drive unintended consequences for equity. We conclude with a discussion of opportunities for diverse stakeholders to begin to address these challenges.
    Keywords:  Bioethics; genetics; health equity; patient advocacy; rare diseases; word
    DOI:  https://doi.org/10.1080/15265161.2023.2207500
  9. Healthcare (Basel). 2023 May 08. pii: 1351. [Epub ahead of print]11(9):
    Pregnancy, Childbirth, Puerperium, Breastfeeding, and Sexuality in the World of Rare Diseases.
    Raquel Rodríguez-Blanque, Juan Carlos Sánchez-García, Jonathan Cortés-Martín.
      Rare diseases, also known as orphan diseases, are medical conditions that affect a small percentage of the population [...].
    DOI:  https://doi.org/10.3390/healthcare11091351
  10. Stud Health Technol Inform. 2023 May 18. 302 358-359
    RD-MON - Building a Rare Disease Monitor to Enhance Awareness for Patients with Rare Diseases in Intensive Care.
    Romina Blasini, Achim Michel-Backofen, Henning Schneider, Kurt Marquardt.
      Rare diseases are commonly defined by an incidence of less than 5/10000 inhabitants. There are some 8000 different rare diseases known. So even if a single rare disease is seldom, together they pose a relevant problem for diagnosis and treatment. This is especially true if a patient is treated for another common disease. University hospital of Gießen is part of the CORD-MI Project on rare diseases within the German Medical Informatics Initiative (MII) and a member of the MIRACUM consortium within the MII. As part of the ongoing Development for a clinical research study monitor within the use case 1 of MIRACUM, the study monitor has been configured to detect patients with rare diseases during their routine clinical encounters. The goal was to send a documentation request to the corresponding patient chart within the patient data management system for extended disease documentation to enhance clinical awareness for the patients' potential problems. The project was started in late 2022 and has so far been successfully tuned to detect patients with Mucoviscidosis and place notifications within the patient chart of the patient data management system (PDMS) on intensive care units.
    Keywords:  FHIR; OMOP; Rare diseases; mucoviscidosis; patient data management system; study monitor
    DOI:  https://doi.org/10.3233/SHTI230139
  11. Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231164425
    Emerging roles and opportunities for rare disease patient advocacy groups.
    Amy M Patterson, Megan O'Boyle, Grace E VanNoy, Kira A Dies.
       Background: Patient advocacy groups (PAGs) serve a vital role for rare disease patients and families by providing educational resources, support, and a sense of community. Motivated by patient need, PAGs are increasingly at the forefront of policy, research, and drug development for their disease of interest.
    Objectives: The study explored the current landscape of PAGs in order to guide new and existing PAGs on available resources and challenges to research engagement. We aim to inform industry, advocates, and healthcare personnel about PAG achievements and ways they are increasingly involved in research.
    Design: We chose PAGs from the Rare Diseases Clinical Research Network (RDCRN) Coalition for Patient Advocacy Groups (CPAG) listserv and the National Organization for Rare Disorders (NORD) 'Find a patient organization'.
    Methods: We surveyed eligible PAG leaders about the demographics, goals, and research activities of their organization. For analysis, PAGs were bucketed by size, age, prevalence of disease, and budget. Data were de-identified for cross-tabulation and multinomial logistic regression analysis with R.
    Results: Research engagement was an extremely important goal for most PAGs (81%), though ultra-rare disease and high-budget PAGs were most likely to cite it as the top priority. In total, 79% reported research engagement in some capacity, including registries, translational research, and clinical trials. 'Ultra-rare' PAGs were less likely than 'rare' PAGs to have an ongoing clinical trial.
    Conclusion: While PAGs of varying sizes, budgets, and maturity levels reported an interest in research, limited funding and lack of disease awareness continue to create barriers to achieving their goals. While support tools exist to make research more accessible, often their utility depends on the funding, sustainability, maturity of the PAG itself, and the level of investment of collaborators. Despite the availability of current support systems, there are challenges related to both the start-up and sustainability of patient-centric research efforts.
    Keywords:  clinical trial; drug development; patient advocacy group; registry; research; support
    DOI:  https://doi.org/10.1177/26330040231164425
  12. J Thromb Haemost. 2023 May 17. pii: S1538-7836(23)00420-8. [Epub ahead of print]
    MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.
