Asta Literature Retrieval: Pathophysiology and clinical mechanisms of DK1-congenital disorder of glycosylation. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS

• Authors: I. Muffels, R. Budhraja, R. Shah, S. Radenkovic, E. Morava et al.
• Year: 2025
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/8f9edb863a2ede55b3a106e304d7bef842ac19b5
• DOI: 10.1101/2025.07.07.663468
• PMID: 40672295
• PMCID: 12265611
• Summary: Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies and several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
• Evidence snippets:
• Snippet 1 (score: 0.515) > Congenital disorders of glycosylation (CDG) result from impaired glycosylation and are categorized according to their primarily affected glycosylation type: N-glycosylation, O-glycosylation, combined glycosylation defects, glycolipid synthesis, or other related pathway abnormalities (Lefeber et al., 2022) CDG have been associated with pathogenic variants in over 190 different genes. (Ng et al., 2024) Protein glycosylation is highly abundant, with over 50% of proteins being glycosylated. (Apweiler et al., 1999) Glycosylated proteins are involved in a plethora of cellular functions, and contribute to proper protein folding and function, extracellular matrix structure, energy metabolism and cellular signaling. (Gagneux et al., 2022) The clinical phenotype of CDG is highly heterogenous. This might be due to the multitude of dysregulated pathways observed in these diseases. (Ligezka et al., 2023;Zdrazilova et al., 2023) Currently available treatment options for CDG are mostly symptomatic. Dietary supplementation of monosaccharides has been used for many years, although it is only effective for a subset of CDG. (Verheijen et al., 2020) Recently, large-scale drug screenings of FDA-approved drugs have come into play, providing a novel approach to discover therapies for CDG. (Dalton et al., 2024;Iyer et al., 2019;Ligezka et al., 2021;Radenkovic et al., 2023) Drug screening is usually performed by introducing a specific genetic defect in simple disease models (yeast, worm or fly), and verifying which compounds increase overall growth or survival. However, as these models are tailored to a specific genetic defect or variant, the results might not be translatable to other patients or other CDG. Developing novel treatments by modeling each of the 190 known CDG-associated genes individually is a time-intensive endeavor that could take years.

[2] Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis

• Authors: E. Klaver, Lynn Dukes-Rimsky, B. Kumar, Zhi-Jie Xia, Tammie Dang et al.
• Year: 2021
• Venue: JCI Insight
• URL: https://www.semanticscholar.org/paper/1964b8cddfd573cfd6e04b619109ace9f23d48e8
• DOI: 10.1172/jci.insight.153474
• PMID: 34784297
• PMCID: 8783681
• Citations: 9
• Summary: It is demonstrated in CDG that targeted alterations in protease activity create a pathogenic cascade that affects the maturation of cell adhesion proteins critical for tissue development.
• Evidence snippets:
• Snippet 1 (score: 0.503) > Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic diseases caused by defects in enzymes, transporters, and trafficking factors needed for protein and lipid glycosylation (1). The most common of the CDG, PMM2-CDG, results from variants in phosphomannomutase 2 (PMM2), encoding an enzyme that converts mannose-6-phospate (M6P) to mannose-1-phosphate (M1P) (2,3). M1P is a precursor for guanosine diphosphate-mannose (GDP-mannose), a nucleotide sugar essential for the synthesis of lipid-linked oligonucleotide precursors needed for N-linked glycosylation (4). Defects in PMM2 limit the production of GDP-mannose, causing reduced glycosylation of serum glycoproteins and numerous clinical manifestations. Common features include failure to thrive, neurological and cognitive impairment, and skeletal dysplasia (5). Despite nearly 4 decades of research on PMM2-CDG, the connection between hypoglycosylation of proteins and phenotypes remains enigmatic. To date no underglycosylated glycoprotein has been mechanistically linked to disease in an affected tissue. This barrier has created a major gap in our understanding of the molecular and cellular mechanisms driving CDG pathogenesis, and thus, has limited the development of therapies. > A major hurdle in defining CDG pathogenesis is the ability to identify sensitive glycoproteins beyond the classic markers, such as transferrin found in serum. Elucidating the pathogenic mechanisms associated with PMM2-CDG is further challenged by the difficulty in generating animal models that faithfully mimic the human disease. Complete loss of many N-glycosylation genes, particularly those involved in lipid-linked oligosaccharide biosynthesis, is lethal. Thus, complete gene knockout is not tenable. Early attempts to either knock out PMM2 or knock in the most common human PMM2-CDG allele, > The genetic bases for the congenital disorders of glycosyla

