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Barth syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Barth syndrome. Core disease mechanisms, molecular and cellular pathways,...

2026-04-12
Asta MONDO:0010543 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Barth syndrome. Core disease mechanisms, molecular and cellular pathways,...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Emerging Role of Organ‐on‐a‐Chip Technologies in Quantitative Clinical Pharmacology Evaluation

  • Authors: N. Isoherranen, R. Madabushi, Shiew-Mei Huang
  • Year: 2019
  • Venue: Clinical and Translational Science
  • URL: https://www.semanticscholar.org/paper/6050d8e5592be35f6dc371e5ad8ba57f852c360c
  • DOI: 10.1111/cts.12627
  • PMID: 30740886
  • PMCID: 6440571
  • Citations: 42
  • Influential citations: 2
  • Summary: This paper describes the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD and how emerging novel tools can provide new insights into physiology and disease mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.497) > 2 Potential role of microphysiological systems to inform quantitative clinical pharmacology models. Better understanding of physiology, pathology, and pharmacology is critical for developing systems biology and systems pharmacology models. Microphysiological systems can be viewed as an innovative technology that has the potential to enhance the understanding of physiology, pathology, and pharmacology. Specific applications of the microphysiological systems in the areas of biomarker development; demonstrating proof-of-concept, elucidating the mechanism of drug toxicity, and characterizing the complex physiologic changes that occur in disease states can provide the necessary information to advance the role of quantitative clinical pharmacology models in drug development. > work done to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome. Using Barth syndrome iPSC-derived cardiomyocytes, the metabolic, structural, and functional abnormalities associated with mutations in the gene encoding tafazzin were defined. The authors further demonstrated with Cas9-mediated genome editing that mutation in the gene encoding tafazzin was sufficient to cause the disease phenotype. 35 The use of patient-derived cells opens the potential for personalized disease modeling as well as the ability to model the longitudinal progression of the disease both at an individual as well as at the population level.

[2] Metabolic cardiomyopathies: untangling clinical heterogeneity with human stem-cell derived models

  • Authors: Adriana S. Passadouro, B. Balfoort, M. Langeveld, C. V. van Karnebeek, J. van der Velden et al.
  • Year: 2025
  • Venue: EMBO Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/b325b119830caf533cae0e65712444415c0bab13
  • DOI: 10.1038/s44321-025-00313-4
  • PMID: 40983718
  • PMCID: 12603204
  • Citations: 1
  • Summary: This review summarises literature on metabolic cardiomyopathies, focusing on long-chain fatty acid oxidation disorders and Barth syndrome, and highlights the potential of patient-specific hiPSC-derived cardiomyocytes as clinically relevant platforms to study disease mechanisms and therapeutic responses.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Inherited metabolic diseases are rare monogenic conditions that disrupt biochemical pathways, affecting energy production and homeostasis, often leading to damaging metabolite accumulation. These disorders are clinically heterogeneous and can impact all organs, including the heart. Metabolic cardiomyopathies present with varying severity and unpredictable prognosis, complicating patient care. Pre-clinical research aims to model these cardiomyopathies to understand their pathophysiological mechanisms and develop personalised treatments. Animal models have provided insights into cardiac pathology and treatment, but species differences limit data translation. Human induced pluripotent stem cells (hiPSC) offer a valuable tool for establishing disease models using reprogrammed somatic cells from patients and healthy donors, differentiated into disease-relevant cell types. Cardiomyocytes generated in significant numbers are crucial for investigating cardiac mechanisms and assessing patient-specific drug responses. This review summarises literature on metabolic cardiomyopathies, focusing on long-chain fatty acid oxidation disorders and Barth syndrome. We highlight cardiac readouts from various models and discuss the potential of hiPSC technologies as clinically relevant disease models. In this review, S. Mosegaard, R.H. Houtkooper and colleagues discuss metabolic cardiomyopathies, highlighting the potential of patient-specific hiPSC-derived cardiomyocytes as clinically relevant platforms to study disease mechanisms and therapeutic responses.

[3] Age-related changes in cardiomyopathic phenotype in patients with barth syndrome

  • Authors: Hani N. Sabbah
  • Year: 2023
  • Venue: Open Access Government
  • URL: https://www.semanticscholar.org/paper/6d33a25cbc34bf580ca605a961b4a35f22563801
  • DOI: 10.56367/oag-040-11042
  • Summary: The BTHS cardiomyopathic phenotypes appear to evolve with advancing age, which may be useful in treatment selection, and the potential of more targeted treatment approaches is explored.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > With current treatment options for BTHS cardiomyopathic phenotype focused predominantly on alleviating symptoms, Dr Hani N. Sabbah, Director of Cardiovascular Research at Henry Ford Health, explores the potential of more targeted treatment approaches. Barth syndrome (BTHS) is a rare, X-linked disease caused by defects in the TAFAZZIN gene encoding an acyltransferase responsible for the remodeling/maturation of cardiolipin (critical to mitochondrial structure/function).(1) The most common clinical manifestation of BTHS is cardiomyopathy (~90% of BTHS patients) with a wide range of phenotypical presentations.(2,3) Mechanisms contributing to BTHS cardiomyopathy pathophysiology include abnormal mitochondrial structure/function,(4) defective mitochondrial calcium uptake,(5) a mismatch between ATP supply and demand,(6) and altered lipid/glucose metabolism.(7) The BTHS cardiomyopathic phenotypes appear to evolve with advancing age, which may be useful in treatment selection.

