bims-meglyc 2023-03-19 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–03–19
twenty-one papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Long-term outcomes in ALG13-Congenital Disorder of Glycosylation.
Discovering the genetic etiologies of rare diseases in large patient collections.
Congenital Disorders of the Pericardium.
Passing the post: Roles of post-translational modifications in the form and function of extracellular matrix.
Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.
Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
Quantification of Glycosaminoglycans in Urine by Isotope-Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.
The role of O-GlcNAcylation in development.
Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes.
PHARMACOGENOMICS: Driving Personalized Medicine.
The role of protein glycosylation in the occurrence and outcome of acute ischemic stroke.
Metabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications.
Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism.
Emerging Promise of the Therapeutic Approaches of Mitochondria for Neurodegenerative Disorders.
Foetal genome editing.
The evolution of comprehensive genetic analysis in neurology: Implications for precision medicine.
Roles of N-linked glycosylation and glycan-binding proteins in placentation: trophoblast infiltration, immunomodulation, angiogenesis, and pathophysiology.
New insights into the inter-organ crosstalk mediated by ChREBP.
Ex vivo gene therapy for lysosomal storage disorders: future perspectives.
Role of amino acid metabolism in mitochondrial homeostasis.
Brain organoids are new tool for drug screening of neurological diseases.

Am J Med Genet A. 2023 Mar 17.

Long-term outcomes in ALG13-Congenital Disorder of Glycosylation.

Rameen Shah, Christin Johnsen, Beth A Pletcher, Andrew C Edmondson, Tamas Kozicz, Eva Morava.

  ALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13-CDG, and there were no surviving males older than 16 years with a confirmed ALG13-CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13-CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long-term outcome in ALG13-CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non-progressive neurologic phenotype.

Keywords:  ALG13-CDG; glycosylation; hearing loss; scoliosis; seizures; survival

DOI:  https://doi.org/10.1002/ajmg.a.63179
Nat Med. 2023 Mar 16.

Discovering the genetic etiologies of rare diseases in large patient collections.

DOI: https://doi.org/10.1038/s41591-023-02218-6
Can J Cardiol. 2023 Mar 15. pii: S0828-282X(23)00246-5. [Epub ahead of print]

Congenital Disorders of the Pericardium.

Jared A Sheridan, Michelle Noga, Andrew S Mackie.

DOI: https://doi.org/10.1016/j.cjca.2023.03.012
Am J Physiol Cell Physiol. 2023 Mar 13.

Passing the post: Roles of post-translational modifications in the form and function of extracellular matrix.

Josephine C Adams.

  The extracellular matrix (ECM) is central to the physiology of animal tissues, through its multifaceted roles in tissue structure, mechanical properties and cell interactions, and by its cell-signalling activities that regulate cell phenotype and behaviour. The secretion of ECM proteins typically involves multiple transport and processing steps within the endoplasmic reticulum and the subsequent compartments of the secretory pathway. Many ECM proteins are substituted with various post-translational modifications (PTMs) and there is increasing evidence of how PTM additions are required for ECM protein secretion or functionality within the extracellular milieu. The targeting of PTM-addition steps may thus offer opportunities to manipulate ECM quality or quantity, in vitro or in vivo. This review discusses selected examples of PTMs of ECM proteins for which the PTM has known importance for anterograde trafficking and secretion of the core protein, and/or loss-of-function of the respectively modifying enzyme leads to alterations of ECM structure or function with pathophysiological consequences in humans. Members of the protein disulphide isomerase (PDI) family have central roles in disulphide bond formation and isomerisation within the endoplasmic reticulum, and are discussed in relation to emerging knowledge of the roles of certain PDIs in ECM production in the pathophysiological context of breast cancer. Cumulative data suggest the possible applicability of inhibition of PDIA3 activity to modulate ECM composition and functionality within the tumour microenvironment.

Keywords:  breast cancer; cell adhesion; extracellular matrix; secretome

DOI:  https://doi.org/10.1152/ajpcell.00054.2023
Curr Cardiol Rep. 2023 Mar 17.

Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.

Lauren E Parker, Leonie M Kurzlechner, Andrew P Landstrom.