[3] Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1

• Authors: N. A. Bakar, A. Ashikov, J. M. Brum, R. Smeets, Marjan Kersten et al.
• Year: 2022
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/09b821b1ecfa8a382de9199bd325ef26a3eadac7
• DOI: 10.1002/jimd.12496
• PMID: 35279850
• PMCID: 9545396
• Citations: 19
• Summary: Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG‐I patient cohorts.
• Evidence snippets:
• Snippet 1 (score: 0.498) > Congenital disorders of glycosylation (CDG) form a large group of inherited diseases with extremely broad spectrum of clinical symptoms. Since its first description in 1980, more than 140 types of CDG have been reported of which 70 types with deficient N-linked protein glycosylation. 1 CDG type 1 (CDG-I) are seen as the classical form of CDG and comprise defects in the endoplasmic reticulum N-glycosylation pathway. CDG-I patients generally present with multisystem clinical phenotypes with the majority affected by neurological symptoms. Clinical clues might be useful to diagnose CDG-I defects such as (a) nonneurological involvements in MPI-CDG (gastrointestinal/liver phenotype) and DPM3-CDG (heart and muscle phenotype); (b) ichthyosis in MPDU1-CDG, DOLK-CDG, and SRD5A3-CDG; (c) neurosyndromic cataract and/or coloboma in SRD5A3-CDG and ALG2-CDG; and (d) neurosyndromic sensorineural deafness in ALG11-CDG and RFT1-CDG. 2 Traditionally, plasma transferrin has been used as the diagnostic protein marker to screen for CDGs with deficient N-glycosylation. Defects in CDG-I result in a partial absence of complete glycans on the transferrin protein. Introduction of plasma intact transferrin mass spectrometry (MS) has significantly improved the identification of CDG-I patients due to the sensitive detection of a glycan loss. 3,4 To date, at least 27 different genetic defects are known that result in CDG-I screening profiles. 5 Further confirmation of CDG-I gene defects has long depended on enzymatic assays in blood cells, analysis of dolichol-linked oligosaccharide (DLO) in patient fibroblasts or additional biochemical tests, such as analysis of dolichol metabolites in plasma or urine.

[4] Glycosylation in kidney diseases

• Authors: Yingying Ling, Fei Cai, Tao Su, Y. Zhong, Ling Li et al.
• Year: 2025
• Venue: Precision Clinical Medicine
• URL: https://www.semanticscholar.org/paper/2433e37bf6e26c841c86788356290cf02a7b6ef0
• DOI: 10.1093/pcmedi/pbaf017
• PMID: 40852041
• PMCID: 12368498
• Citations: 7
• Summary: This review provides a comprehensive overview of protein glycosylation mechanisms, its biological roles, molecular pathways, and significant functions in renal physiology and pathology and specifically highlights the dynamic changes and regulatory networks associated with aberrant glycosylation in kidney diseases.
• Evidence snippets:
• Snippet 1 (score: 0.483) > Human glycosylation encompasses 16 distinct pathways, including 14 forms of protein glycosylation and two types of lipid glycosylation. Protein glycosylation is broadly classified into N -glycosylation, O -glycosylation, glycosylphosphatidylinositol (GPI) anchor linkage, tryptophan C -mannosylation, S -glycosylation (e.g. cysteine-S -glycosylation), and P -glycosylation (e.g. phosphorylation-associated glycosylation), with N/O -glycosylation representing the predominant subtypes [ 11 ]. > Protein glycosylation regulates cellular functions through various pathways. Glycans have the capacity to modulate protein structure, subcellular localization, and trafficking, thereby exerting a profound impact on protein folding, activity, and stability. These effects, in turn, underpin fundamental biological processes such as cell-cell recognition, signal transduction, and immune responses [ 12 , 13 ]. Recent advances in high-throughput glycoproteomic technology have enabled systematic analysis of glycoproteins in preclinical and clinical studies, revealing that aberrant glycosylation is closely associated with major diseases, including cancers, kidney disorders, neurodegenerative diseases, and metabolic conditions [ 12 , 14-18 ]. Aberrant alterations in proteins and their attached glycans hold promise as diagnostic and prognostic biomarkers, and as therapeutic targets for managing or slowing disease progression. Therefore, understanding glycosylation modifications is essential for deciphering kidney disease mechanisms. In this review, we first briefly introduce the process of protein glycosylation, including its biological functions and underlying molecular mechanisms.