[4] Barth syndrome: mechanisms and management

  • Authors: J. Finsterer
  • Year: 2019
  • Venue: The Application of Clinical Genetics
  • URL: https://www.semanticscholar.org/paper/fb97e79fcdebf4e739bdfd19c2f54a99ecfca9b1
  • DOI: 10.2147/TACG.S171481
  • PMID: 31239752
  • PMCID: 6558240
  • Citations: 31
  • Summary: Although Barth syndrome is still an orphan disease, there is extensive ongoing research with regard to its pathomechanism and new therapeutic approaches, and most of these approaches are still experimental, it can be expected that causative strategies will be developed in the near future.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > Barth syndrome: mechanisms and management

[5] Application of Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiomyocyte Modelling

  • Authors: P. Katili, Amira P. Karima, Winda Azwani, R. Antarianto, M. Djer
  • Year: 2023
  • Venue: Regenerative Engineering and Translational Medicine
  • URL: https://www.semanticscholar.org/paper/230ce81f53920be5341915add9ac3de36432f6f2
  • DOI: 10.1007/s40883-023-00294-1
  • Citations: 5
  • Summary: The cardiac patch is currently the most effective delivery system, proving safety and improvements in animal models, which are suggested to be the role of the paracrine mechanism.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Disease models of cardiac diseases had been reported for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), Friedreich's ataxia and Barth syndrome, and syndromic diagnosis associated with cardiomyopathy (LEOPARD syndrome, Pompe disease, laminopathies) [52][53][54][55]. These diagnoses comprise largely of genetic mutations; however, direct causality between genetic and environmental factors that affect disease phenotypes is still largely unknown, and until recently, there has been no reliable, human-sourced model to reenact disease progression outside the human body. hiPSCs allow the collection of diseased cell types to be investigated as cardiomyocytes develop in vitro, enabling the investigation of molecular and cellular mechanisms that contribute to pathological changes in an individual context. > Current studies focus on identifying new genetic mutations and reproducing their phenotypes in vitro using cell lines from diagnosed patients and their families. Disease models of hypertrophic cardiomyopathy (HCM) showed hypertrophy of cardiomyocytes, irregular sarcomere, and interstitial fibrosis in a hiPSC-CMs model. In the study by Lan et al., genetic analysis was carried out on ten patients in 2nd-and 3rd-generation families where one family member had been diagnosed with HCM. A missense mutation confirmed genetic aetiology in the myosin heavy chain (MYH7 gene) in 5 family members, but only one family member showed clinical manifestation [56]. Arrhythmias and irregular calcium handling were also found in the cellular level analysis. Genetic mutations without clinical phenotypes are an exciting area of research, and mechanisms regarding environmental influence on the genetic background are yet to be discovered. To confirm this hypothesis, Tanaka et al. analysed the influence of multiple hypertrophy-promoting factors in the hiPSC-CMs disease model from 3 known HCM patients, in which two of them were negative for known sarcomeric mutations. hiPSC-CMs HCM model treated with endothelin-1 (ET-1) showed disorganised cell hypertrophy and myofibrils compared to negative controls.

[6] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[7] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.387) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[8] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[9] 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: 0.379) > 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.

[10] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[11] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

  • Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
  • Year: 2025
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
  • DOI: 10.1038/s41598-025-97642-8
  • PMID: 40229542
  • PMCID: 11997208
  • Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
  • Evidence snippets:
  • Snippet 1 (score: 0.369) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[12] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[13] The ties that bind: functional clusters in limb-girdle muscular dystrophy

  • Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
  • Year: 2020
  • Venue: Skeletal Muscle
  • URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
  • DOI: 10.1186/s13395-020-00240-7
  • PMID: 32727611
  • PMCID: 7389686
  • Citations: 24
  • Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[14] The ties that bind: functional clusters in limb-girdle muscular dystrophy

  • Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
  • Year: 2020
  • Venue: Skeletal Muscle
  • URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
  • DOI: 10.1186/s13395-020-00240-7
  • Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[15] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

  • Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
  • DOI: 10.3390/ijms22083930
  • PMID: 33920294
  • PMCID: 8069124
  • Citations: 6
  • Influential citations: 1
  • Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[16] Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