    Alexandre Kauskot, Coralie Mallebranche, Arnaud Bruneel, François Fenaille, Jean Solarz, Toscane Viellard, Miao Feng, Christelle Repérant, Jean-Claude Bordet, Sophie Cholet, Cécile V Denis, Geneviève McCluskey, Sylvain Latour, Emmanuel Martin, Isabelle Pellier, Dominique Lasne, Delphine Borgel, Sven Kracker, Alban Ziegler, Marie Tuffigo, Benjamin Fournier, Charline Miot, Frédéric Adam.
       BACKGROUND: X-Linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for the magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a Congenital Disorder of Glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and responsible for life-threatening bleeding events have never been investigated.
    OBJECTIVES: To assess platelet functions in XMEN patients.
    PATIENTS/METHODS: Two unrelated young boys, including one before and after hematopoietic stem-cell transplantation (HSCT), were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans.
    RESULTS: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbβ3 activation, calcium mobilization and protein kinase C (PKC) activity were impaired in both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide (PAR1-AP) were absent at both low and high concentrations. These defects were also associated with decreased molecular weight of glycoprotein (GP)Ibα, GPVI and integrin αIIb due to a partial impairment of N-glycosylation. All these defects were corrected after HSCT.
    CONCLUSIONS: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and a defective N-glycosylation in several platelet proteins, that could explain the hemorrhages reported in XMEN patients.
    Keywords:  Congenital disorder of glycosylation (CDG); Magnesium transporter 1 (MAGT1); N-glycosylation defect; Platelet function; XMEN disease
    DOI:  https://doi.org/10.1016/j.jtha.2023.05.007
  13. Int J Mol Sci. 2023 Apr 27. pii: 7942. [Epub ahead of print]24(9):
    Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells.
    Agata Wawrzkiewicz-Jałowiecka, Anna Lalik, Agnieszka Lukasiak, Monika Richter-Laskowska, Paulina Trybek, Maciej Ejfler, Maciej Opałka, Sonia Wardejn, Domenico V Delfino.
      Potassium channels emerge as one of the crucial groups of proteins that shape the biology of cancer cells. Their involvement in processes like cell growth, migration, or electric signaling, seems obvious. However, the relationship between the function of K+ channels, glucose metabolism, and cancer glycome appears much more intriguing. Among the typical hallmarks of cancer, one can mention the switch to aerobic glycolysis as the most favorable mechanism for glucose metabolism and glycome alterations. This review outlines the interconnections between the expression and activity of potassium channels, carbohydrate metabolism, and altered glycosylation in cancer cells, which have not been broadly discussed in the literature hitherto. Moreover, we propose the potential mediators for the described relations (e.g., enzymes, microRNAs) and the novel promising directions (e.g., glycans-orinented drugs) for further research.
    Keywords:  TCA cycle; Warburg effect; cancer biomarkers; cancer metabolism; channel glycanes; glutaminolysis; glycolysis; glycosylation; microRNA; potassium channels
    DOI:  https://doi.org/10.3390/ijms24097942
  14. Cells. 2023 05 06. pii: 1329. [Epub ahead of print]12(9):
    Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
    Jaylyn Waddell, Rehana Khatoon, Tibor Kristian.
      The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.
    Keywords:  NAD; brain; mitochondria
    DOI:  https://doi.org/10.3390/cells12091329
  15. Brain Res Bull. 2023 May 14. pii: S0361-9230(23)00090-4. [Epub ahead of print] 110667
    Extracellular vesicles: a new communication paradigm of complement in neurological diseases.
    Xinmei Gu, Anqi Chen, Yingsu, Mingfeng You, Hongxiu Guo, Senwei Tan, Quanwei He, Bo Hu.
      The complement system is crucial to the innate immune system. It has the function of destroying pathogens by activating the classical, alternative, and lectin pathways. The complement system is important in nervous system diseases such as cerebrovascular and neurodegenerative diseases. Activation of the complement system involves a series of intercellular signaling and cascade reactions. However, research on the source and transport mechanisms of the complement system in neurological diseases is still in its infancy. Studies have increasingly found that extracellular vesicles (EVs), a classic intercellular communication paradigm, may play a role in complement signaling disorders. Here, we systematically review the EV-mediated activation of complement pathways in different neurological diseases. We also discuss the prospect of EVs as future immunotherapy targets.