[5] A comprehensive update of genotype–phenotype correlations in PMM2-CDG: insights from molecular and structural analyses

• Authors: Tiago Oliveira, R. Ferraz, Luis Da Silva Azevedo, D. Quelhas, João Carneiro et al.
• Year: 2025
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/5c5fbf9aa8f1e32368a68a03ebd50b088c22ad47
• DOI: 10.1186/s13023-025-03669-5
• PMID: 40307862
• PMCID: 12042452
• Citations: 6
• Influential citations: 1
• Summary: This work broadens the understanding of the intricate relationships between genotype and clinical manifestations of PMM2-CDG, evaluating at a structural level 41 missense mutations in PMM2-CDG, examining their phenotypical characteristics and clinical severity, protein properties and interference at the enzymatic level.
• Evidence snippets:
• Snippet 1 (score: 0.466) > PMM2-CDG (phosphomannomutase 2-deficiency) is the most prevalent N-glycosylation disorder and results from impairments of PMM2 activity. This disease presents a large variety of pathogenic variants, which cause a wide phenotypical spectrum. This diversity, together with the low number of affected patients, raises the challenge of determining genotype–phenotype correlations in PMM2-CDG. This type of correlation could be highly significant in determining disease progression, prognosis, severity and in developing genome-personalized therapies. Structural analyses offer a valuable approach for assessing the pathogenic mechanisms within the PMM2 protein structure at a molecular level. Such an approach can reveal novel insights into the consequences of missense variants and their relationship with patients'phenotype. In this comprehensive review, we evaluate at a structural level 41 missense mutations in PMM2-CDG, examining their phenotypical characteristics and clinical severity, protein properties and interference at the enzymatic level. This work broadens the understanding of the intricate relationships between genotype and clinical manifestations of PMM2-CDG.

[6] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.446) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[7] Glycosylation in aging and neurodegenerative diseases

• Authors: Weilong Zhang, Tian Chen, Huijuan Zhao, Shifang Ren
• Year: 2024
• Venue: Acta Biochimica et Biophysica Sinica
• URL: https://www.semanticscholar.org/paper/70ccf81681b927b8fab87bc148d9d14f687e58a8
• DOI: 10.3724/abbs.2024136
• PMID: 39225075
• PMCID: 11466714
• Citations: 21
• Summary: The potential of glycosylation research as a tool to enhance the understanding of aging and its related diseases is highlighted and the mechanisms of glycosylation explored.
• Evidence snippets:
• Snippet 1 (score: 0.436) > These disorders share mechanistic pathways with the natural aging process, indicating that alterations in glycosylation may play a role in disease pathogenesis and progression [15]. Among these diseases, neurodegenerative diseases have garnered extensive attention in recent research due to their significant impact on health span and quality of life in aging populations. Accumulating evidence suggests that glycosylation modifications are closely linked to the pathophysiology of these disorders, possibly through mechanisms involving protein misfolding and aggregation, which are hallmark features of neurodegenerative diseases. > The relationship between glycosylation and aging or neurodegenerative diseases is particularly compelling as it offers insights into the molecular underpinnings that bridge chronic disease and aging. Research into the molecular basis of aging and neurodegenerative diseases can significantly enhance our understanding of how these processes are interlinked, potentially leading to novel diagnostic and therapeutic strategies. These strategies could focus on modifying glycosylation pathways to mitigate the adverse effects of aging and disease progression. > Given the established connections between glycosylation and aging or age-related diseases, this review focuses primarily on the characteristics of glycosylation modifications in the context of aging and selected neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. By delving into recent research advancements, we aim to highlight how glycosylation impacts these diseases within the broader spectrum of aging, thereby offering new avenues for intervention that could improve diagnosis, treatment, and ultimately patient outcomes. This focused approach allows for a detailed exploration of potential therapeutic targets within glycosylation pathways that could influence both aging and the pathogenesis of neurodegenerative diseases in the future.

[8] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.432) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[9] Identification and immune characteristics of molecular subtypes related to protein glycosylation in Alzheimer’s disease