  • Authors: C. Çubuk, F. Can, M. Peña-Chilet, J. Dopazo
  • Year: 2020
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/e40f7a3b8f72ba01374ba00fbf308a47a3fa5dd4
  • DOI: 10.3390/cells9071579
  • PMID: 32610626
  • PMCID: 7408716
  • Citations: 9
  • Summary: Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-s...
  • Evidence snippets:
  • Snippet 1 (score: 0.363) > Therefore, a proper interpretation of the effect that differences in gene expression have over phenotypes, such as drug response or disease progression, involves understanding the mechanisms of the disease or the mode of action of drugs, which can be interpreted through mechanistic models of cell signaling [12] or cell metabolism [13]. Mechanistic models have helped to understand the disease mechanisms behind different cancers [14,15], including neuroblastoma [16,17], breast cancer [18], rare diseases [19], complex diseases [20], the mechanisms of action of drugs [21,22], and other biologically interesting scenarios such as the molecular mechanisms that explain how stress-induced activation of brown adipose tissue prevents obesity [23] or the molecular mechanisms of death and the post-mortem ischemia of a tissue [24]. Among the few available proposals of mechanistic modeling algorithms that model different aspects of signaling pathway activity, Hipathia has demonstrated having superior sensitivity and specificity [12]. > Here, we propose the use of mechanistic models [13,14] of signaling activity related with cancer hallmarks [25], other cancer-related signaling pathways, and some extra relevant cellular functions to understand the functional consequences of the gender bias in gene expression. Such mechanistic models use gene expression data to produce an estimation of profiles of signaling or metabolic circuit activity within pathways [13,14]. An interesting property of mechanistic models is that they can be used not only to understand molecular mechanisms of disease or of drug action but also to predict the potential consequences of gene perturbations over the circuit activity in a given condition [26]. Actually, in a recent work, our group has successfully predicted therapeutic targets in cancer cell lines with a precision over 60% [15]. Therefore, we will use this mechanistic framework to understand what is the molecular basis of the different effects of cancer drugs by directly simulating their effect in the patients. This approach has recently been used by us to understand the generation of resistances in cancer at the single cell level in glioblastoma [27].

[17] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

  • Authors: M. Saporta
  • Year: 2015
  • Venue: Neural Regeneration Research
  • URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
  • DOI: 10.4103/1673-5374.158345
  • PMID: 26199602
  • PMCID: 4498347
  • Citations: 4
  • Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[18] Molecular insights into the premature aging disease progeria

  • Authors: Sandra Vidak, R. Foisner
  • Year: 2016
  • Venue: Histochemistry and Cell Biology
  • URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
  • DOI: 10.1007/s00418-016-1411-1
  • PMID: 26847180
  • PMCID: 4796323
  • Citations: 105
  • Influential citations: 3
  • Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[19] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

  • Authors: Michael Harris, K. Bhuvaneshwar, Thanemozhi Natarajan, L. Sheahan, Difei Wang et al.
  • Year: 2013
  • Venue: Pharmacogenetics and Genomics
  • URL: https://www.semanticscholar.org/paper/1382ddf84b87736a73c2f2f81164ca876c29f4c4
  • DOI: 10.1097/FPC.0000000000000015
  • PMID: 24401833
  • PMCID: 3888473
  • Citations: 16
  • Summary: This in-silico study identified gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic and gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews.
  • Evidence snippets:
  • Snippet 1 (score: 0.358) > Understanding the genetic and molecular mechanisms underlying complex diseases such as cancer is extremely challenging. Genome-wide association studies (GWAS) have been extensively used in the past decade to discover important genetic variants. However, the identified SNPs explain only a small proportion of the phenotypic variation, and the predictive power of these SNPs remains low for many complex diseases [10]. To fully elucidate genetic underpinnings of disease a systems biology approach is necessary to characterize variants, mRNA, copy number, proteins, and metabolites, as well as their cellular interactions [11]. Gene set and pathway association analyses are playing an increasingly important role in explaining disease mechanisms through the identification of functional genetic interactions [12]. Many gene-disease association analyses are based on SNP genotype profiling or gene expression studies. However, SNPs can influence many downstream processes including the expression levels of multiple genes and/or protein levels, and variations in expression levels can directly or indirectly impact disease progression and even drug response [13]. An integrative approach combining multiple data types can more accurately capture pathway associations [12] for discovery of clinically actionable variants. > Statistical approaches commonly used to associate variants with disease and/or drug response Fisher's exact test (FET) is commonly used in the association of germline polymorphisms with drug response [14]. The use of probabilistic networks in conjunction with traditional statistical models for mining relationships and associations from genotype-phenotype data is well established [15]. Probabilistic network methods for pharmacogenomics and newer methods such as the Markov Blanket concept may be helpful to better analyze these complex genotype-phenotype associations [16]. Considering the complexity of both cancer prognosis and individual drug response to chemotherapeutics, application of these association methods in conjunction with novel informatics and data integration approaches is necessary to identify clinically relevant variants for validation studies and ultimately testing in the clinic for pharmacogenomics applications.

[20] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

  • Authors: K. Lourida, G. Louridas
  • Year: 2022
  • Venue: Cardiogenetics
  • URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
  • DOI: 10.3390/cardiogenetics12020015
  • Citations: 4
  • Influential citations: 1
  • Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
  • Evidence snippets:
  • Snippet 1 (score: 0.357) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

Notes

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