    Keywords:  Alzheimer's disease; EVs; complement; prospects of EV therapy; psychosis; stroke
    DOI:  https://doi.org/10.1016/j.brainresbull.2023.110667
  16. Comput Struct Biotechnol J. 2023 ;21 2717-2731
    Single-cell and spatial transcriptomics: Advances in heart development and disease applications.
    Xianglin Long, Xin Yuan, Jianlin Du.
      Current transcriptomics technologies, including bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), single-nucleus RNA-sequencing (snRNA-seq), and spatial transcriptomics (ST), provide novel insights into the spatial and temporal dynamics of gene expression during cardiac development and disease processes. Cardiac development is a highly sophisticated process involving the regulation of numerous key genes and signaling pathways at specific anatomical sites and developmental stages. Exploring the cell biological mechanisms involved in cardiogenesis also contributes to congenital heart disease research. Meanwhile, the severity of distinct heart diseases, such as coronary heart disease, valvular disease, cardiomyopathy, and heart failure, is associated with cellular transcriptional heterogeneity and phenotypic alteration. Integrating transcriptomic technologies in the clinical diagnosis and treatment of heart diseases will aid in advancing precision medicine. In this review, we summarize applications of scRNA-seq and ST in the cardiac field, including organogenesis and clinical diseases, and provide insights into the promise of single-cell and spatial transcriptomics in translational research and precision medicine.
    Keywords:  Cardiogenesis; Cardiology; Precision medicine; Single-cell RNA sequencing; Spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.csbj.2023.04.007
  17. Phenomics. 2023 Apr;3(2): 204-215
    High-Resolution and Multidimensional Phenotypes Can Complement Genomics Data to Diagnose Diseases in the Neonatal Population.
    Tiantian Xiao, Xinran Dong, Yulan Lu, Wenhao Zhou.
      Advances in genomic medicine have greatly improved our understanding of human diseases. However, phenome is not well understood. High-resolution and multidimensional phenotypes have shed light on the mechanisms underlying neonatal diseases in greater details and have the potential to optimize clinical strategies. In this review, we first highlight the value of analyzing traditional phenotypes using a data science approach in the neonatal population. We then discuss recent research on high-resolution, multidimensional, and structured phenotypes in neonatal critical diseases. Finally, we briefly introduce current technologies available for the analysis of multidimensional data and the value that can be provided by integrating these data into clinical practice. In summary, a time series of multidimensional phenome can improve our understanding of disease mechanisms and diagnostic decision-making, stratify patients, and provide clinicians with optimized strategies for therapeutic intervention; however, the available technologies for collecting multidimensional data and the best platform for connecting multiple modalities should be considered.
    Keywords:  Multidimensional phenotype; Neonatal diseases; Neonatal phenome; Personalized medicine
    DOI:  https://doi.org/10.1007/s43657-022-00071-0
  18. Ther Adv Rare Dis. 2022 Jan-Dec;3:3 26330040221100840
    Future of genetic therapies for rare genetic diseases: what to expect for the next 15 years?
    Luiza Amara Maciel Braga, Carlos Gilbert Conte Filho, Fabio Batista Mota.
       Introduction: Rare genetic diseases affect millions of people worldwide. Most of them are caused by defective genes that impair quality of life and can lead to premature death. As genetic therapies aim to fix or replace defective genes, they are considered the most promising treatment for rare genetic diseases. Yet, as these therapies are still under development, it is still unclear whether they will be successful in treating these diseases. This study aims to address this gap by assessing researchers' opinions on the future of genetic therapies for the treatment of rare genetic diseases.
    Methods: We conducted a global cross-sectional web-based survey of researchers who recently authored peer-reviewed articles related to rare genetic diseases.
    Results: We assessed the opinions of 1430 researchers with high and good knowledge about genetic therapies for the treatment of rare genetic diseases. Overall, the respondents believed that genetic therapies would be the standard of care for rare genetic diseases before 2036, leading to cures after this period. CRISPR-Cas9 was considered the most likely approach to fixing or replacing defective genes in the next 15 years. The respondents with good knowledge believed that genetic therapies would only have long-lasting effects after 2036, while those with high knowledge were divided on this issue. The respondents with good knowledge on the subject believed that non-viral vectors are more likely to be successful in fixing or replacing defective genes in the next 15 years, while most of the respondents with high knowledge believed viral vectors would be more successful.
    Conclusion: Overall, the researchers who participated in this study expect that in the future genetic therapies will greatly benefit the treatment of patients with rare genetic diseases.