   PURPOSE OF REVIEW: Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of the developmental etiology of these conditions is limited. Model organisms offer a window into normal and abnormal cardiogenesis yet often fail to recapitulate complex congenital heart defects seen in patients. The use of induced pluripotent stem cells (iPSCs) derived from patients with single-ventricle defects opens the door to studying SVD in patient-derived cardiomyocytes (iPSC-CMs) in a variety of different contexts, including organoids and chamber-specific cardiomyocytes. As the genetic and cellular causes of SVD are not well defined, patient-derived iPSC-CMs hold promise for uncovering mechanisms of disease development and serve as a platform for testing therapies. The purpose of this review is to highlight recent advances in iPSC-based models of SVD.
RECENT FINDINGS: Recent advances in patient-derived iPSC-CM differentiation, as well as the development of both chamber-specific and non-myocyte cardiac cell types, make it possible to model the complex genetic and molecular architecture involved in SVD development. Moreover, iPSC models have become increasingly complex with the generation of 3D organoids and engineered cardiac tissues which open the door to new mechanistic insight into SVD development. Finally, iPSC-CMs have been used in proof-of-concept studies that the molecular underpinnings of SVD may be targetable for future therapies. While each platform has its advantages and disadvantages, the use of patient-derived iPSC-CMs offers a window into patient-specific cardiogenesis and SVD development. Advancement in stem-cell based modeling of SVD promises to revolutionize our understanding of the developmental etiology of SVD and provides a tool for developing and testing new therapies.

Keywords:  Congenital heart disease; Genetics; Model organisms; Organoids; Single ventricle; Stem cells

DOI:  https://doi.org/10.1007/s11886-023-01852-3
Nat Med. 2023 Mar 16.

Genetic association analysis of 77,539 genomes reveals rare disease etiologies.

Genomics England Research Consortium

The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.

DOI: https://doi.org/10.1038/s41591-023-02211-z
Curr Protoc. 2023 Mar;3(3): e701

Quantification of Glycosaminoglycans in Urine by Isotope-Dilution Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry.

Haoyue Zhang, Sarah P Young, David S Millington.

  Mucopolysaccharidoses (MPSs) are complex lysosomal storage disorders that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, and tissues. Lysosomal enzymes responsible for GAG degradation are defective in MPSs. GAGs including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) are disease-specific biomarkers for MPSs. This article describes a stable isotope dilution-tandem mass spectrometric method for quantifying CS, DS, and HS in urine samples. The GAGs are methanolyzed to uronic or iduronic acid-N-acetylhexosamine or iduronic acid-N-sulfo-glucosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS, and CS are separated by ultra-performance liquid chromatography (UPLC) and analyzed by electrospray ionization tandem mass spectrometry (MS/MS) using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. This UPLC-MS/MS GAG assay is useful for identifying patients with MPS types I, II, III, VI, and VII. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary GAG analysis by ESI-MS/MS Support Protocol 1: Prepare calibration samples Support Protocol 2: Preparation of stable isotope-labeled internal standards Support Protocol 3: Preparation of quality controls for GAG analysis in urine Support Protocol 4: Optimization of the methanolysis time Support Protocol 5: Measurement of the concentration of methanolic HCl.

Keywords:  LC-ESI-MS/MS; dermatan sulfate; glycosaminoglycans; heparan sulfate; isotope dilution; mucopolysaccharidosis

DOI:  https://doi.org/10.1002/cpz1.701
Development. 2023 Mar 15. pii: dev201370. [Epub ahead of print]150(6):

The role of O-GlcNAcylation in development.

Ignacy Czajewski, Daan M F van Aalten.

  O-GlcNAcylation is a dynamic post-translational modification performed by two opposing enzymes: O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation is generally believed to act as a metabolic integrator in numerous signalling pathways. The stoichiometry of this modification is tightly controlled throughout all stages of development, with both hypo/hyper O-GlcNAcylation resulting in broad defects. In this Primer, we discuss the role of O-GlcNAcylation in developmental processes from stem cell maintenance and differentiation to cell and tissue morphogenesis.

Keywords:  Differentiation; Glycosylation; O-GlcNAcylation; Polycomb group proteins; Stem cells

DOI:  https://doi.org/10.1242/dev.201370
Diabetologia. 2023 Mar 13.

Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes.

Najda Rudman, Simranjeet Kaur, Vesna Simunović, Domagoj Kifer, Dinko Šoić, Toma Keser, Tamara Štambuk, Lucija Klarić, Flemming Pociot, Grant Morahan, Olga Gornik.