• Authors: Zhaotian Ma, Fan Yang, Jiajia Fan, Xin Li, Yuanyuan Liu et al.
• Year: 2022
• Venue: Frontiers in Aging Neuroscience
• URL: https://www.semanticscholar.org/paper/23a1b3535085433d1eedf0733e0a9b4973b50142
• DOI: 10.3389/fnagi.2022.968190
• PMID: 36408104
• PMCID: 9667030
• Citations: 6
• Summary: Protein glycosylation and its corresponding immune process play an important role in the occurrence and development of AD and understanding the role of PGRGs in AD may provide a new potential therapeutic target.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Alzheimer's disease (AD) is an irreversible, progressive, polygenic, neurodegenerative disease that accounts for approximately 70% of dementia cases (Li et al., 2022;Tank et al., 2022). The onset of AD is unknown, and nerves undergo pathological changes decades before the onset of symptoms (Alzheimer's Association, 2021). Exploring the prominent clinical features of AD, including its complex etiology and high phenotypic heterogeneity, is essential because the exact pathogenesis of AD remains to be fully elucidated, which limits the development of effective drugs (Servick, 2021;Gherardelli et al., 2022). The course of disease evolution and differences in drug sensitivity among patients are generally believed to be related to the molecular heterogeneity of the disease (Mohamed Abd-El-Halim et al., 2021). Therefore, considering that existing therapeutic drugs and regimens can only slow down the progression of AD but not prevent or reverse it, evaluating the types of AD based on specific molecular mechanisms and developing corresponding therapeutic drugs is an effective strategy for achieving accurate medical goals. > Protein glycosylation, the process by which glycosidic chains form glycosidic bonds with certain amino acid residues on proteins catalyzed by glycosyltransferases, is an important posttranslational modification that occurs in 50-70% of proteins in cells. According to the glycoside chain type, protein glycosylation modification is mainly divided into four types, of which N-linked and O-linked glycosylation are the two main modification types (Schjoldager et al., 2020). Protein glycosylation regulates the function and activity of proteins, affecting many important cellular activities, such as cell recognition, differentiation, signal transduction, and immune response. Protein glycosylation disorders affect the pathological mechanisms of AD by mediating a variety of biological processes, such as neuroinflammation and cellular signal transduction (Zhang et al., 2020).

[10] Omics era in type 2 diabetes: From childhood to adulthood

• Authors: A. Passaro, P. Marzuillo, S. Guarino, Federica Scaglione, E. Miraglia del Giudice et al.
• Year: 2021
• Venue: World Journal of Diabetes
• URL: https://www.semanticscholar.org/paper/bbdc268c49f55cb23431fd8d41fde952f9829f7f
• DOI: 10.4239/wjd.v12.i12.2027
• PMID: 35047117
• PMCID: 8696648
• Citations: 10
• Influential citations: 1
• Summary: Omics data are responsible for the expanding knowledge of T2D pathophysiology, by providing novel insights to improve therapeutic strategies for this tangled disease, both in adults and children.
• Evidence snippets:
• Snippet 1 (score: 0.430) > The rising prevalence of the diabesity epidemic has highlighted the urgent need for more effective both prevention and treatment strategies. In this view, the growing knowledge regarding omics pathways affected by insulin signaling has favored the identification of novel potential biomarkers for this alarming epidemic. > Distinct metabolomics and lipidomics pathways have been recently linked to obesity, IR and T2D not only in adults but also in children, by allowing us to expand knowledge about the pathophysiology of several cardiometabolic diseases. > Given the unfavorable prognostic role of metabolic derangements in childhood, a better understanding, such as with omics profiles, of the pathophysiological mechanisms underlying beta-cell dysfunction is crucial. Findings from these studies are providing new insights into the intriguing field of molecular pathways related to IR as a predisposing factor for T2D. Therefore, novel attractive tools are emerging as potential therapeutic agents to counteract the risk of T2D and its related cardiometabolic burden already in childhood [31,33,34]. > In particular, lipidomic profiling accompanied by experimental studies using pharmacological reagents to alter synthesis or metabolism of certain lipids, has given additional insights into mechanisms governing lipotoxicity and disease progression, by providing evidence about a role in several crucial cellular responses (e.g., apoptosis, cell cycle and autophagy). > Recently, there has been significant progress in the understanding of the processes of insulin action and molecular defects determining IR, but many gaps according to the pathophysiology of metabolic disorders remain. Published data from studies conducted both on animals and humans have revealed a role for sphingolipids and metabolites in IR in different tissues such as skeletal muscle, liver and adipose tissue. > Among lipid classes, ceramides have gained remarkable attention as the major suspects in the development of IR. Therefore, changes in ceramide generation may become a desired therapeutic target, as shown in rodent models. > Further research is needed to identify the emerging role of both lipids and metabolites in the pathogenesis of cardiometabolic diseases in children in an attempt to provide novel clinical tools with potential therapeutic implications.