    Keywords:  expert opinion; future; genetic therapies; rare genetic diseases; survey
    DOI:  https://doi.org/10.1177/26330040221100840
  19. Clin Genet. 2023 May 20.
    Morphological and genetic causes of fetal cardiomyopathies.
    Eva Kohaut, Flavie Ader, Caroline Rooryck, Fanny Pelluard, Maryse Bonnière, Gwenaelle André, Fanny Sauvestre, Philippe Roth, Diala Khraiche, Bettina Bessières, Tania Attié-Bitach, Pascale Richard.
      Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.
    Keywords:  dilated cardiomyopathy; fetal cardiomyopathy; genetics; hypertrophic cardiomyopathy; left ventricle noncompaction; next generation sequencing; phenotype genotype relation
    DOI:  https://doi.org/10.1111/cge.14333
  20. Stem Cell Reports. 2023 Apr 29. pii: S2213-6711(23)00141-8. [Epub ahead of print]
    Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation.
    Andrew R Yale, Estelle Kim, Brenda Gutierrez, J Nicole Hanamoto, Nicole S Lav, Jamison L Nourse, Marc Salvatus, Robert F Hunt, Edwin S Monuki, Lisa A Flanagan.
      Undifferentiated neural stem and progenitor cells (NSPCs) encounter extracellular signals that bind plasma membrane proteins and influence differentiation. Membrane proteins are regulated by N-linked glycosylation, making it possible that glycosylation plays a critical role in cell differentiation. We assessed enzymes that control N-glycosylation in NSPCs and found that loss of the enzyme responsible for generating β1,6-branched N-glycans, N-acetylglucosaminyltransferase V (MGAT5), led to specific changes in NSPC differentiation in vitro and in vivo. Mgat5 homozygous null NSPCs in culture formed more neurons and fewer astrocytes compared with wild-type controls. In the brain cerebral cortex, loss of MGAT5 caused accelerated neuronal differentiation. Rapid neuronal differentiation led to depletion of cells in the NSPC niche, resulting in a shift in cortical neuron layers in Mgat5 null mice. Glycosylation enzyme MGAT5 plays a critical and previously unrecognized role in cell differentiation and early brain development.
    Keywords:  MGAT5; N-glycan branching; astrocyte; brain; cerebral cortex; glycosylation; neural stem cell; neuron
    DOI:  https://doi.org/10.1016/j.stemcr.2023.04.007
  21. Eye (Lond). 2023 Apr 25.
    Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
    Benson S Chen, Joshua P Harvey, Michael J Gilhooley, Neringa Jurkute, Patrick Yu-Wai-Man.
      Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.
    DOI:  https://doi.org/10.1038/s41433-023-02523-x
  22. Traffic. 2023 May 15.
    Genetic disruption of mammalian endoplasmic reticulum-associated protein degradation: Human phenotypes and animal and cellular disease models.
    Sally Badawi, Feda E Mohamed, Divya Saro Varghese, Bassam R Ali.
      Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.
    Keywords:  ERAD genetic diseases; animal model; cellular disease model; cellular knockout; endoplasmic reticulum-associated protein degradation (ERAD)
    DOI:  https://doi.org/10.1111/tra.12902
  23. Database (Oxford). 2023 May 17. pii: baad035. [Epub ahead of print]2023
    scBrainMap: a landscape for cell types and associated genetic markers in the brain.
    Yuhao Chi, Ruicheng Qi, Yue Zhou, Huige Tong, Hanbo Jin, Christoph W Turck, Wei-Hua Chen, Guang-Zhong Wang.
      The great variety of brain cell types is a fundamental element for neuronal circuits. One major goal of modern neuroscience is to decipher the various types of cellular composition and characterize their properties. Due to the high heterogeneity of neuronal cells, until recently, it was not possible to group brain cell types at high resolution. Thanks to the single-cell transcriptome technology, a dedicated database of brain cell types across species has been established. Here, we developed scBrainMap, a database for brain cell types and associated genetic markers for several species. The current scBrainMap database contains 4881 cell types with 26 044 genetic markers identified from 6 577 222 single cells, which link to 14 species, 124 brain regions and 20 different disease states. scBrainMap enables users to perform customized, cross-linked, biologically relevant queries for different cell types of interest. This quantitative information facilitates exploratory research on the role of cell types with regard to brain function in health and disease. Database URL https://scbrainmap.sysneuro.net/.
    DOI:  https://doi.org/10.1093/database/baad035
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