   AIMS/HYPOTHESIS: We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes.
METHODS: A total of 1105 recent-onset type 1 diabetes patients from the Danish Registry of Childhood and Adolescent Diabetes were genotyped at 183,546 genetic markers, testing these for genetic association with variable levels of 24 IgG and 39 plasma protein N-glycan traits. In the follow-up study, significant associations were validated in 455 samples.
RESULTS: This study confirmed previously known plasma protein and/or IgG N-glycosylation loci (candidate genes MGAT3, MGAT5 and ST6GAL1, encoding beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 gene, respectively) and identified novel associations that were not previously reported for the general European population. First, novel genetic associations of IgG-bound glycans were found with SNPs on chromosome 22 residing in two genomic intervals close to candidate gene MGAT3; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting N-acetylglucosamine (GlcNAc) (pdiscovery=7.65 × 10-12, preplication=8.33 × 10-6 for the top associated SNP rs5757680) and core fucosylated digalactosylated glycan with bisecting GlcNAc (pdiscovery=2.88 × 10-10, preplication=3.03 × 10-3 for the top associated SNP rs137702). The most significant genetic associations of IgG-bound glycans were those with MGAT3. Second, two SNPs in high linkage disequilibrium (missense rs1047286 and synonymous rs2230203) located on chromosome 19 within the protein coding region of the complement C3 gene (C3) showed association with the oligomannose plasma protein N-glycan (pdiscovery=2.43 × 10-11, preplication=8.66 × 10-4 for the top associated SNP rs1047286).
CONCLUSIONS/INTERPRETATION: This study identified novel genetic associations driving the distinct N-glycosylation of plasma proteins and IgGs identified previously at type 1 diabetes onset. Our results highlight the importance of further exploring the potential role of N-glycosylation and its influence on complement activation and type 1 diabetes susceptibility.

Keywords:  C3; GWAS; IgG N-glycosylation; MGAT3; ST6GAL1; plasma protein N-glycosylation; type 1 diabetes

DOI:  https://doi.org/10.1007/s00125-023-05881-z
Pharmacol Rev. 2023 Mar 16. pii: PHARMREV-AR-2022-000810. [Epub ahead of print]

PHARMACOGENOMICS: Driving Personalized Medicine.

Wolfgang Sadee, Danxin Wang, Katherine Hartmann, Amanda Ewart Toland.

  Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool to improve outcomes and prevent adverse effects. Advances in genomics have transformed pharmacogenetics, traditionally focused on single gene-drug pairs, into pharmacogenomics, encompassing all 'omics' fields, e.g., proteomics, transcriptomics, metabolomics, and metagenomics. This review summarizes basic genomics principles relevant to translation into therapies, assessing pharmacogenomics' central role in converging diverse elements of personalized medicine. We discuss genetic variations in pharmacogenes (drug-metabolizing enzymes, drug transporters, and receptors), their clinical relevance as biomarkers, and the legacy of decades of research in pharmacogenetics. All types of therapies, including proteins, nucleic acids, viruses, cells, genes, and irradiation, can benefit from genomics, expanding the role of pharmacogenomics across medicine. FDA approvals of personalized therapeutics involving biomarkers increase rapidly, demonstrating the growing impact of pharmacogenomics. A beacon for all therapeutic approaches, molecularly targeted cancer therapies highlight trends in drug discovery and clinical applications. To account for human complexity, multi-component biomarker panels encompassing genetic, personal, and environmental factors can guide diagnosis and therapies, increasingly involving artificial intelligence to cope with extreme data complexities. However, clinical application encounters substantial hurdles, such as unknown validity across ethnic groups, underlying bias in health care, and real-world validation. This review will address the underlying science and technologies germane to pharmacogenomics and personalized medicine, integrated with economic, ethical, and regulatory issues - providing insights into the current status and future direction of health care. Significance Statement Personalized medicine aims to optimize health care for the individual patients with use of predictive biomarkers to improve outcomes and prevent adverse effects. Pharmacogenomics drives biomarker discovery and guides the development of targeted therapeutics. This review addresses basic principles and current trends in pharmacogenomics, with large-scale data repositories accelerating medical advances. The impact of pharmacogenomics is discussed, along with hurdles impeding broad clinical implementation, in the context of clinical care, ethics, economics, and regulatory affairs.

Keywords:  Genetic polymorphisms; cancer; developmental pharmacology; drug metabolism; drug-drug interactions; gene regulation/transcription; pharmacogenetics/pharmacogenomics; systems pharmacology

DOI:  https://doi.org/10.1124/pharmrev.122.000810
Pharmacol Res. 2023 Mar 10. pii: S1043-6618(23)00082-8. [Epub ahead of print] 106726

The role of protein glycosylation in the occurrence and outcome of acute ischemic stroke.