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 25
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.430) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[12] The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

• Authors: L. Averdunk, H. Sticht, H. Surowy, H. Lüdecke, M. Koch-Hogrebe et al.
• Year: 2021
• Venue: Journal of Molecular Medicine (Berlin, Germany)
• URL: https://www.semanticscholar.org/paper/bb20022a67ad80532547d5db6abf8062fc2dfefc
• DOI: 10.1007/s00109-021-02124-9
• PMID: 34536092
• PMCID: 8599376
• Citations: 6
• Summary: In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders.
• Evidence snippets:
• Snippet 1 (score: 0.430) > endocrine abnormalities and show the greatest clinical overlap with the YARS1 p.(Arg367Trp)-associated phenotype delineated here. > Another example of ARS1-associated disorders, in which an impaired protein synthesis as the causative disease mechanism can be questioned is VARS1 causing developmental delay with microcephaly [38]. Interestingly, in in vitro assays, the authors found a 50% residual aminoacylation activity. Because reductions in enzyme activity of approximately 50% are often well tolerated, it can be speculated that reduced aminoacylation is not the underlying disease mechanism, but that dysregulated secondary functions (for example, dysregulation of VEGF) might be involved. In many ARS1 genes, over 200 "catalytic nulls" natural splice variants have been annotated which primarily ablate or disrupt the catalytic domain but retain the noncatalytic section. This observation underpins the diverse, functions of nonenzymatic domains of ARS1 genes [50]. > CMT is another disease reflecting the significance of secondary protein functions of YARS1. Since the discovery of pathogenic variants in YARS1 causing CMT type C more than 15 years ago, the exact disease mechanism has not been understood, yet. All five CMT-causing mutations in YARS1 reside in the N-terminal catalytic domain (Fig. 1A). Because aminoacylation activity is not a shared property of pathogenic variations, it is unlikely that haploinsufficiency affecting the aminoacylation enzyme activity is the underlying mechanism [7,51]. Currently, gain-of-function pathogenic variants in non-catalytical domains or transcriptional dysregulation are discussed to be the potential underlying disease mechanism [52]. Of note, none of the patients or parents reported here is affected by CMT neuropathy. This is in line with the absence of neuropathy in patients with recessive disorders caused by other ARS1 genes which have been implicated with CMT [8]. > One limitation in the interpretation of the impact of YARS1 variants on protein function is that to date no structural model of the full-length protein is available and that separate structures of mini-TyrRS and C-domains are the basis for functional predictions. Another limitation is

[13] SLC35A2 Deficiency Promotes an Epithelial-to-Mesenchymal Transition-like Phenotype in Madin–Darby Canine Kidney Cells

• Authors: M. Kot, Ewa Mazurkiewicz, M. Wiktor, Wojciech Wiertelak, A. Mazur et al.
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/4e73e40211e8c96bcc3baaaea1db701e0cc53cc5
• DOI: 10.3390/cells11152273
• PMID: 35892570
• PMCID: 9331475
• Citations: 4
• Summary: A novel role for SLC35A2 as a gatekeeper of the epithelial phenotype is pointed to in a non-malignant epithelial cell line that shows several hallmarks of EMT.
• Evidence snippets:
• Snippet 1 (score: 0.425) > Congenital disorders of glycosylation (CDGs) are a large and heterogenous group of rare genetic metabolic diseases caused by defects in glycan synthesis and/or modification pathways [20]. To date, more than 130 CDG subtypes have been characterized. The majority of CDGs are autosomal recessive in inheritance, although autosomal dominant as well as X-linked forms have also been reported [21]. The clinical manifestations of CDGs are very diverse and the most commonly occurring symptoms include developmental retardation, failure to thrive, hypotonia, neurological problems, hepatopathy, and coagulopathy [21]. > For certain CDG subtypes, the relationship between the glycosylation defect and the disease symptoms is well-established. In SLC35C1-CDG, for example, selectin ligands on leukocytes are significantly underfucosylated due to compromised activity of the Golgi GDP-fucose transporter [22]. This prevents tethering and rolling of leukocytes on vascular endothelium which ultimately attenuates inflammatory response. However, for many CDGs, the influence of defective glycosylation on the downstream cellular phenotypes is poorly understood. > Mutations in the SLC35A2 gene are also a cause of a CDG subtype (SLC35A2-CDG; CDG IIm) [e.g., [23][24][25][26][27][28]]. The affected individuals usually experience neurological problems (global developmental delay, epilepsy, encephalopathy), as well as hypotonia. A number of SLC35A2-CDG patients fail to thrive due to gastrointestinal disease and impairment of the growth hormone-insulin-like growth factor axis [29]. They also show dysfunctions of the liver, spleen, kidney, and skeleton. However, it is not clear how an impaired Golgi UDP-galactose transporting activity mechanistically contributes to pathophysiology and clinical manifestation of SLC35A2-CDG.