Jianzhuang Li, Yanmei Qiu, Chunlin Zhang, Hailing Wang, Rentang Bi, Yanhao Wei, Yanan Li, Bo Hu.

  Acute ischemic stroke (AIS) is a serious and life-threatening disease worldwide. Despite thrombolysis or endovascular thrombectomy, a sizeable fraction of patients with AIS have adverse clinical outcomes. In addition, existing secondary prevention strategies with antiplatelet and anticoagulant drugs therapy are not able to adequately decrease the risk of ischemic stroke recurrence. Thus, exploring novel mechanisms for doing so represents an urgent need for the prevention and treatment of AIS. Recent studies have discovered that protein glycosylation plays a critical role in the occurrence and outcome of AIS. As a common co- and post-translational modification, protein glycosylation participates in a wide variety of physiological and pathological processes by regulating the activity and function of proteins or enzymes. Protein glycosylation is involved in two causes of cerebral emboli in ischemic stroke: atherosclerosis and atrial fibrillation. Following ischemic stroke, the level of brain protein glycosylation becomes dynamically regulated, which significantly affects stroke outcome through influencing inflammatory response, excitotoxicity, neuronal apoptosis, and blood-brain barrier disruption. Drugs targeting glycosylation in the occurrence and progression of stroke may represent a novel therapeutic idea. In this review, we focus on possible perspectives about how glycosylation affects the occurrence and outcome of AIS. We then propose the potential of glycosylation as a therapeutic drug target and prognostic marker for AIS patients in the future.

Keywords:  Acute ischemic stroke; Atherosclerosis; Atrial fibrillation; Neuronal survival; Protein glycosylation

DOI:  https://doi.org/10.1016/j.phrs.2023.106726
Signal Transduct Target Ther. 2023 Mar 14. 8(1): 114

Metabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications.

Saiyang Xie, Si-Chi Xu, Wei Deng, Qizhu Tang.

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

DOI: https://doi.org/10.1038/s41392-023-01378-8
Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00050-5. [Epub ahead of print]

Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism.

Masaki Tsuchiya, Nobuhiko Tachibana, Kohjiro Nagao, Tomonori Tamura, Itaru Hamachi.

  Cellular lipid synthesis and transport are governed by intricate protein networks. Although genetic screening should contribute to deciphering the regulatory networks of lipid metabolism, technical challenges remain-especially for high-throughput readouts of lipid phenotypes. Here, we coupled organelle-selective click labeling of phosphatidylcholine (PC) with flow cytometry-based CRISPR screening technologies to convert organellar PC phenotypes into a simple fluorescence readout for genome-wide screening. This technique, named O-ClickFC, was successfully applied in genome-scale CRISPR-knockout screens to identify previously reported genes associated with PC synthesis (PCYT1A, ACACA), vesicular membrane trafficking (SEC23B, RAB5C), and non-vesicular transport (PITPNB, STARD7). Moreover, we revealed previously uncharacterized roles of FLVCR1 as a choline uptake facilitator, CHEK1 as a post-translational regulator of the PC-synthetic pathway, and CDC50A as responsible for the translocation of PC to the outside of the plasma membrane bilayer. These findings demonstrate the versatility of O-ClickFC as an unprecedented platform for genetic dissection of cellular lipid metabolism.

Keywords:  CRISPR screens; flow cytometry; lipid metabolism; organelle-selective labeling: click chemistry; phosphatidylcholine

DOI:  https://doi.org/10.1016/j.cmet.2023.02.014
Curr Neuropharmacol. 2023 Mar 16.

Emerging Promise of the Therapeutic Approaches of Mitochondria for Neurodegenerative Disorders.

Md Mominur Rahman, Afroza Alam Tumpa, Md Saidur Rahaman, Fahadul Islam, Popy Rani Sutradhar, Muniruddin Ahmed, Badrah S Alghamdi, Abdul Hafeez, Athanasios Alexiou, Asma Perveen, Ghulam Md Ashraf.

  Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.

Keywords:  Alzheimer’s disease; Mitochondria; Parkinson’s disease; antioxidants; gene therapy; neurodegenerative disorders

DOI:  https://doi.org/10.2174/1570159X21666230316150559
Curr Opin Obstet Gynecol. 2023 Apr 01. 35(2): 134-139

Foetal genome editing.