[14] Inborn errors of metabolism leading to neuronal migration defects

• Authors: S. Schiller, H. Rosewich, S. Grünewald, J. Gärtner
• Year: 2019
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/8a99628274b23ee1a0aca9f3d35056be88f5c820
• DOI: 10.1002/jimd.12194
• PMID: 31747049
• Citations: 22
• Influential citations: 1
• Summary: An overview of the most important cortical malformations and potential underlying neurometabolic disorders in NMDs is provided.
• Evidence snippets:
• Snippet 1 (score: 0.422) > The development and organisation of the human brain start in the embryonic stage and is a highly complex orchestrated process. It depends on series of cellular mechanisms that are precisely regulated by multiple proteins, signalling pathways and non‐protein‐coding genes. A crucial process during cerebral cortex development is the migration of nascent neuronal cells to their appropriate positions and their associated differentiation into layer‐specific neurons. Neuronal migration defects (NMD) comprise a heterogeneous group of neurodevelopmental disorders including monogenetic disorders and residual syndromes due to damaging factors during prenatal development like infections, maternal diabetes mellitus or phenylketonuria, trauma, and drug use. Multifactorial causes are also possible. Classification into lissencephaly, polymicrogyria, schizencephaly, and neuronal heterotopia is based on the visible morphologic cortex anomalies. Characteristic clinical features of NMDs are severe psychomotor developmental delay, severe intellectual disability, intractable epilepsy, and dysmorphisms. Neurometabolic disorders only form a small subgroup within the large group of NMDs. The prototypes are peroxisomal biogenesis disorders, peroxisomal ß‐oxidation defects and congenital disorders of O‐glycosylation. The rapid evolution of biotechnology has resulted in an ongoing identification of metabolic and non‐metabolic disease genes for NMDs. Nevertheless, we are far away from understanding the specific role of cortical genes and metabolites on spatial and temporal regulation of human cortex development and associated malformations. This limited understanding of the pathogenesis hinders the attempt for therapeutic approaches. In this article, we provide an overview of the most important cortical malformations and potential underlying neurometabolic disorders.

[15] Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models

• Authors: M. Haskovic, A. I. Coelho, Jörgen Bierau, Jo M. Vanoevelen, L. Steinbusch et al.
• Year: 2019
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/dea4d7499797ec21ed9d0b65b0549abfe1322ff8
• DOI: 10.1002/jimd.12202
• PMID: 31808946
• PMCID: 7317974
• Citations: 47
• Influential citations: 1
• Summary: An overview of the scattered information resulting from animal and cellular studies performed in the past decades is provided, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
• Evidence snippets:
• Snippet 1 (score: 0.422) > Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose‐restricted diet, fails to prevent long‐term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long‐term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal‐1‐P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)‐hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP‐glucose pyrophosphorylase (UGP) up‐regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co‐adjuvant therapies include antioxidant therapy and UGP up‐regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.

[16] Neural and Synaptic Defects in slytherin, a Zebrafish Model for Human Congenital Disorders of Glycosylation

• Authors: Yuanquan Song, J. Willer, Paul C. Scherer, J. Panzer, Amy Kugath et al.
• Year: 2010
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/07df2fc2414fd48dc00cb808704fe9a044b25437
• DOI: 10.1371/journal.pone.0013743
• PMID: 21060795
• PMCID: 2966427
• Citations: 33
• Influential citations: 1
• Summary: It is shown, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Over the last decade, a large number of human genetic diseases with aberrant glycoprotein synthesis have been identified and grouped as congenital disorders of glycosylation (CDG). Since glycosylation is essential for the function of many proteins, it is not surprising that disruption of glycosylation can lead to severe, multisystemic phenotypes, including neurodevelopmental and cognitive disorders. In srn mutants, the gmds mutation largely abolishes the synthesis of GDP-fucose, resulting in reduction or elimination of both O-linked and N-linked fucosylation of Notch and many other proteins. Thus it is possible that disruption of O-as well as Nlinked glycosylation of Notch and other proteins contributes to CDG IIc pathogenesis, although this has not been examined extensively in humans. > There are several reports of neural deficits in CDGIIc patients, including severe mental retardation, microcephaly, cortical atrophy, seizures, psychomotor retardation and hypotonia [2,4,51]. These clinical observations are consistent with the CNS and PNS cellular phenotypes observed in srn. Giving the advantage of performing imaging, genetic and pharmacological manipulations in zebrafish, srn will be a useful tool to guide future analyses in human CDG IIc patients and contribute to a better understanding of the mechanisms responsible for this devastating disorder that affects nervous system and other organ development.

[17] Strain-Specific Liver Metabolite Profiles in Medaka

• Authors: Hannah Soergel, F. Loosli, C. Muhle‐Goll
• Year: 2021
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/0780c9fe74e73c6ac0628ca64f8ffc86475bd209
• DOI: 10.3390/metabo11110744
• PMID: 34822402
• PMCID: 8617739
• Citations: 5
• Summary: NMR spectroscopy has the potential to address genotype–phenotype associations in medaka, providing an additional level of phenotypic analysis, and is shown to be a suitable method to detect variance of the metabolome caused by subtle genetic differences.
• Evidence snippets:
• Snippet 1 (score: 0.421) > The advent of whole genome sequencing stimulated hope that the genetic variations in a population could be associated with pathology, especially for multi-causal diseases such as diabetes or cardiovascular diseases. The study of single gene mutations in the past forty years had revealed the impact of single genes and their protein products on disease etiology. Prominent examples include Huntington's disease [1] or Duchenne muscular dystrophy [2]. In these cases, analysis of a particular gene by mutational or knockout studies led to a detailed understanding of the molecular mechanism underlying the fatal consequences of the respective disease. However, genetic studies have shown that many traits, including disease and its progression, are influenced by more than one gene, so called complex genetic traits [3]. Specifically, recent GWAS (genome wide association studies) revealed also a key influence of the genetic background on specific molecular traits such as the metabolome [4]. > Metabolomic studies aim to identify and quantify comprehensively metabolites that are the products and/or effectors of cellular pathways. These studies are based on the assumption that the metabolic state of an organism provides crucial insight into its physiological state. For example, in many congenital metabolic disorders, the function of a single enzyme is perturbed and abnormal metabolite concentrations of the respective enzymatic reactions indicate a metabolomic disorder. Using this approach, characteristic metabolite patterns were detected in a multi-center clinical neonate metabolomics study in Turkey [5]. > Furthermore, in cases where genomic approaches cannot reveal a unique genotypephenotype correlation, differences in metabolites may correctly identify the pathological state. MODY5 is a specific form of maturity onset diabetes of the young, which causes multisystem disorder with a wide spectrum of clinical symptoms. Although more than 100 different mutations of the underlying causal gene, hepatocyte nuclear factor 1 homeobox B, have been reported, genomic approaches have not yet been able to reveal a genotype-phenotype correlation [6]. Metabolic differences in several tissues in a mouse model, however, clearly distinguished wild type from a mutant line [7]. That the metabolome highly depends on the genetic background is further demonstrated by studies of mouse strains.

[18] Personalized Medicine: The Future of Health Care

• Authors: A. Meiliana, Nurrani Mustika Dewi, A. Wijaya
• Year: 2016
• Venue: The Indonesian Biomedical Journal
• URL: https://www.semanticscholar.org/paper/02edaa39ecdab3dd64c077e71b14398b94beb742
• DOI: 10.18585/inabj.v8i3.271
• Citations: 8
• Summary: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual’s patient care needs to make health care more safe and effective.
• Evidence snippets:
• Snippet 1 (score: 0.416) > (98,170,171) The genetic cardiomyopathies present a window to cardiac pathophysiology when discrete cellular pathways are disrupted. Over the past decades, the role of numerous proteins in triggering cardiomyopathy and hence HF has finally become clear. Despite the genetic complexity, direct application of genetic testing is now a mainstay in managing affected families, and scientifically and clinically useful themes are emerging that should lead to improved treatment.( 95) > Investigations of rare monogenic disorders of heart rhythm has elucidated the fundamental molecular and genetic mechanisms of sickle cell disease. After identification of more than 25 causal genes, there remain many subjects with inherited arrhythmia susceptibility but do not have mutations, this suggests that there is still other genes left unidentified. Newer strategies such as exome and WGS may be valuable to uncover additional molecular etiologies. Efforts to understand mechanisms responsible for incomplete penetrance, including identification of modifier genes, will also contribute to deciphering the complex relationships between genotype and phenotype. (97) In diabetes, personalized medicine refers to utilize the patients specific characters for most effective diagnostic or treatment strategies. These include individual behavioral and phenotypic features, standard clinical laboratory findings, and gene sequences and other molecular markers.( 172) Diabetes mellitus has long been recognized to be a complex, heterogeneous disorder, especially in type 2 diabetes patients with substantial variability in genetic risk factors, underlying pathogenic mechanisms, and clinical features. Therefore it represents a human disease that gains a substantial benefit from personalized approaches to treatment. Nevertheless, patients with type 2 diabetes often are treated similarly, with little consideration of individual characteristics that might affect clinical outcome and therapeutic response.(173) Both type 1 and type 2 diabetes are thought to be complex diseases, which means they need the interplay of numerous susceptibility and protective genes, acting in concert with negative and positive environmental factors to be developed. (174) Type 2 diabetes typically is characterized by a combination of abnormalities in both insulin secretion and responsiveness, plus a more gradual and less extensive loss of β-cell secretory capacity than occurs in type 1 diabetes.