Sourav K Bose, Kara Kennedy, William H Peranteau.

PURPOSE OF REVIEW: The development of modern gene editing tools alongside promising innovations in gene sequencing and prenatal diagnostics as well as a shifting regulatory climate around targeted therapeutics offer an opportunity to address monogenic diseases prior to the onset of pathology. In this review, we seek to highlight recent progress in preclinical studies evaluating the potential in-utero gene editing as a treatment for monogenic diseases that cause morbidity or mortality before or shortly after birth.
RECENT FINDINGS: There has been significant recent progress in clinical trials for postnatal gene editing. Corresponding advances have been made with respect to in-utero cell and enzyme replacement therapies. These precedents establish the foundation for 'one-shot' treatments by way in-utero gene editing. Compelling preclinical data in liver, pulmonary and multisystemic diseases demonstrate the potential benefits of in-utero editing approaches.
SUMMARY: Recent proof-of-concept studies have demonstrated the safety and feasibility of in-utero gene editing across multiple organ systems and in numerous diseases. Clinical translation will require continued evolution of vectors and editing approaches to maximize efficiency and minimize unwanted treatment effects.

DOI: https://doi.org/10.1097/GCO.0000000000000854
J Neurol Sci. 2023 Mar 05. pii: S0022-510X(23)00069-2. [Epub ahead of print]447 120609

The evolution of comprehensive genetic analysis in neurology: Implications for precision medicine.

Eirini Papadopoulou, Georgia Pepe, Spiridon Konitsiotis, Maria Chondrogiorgi, Nikolaos Grigoriadis, Vasilios K Kimiskidis, Georgios Tsivgoulis, Dimos D Mitsikostas, Elisabeth Chroni, Eleni Domouzoglou, Georgios Tsaousis, Georgios Nasioulas.

  Technological advancements have facilitated the availability of reliable and thorough genetic analysis in many medical fields, including neurology. In this review, we focus on the importance of selecting the appropriate genetic test to aid in the accurate identification of disease utilizing currently employed technologies for analyzing monogenic neurological disorders. Moreover, the applicability of comprehensive analysis via NGS for various genetically heterogeneous neurological disorders is reviewed, revealing its efficiency in clarifying a frequently cloudy diagnostic picture and delivering a conclusive and solid diagnosis that is essential for the proper management of the patient. The feasibility and effectiveness of medical genetics in neurology require interdisciplinary cooperation among several medical specialties and geneticists, to select and perform the most relevant test according to each patient's medical history, using the most appropriate technological tools. The prerequisites for a comprehensive genetic analysis are discussed, highlighting the utility of appropriate gene selection, variant annotation, and classification. Moreover, genetic counseling and interdisciplinary collaboration could improve diagnostic yield further. Additionally, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, with a focus on neurology-related genes, to clarify the value of suitable variant categorization. Finally, we review the current applications of genetic analysis in the diagnosis and personalized management of neurological patients and the advances in the research and scientific knowledge of hereditary neurological disorders that are evolving the utility of genetic analysis towards the individualization of the treatment strategy.

Keywords:  Chromosomal microarrays; Genetic analysis; Neurogenetics; Next generation sequencing; Personalized treatment

DOI:  https://doi.org/10.1016/j.jns.2023.120609
Biochem Soc Trans. 2023 Mar 16. pii: BST20221406. [Epub ahead of print]

Roles of N-linked glycosylation and glycan-binding proteins in placentation: trophoblast infiltration, immunomodulation, angiogenesis, and pathophysiology.

Zhengyuan Huang, Pei F Lai, Alexander T H Cocker, Stuart M Haslam, Anne Dell, Hugh J M Brady, Mark R Johnson.

  Protein N-linked glycosylation is a structurally diverse post-translational modification that stores biological information in a larger order of magnitude than other post-translational modifications such as phosphorylation, ubiquitination and acetylation. This gives N-glycosylated proteins a diverse range of properties and allows glyco-codes (glycan-related information) to be deciphered by glycan-binding proteins (GBPs). The intervillous space of the placenta is richly populated with membrane-bound and secreted glycoproteins. Evidence exists to suggest that altering the structural nature of their N-glycans can impact several trophoblast functions, which include those related to interactions with decidual cells. This review summarizes trophoblast-related activities influenced by N-glycan-GBP recognition, exploring how different subtypes of trophoblasts actively adapt to characteristics of the decidualized endometrium through cell-specific expression of N-glycosylated proteins, and how these cells receive decidua-derived signals via N-glycan-GBP interactions. We highlight work on how changes in N-glycosylation relates to the success of trophoblast infiltration, interactions of immunomodulators, and uterine angiogenesis. We also discuss studies that suggest aberrant N-glycosylation of trophoblasts may contribute to the pathogenesis of pregnancy complications (e.g. pre-eclampsia, early spontaneous miscarriages and hydatidiform mole). We propose that a more in-depth understanding of how N-glycosylation shapes trophoblast phenotype during early pregnancy has the potential to improve our approach to predicting, diagnosing and alleviating poor maternal/fetal outcomes associated with placental dysfunction.

Keywords:  N-linked glycosylation; glycan-binding proteins; hydatidiform mole; immunomodulation; pre-eclampsia; trophoblast

DOI:  https://doi.org/10.1042/BST20221406
Front Endocrinol (Lausanne). 2023 ;14 1095440

New insights into the inter-organ crosstalk mediated by ChREBP.

Thais Carbinatti, Marion Régnier, Lucia Parlati, Fadila Benhamed, Catherine Postic.

  Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.

Keywords:  ChREBP; hepatokines; inter-organ crosstalk; metabolic diseases; metabolism

DOI:  https://doi.org/10.3389/fendo.2023.1095440
Expert Opin Biol Ther. 2023 Mar 15.

Ex vivo gene therapy for lysosomal storage disorders: future perspectives.

Edina Poletto, Andrew Oliveira Silva, Ricardo Weinlich, Priscila Keiko Matsumoto Martin, Davi Coe Torres, Roberto Giugliani, Guilherme Baldo.

   INTRODUCTION: Lysosomal storage disorders (LSD) are a group of monogenic rare diseases caused by pathogenic variants in genes that encode proteins related to lysosomal function. These disorders are good candidates for gene therapy for different reasons: they are monogenic, most of lysosomal proteins are enzymes that can be secreted and cross-correct neighboring cells, and small quantities of these proteins are able to produce clinical benefits in many cases. Ex vivo gene therapy can correct different types of cells, including mesenchymal and hematopoietic precursors, and these can be then readministered to the patient, allowing auto transplant, for example.
AREAS COVERED: Here, we summarize the main gene therapy and gene editing strategies that are currently being used as ex vivo gene therapy approaches for lysosomal disorders, highlighting important characteristics, such as vectors used, strategies, types of cells that are modified and main results in different disorders.
EXPERT OPINION: Clinical trials are already ongoing and soon approved therapies for LSD based on ex vivo gene therapy approaches should reach the market.

Keywords:  adeno-associated vectors; ex vivo gene therapy; lentiviral vectors; lysosomal storage disorders

DOI:  https://doi.org/10.1080/14712598.2023.2192348
Front Cell Dev Biol. 2023 ;11 1127618

Role of amino acid metabolism in mitochondrial homeostasis.

Qiaochu Li, Thorsten Hoppe.

  Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.

Keywords:  TCA cycle; amino acid metabolism; amino acid recycling; lifespan; mitochondrial homeostasis; proteasome; respiratory chain

DOI:  https://doi.org/10.3389/fcell.2023.1127618
Neural Regen Res. 2023 Sep;18(9): 1884-1889

Brain organoids are new tool for drug screening of neurological diseases.

Jin-Qi Zhou, Ling-Hui Zeng, Chen-Tao Li, Da-Hong He, Hao-Duo Zhao, Yan-Nan Xu, Zi-Tian Jin, Chong Gao.

  At the level of in vitro drug screening, the development of a phenotypic analysis system with high-content screening at the core provides a strong platform to support high-throughput drug screening. There are few systematic reports on brain organoids, as a new three-dimensional in vitro model, in terms of model stability, key phenotypic fingerprint, and drug screening schemes, and particularly regarding the development of screening strategies for massive numbers of traditional Chinese medicine monomers. This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases. The paper also highlights the prospects from model stability, induction criteria of brain organoids, and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.

Keywords:  brain organoids; disease modeling; high-content system; multiple omic analysis; network pharmacology; neurodegeneration; phenotypic fingerprint; psychiatric diseases; stem cells; traditional Chinese medicine drug screening

DOI:  https://doi.org/10.4103/1673-5374.367983