[19] Multimarker Panels in Diabetic Kidney Disease: The Way to Improved Clinical Trial Design and Clinical Practice?

• Authors: P. Perco, M. Pena, H. Heerspink, G. Mayer
• Year: 2018
• Venue: Kidney International Reports
• URL: https://www.semanticscholar.org/paper/7a5d5fe26a543e117b4bc1adc9ef195d0469aa75
• DOI: 10.1016/j.ekir.2018.12.001
• PMID: 30775618
• PMCID: 6365367
• Citations: 23
• Influential citations: 1
• Summary: Evidence on the variation of DKD disease progression as well as the response to therapy is summarized and procedures to model disease pathophysiology supporting biomarker panel construction are outlined.
• Evidence snippets:
• Snippet 1 (score: 0.416) > The explained variability of annual eGFR loss by the biomarkers indicated by the adjusted R 2 was 15% and 34% for patients with $60 and <60 ml/ min per 1.73 m 2 , respectively, and by clinical predictors 20% and 29%, respectively. A combination of molecular and clinical predictors increased the adjusted R 2 to 35% and 64%, respectively. 41 dentifying specific molecular processes associated with a specific phenotype of DKD and biomarkers associated with these processes, based on a molecular model of DKD, can be used to characterize the progression of patients based on individual pathophysiology. Matching the molecular mode of action of drug(s) to these specific molecular processes might allow selecting a specific drug or drug combinations that prevent or reverse deregulations in identified molecular pathways and thus guide therapy. This situation mirrors the one applied in infectious diseases, in which repetitively pathogens are identified and antimicrobial therapy is adjusted according to the results obtained. Matching a DKD disease progression model to a drug mechanism of action model was used in a study by Pena et al. 45 A panel of serum metabolites being linked to molecular processes of inflammation and stress response, as well as downstream consequences of fibrosis and extracellular matrix rearrangement, was able to predict albuminuria response to ARBs in both type 1 and type 2 DM. This observation supports the concept that improved molecular characterization of drug effect and disease pathophysiology can predict treatment response.

[20] Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients

• Authors: M. Jacob, A. Masood, Anas M. Abdel Rahman
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/9b1f76d2b5d16c76785f7d787eb860909b94a820
• DOI: 10.3390/ijms24032406
• PMID: 36768728
• PMCID: 9916661
• Citations: 3
• Summary: Using multi-omics profiling, the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients are identified and may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.415) > Neurocognitive defects and probable hypomyelinations are the distinct characteristics of PGM3 deficiency but not STAT3 or DOCK8. PGM3 is required for combined N and O-glycosylation through catalyzing the isomerization of N-acetylglucosamine-6-phosphate to N-acetyl glucosamine-1-phosphate during the generation of UDP-GlcNAc (Uridine diphosphate N-acetylglucosamine) The UDP-GlcNAc, in turn, is used in downstream glycosylation to make N-glycans and O-glycans through the salvage pathway. The glycosylation of proteins plays an important role in signal transduction and is critical for cell signaling. O-GlcNacylation underlies important cellular mechanisms seen in chronic and neurogenerative diseases. Many oncogenic proteins and tumor suppressor proteins are regulated by O-GlcNAcylation, thereby explaining the pathophysiology of such diseases [13,14]. > Increased serum IgE levels are characteristic but not specific to allergic diseases. HIES exhibits an unusual constellation of clinical features. Diagnosis can be confusing and difficult, especially during early childhood, and it is potentially life-threatening, although curable with bone marrow transplantation. Thus, the diagnosis of HIES is critical and should be sought at an early definitive therapy. Severe atopic dermatitis (AD) and HIES share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. AD is a chronic inflammatory disease with remission that commonly occurs in early infancy. Clinical manifestations in patients with AD include food allergy, asthma, and allergic rhinitis, probably in response to impaired innate and adaptive immunity and environmental stimuli [15]. Eczematous skin lesions, pruritus, and food allergies are common overlapping clinical features in HIES and AD. > High throughput "omics" technologies are indispensable for understanding HIES disease's underlying molecular mechanisms and in-depth pathogenesis as a complex disorder. Multi-omics technologies have been used in several disease' biomarker discoveries [16].

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.