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Darier Disease

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

2026-08-23
Asta MONDO:0007417 Model: Asta Scientific Corpus Retrieval 16 citations

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

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

  • Papers retrieved: 16
  • Snippets retrieved: 20

Relevant Papers

[1] Genetics of Darier’s Disease: New Insights into Pathogenic Mechanisms

  • Authors: Barbara Moschella, Sabrina Busciglio, Enrico Ambrosini, Sofia Cesarini, L. Caramanna et al.
  • Year: 2025
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/8faec234894d6c3877c742f15d7c98c85c84b9cf
  • DOI: 10.3390/genes16060619
  • PMID: 40565511
  • PMCID: 12191890
  • Citations: 9
  • Summary: A broad overview of the pathology is provided, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression.
  • Evidence snippets:
  • Snippet 1 (score: 0.467) > If ER stress persists, as in the pathological context of Darier's disease, a cellular response shifts from adaptation to apoptosis, through the expression of the pro-apoptotic factor CHOP (Figure 7) [63]. Studies have shown that DD skin lesions display an enhanced expression of ER stress markers, such as CHOP, GRP78, calreticulin, and BiP, suggesting that the keratinocyte apoptosis in DD is mediated by the mitochondrial apoptosis pathway (Figure 7) [64]. > However, another study suggests that DD keratinocytes may undergo apoptosis through a mitochondria-independent mechanism. In fact, this study observed an increased expression of poly (ADP-ribose) polymerase (PARP) and caspase 2 in DD keratinocytes, while the levels of the pro-apoptotic proteins BAK and BAX remained unchanged [5]. > Other signaling pathway alterations have been investigated in DD patients, such as ERK hyper-activation in skin biopsies from DD patients compared to healthy individuals, supporting the hypothesis that MAPK pathway activation via ERK may be a result of SERCA2b dysfunction, highlighting it as a potential pathogenic driver in DD [58]. > Darier's disease is commonly misdiagnosed as eczema, seborrheic dermatitis, Hailey-Hailey disease (HHD), or acanthosis nigricans. Interestingly, HHD is associated with pathogenic variants in ATP2C1, which encodes the secretory pathway Ca 2+ -ATPase 1 (SPCA1) which is a calcium pump transporting Ca 2+ and Mn 2+ ions into the Golgi apparatus, where they are stored until needed. Although both DD and HHD involve abnormalities in calcium pumps and may share certain histologic similarities, their clinical and molecular characteristics are unique [65]. The haploinsufficiency of SPCA1 results in reduced Ca 2+ sequestration in the Golgi, and impaired N-linked glycosylation, protein trafficking, and desmosome assembly.
  • Snippet 2 (score: 0.420) > Biochemical mechanisms link DD and neuropsychiatric phenotypes via the sphingosineceramide pathway and neuroinflammatory responses. > SERCA2b alterations lead to an imbalance of sphingosine-ceramide products which may induce neuron toxicity via an accumulation of ROS and cell death induction through the expression of the P2X7 death receptor (P2X7R), which may promote mood disorders via increased IL-1β and cortisol signaling [70,94]. > Notably, sphingosine phosphate (S1P) plays a crucial role in keratinocyte adhesion and survival, thereby linking dyskeratotic and acantholytic skin phenotypes with neuropsychiatric features [95]. Neurons rely on calcium ions to regulate processes such as neurogenesis, neurotransmission, synaptic plasticity, and gene transcription. Indeed, it was observed that patients with Parkinson's disease (PD) have higher average calcium levels than healthy individuals [96]. In PD patients, complexes formed by STIM1 and TRPC1 can inhibit CaV1.3, a voltage-gated calcium channel. This leads to the disruption of neuronal Ca 2+ homeostasis and the development of PD symptoms. An excess of calcium levels also triggers mitochondrial stress, mitochondrial dysfunction, and even neuronal death [96]. Considering that SERCA2 dysfunction in Darier's disease (DD) leads to intracellular calcium accumulation and TRPC1 overexpression [97], and that similar mechanisms of calcium dysregulation have been implicated in Parkinson's disease (PD), it is plausible that these shared pathways contribute to DD patients' increased risk of being diagnosed with PD [98]. > Considering the high prevalence of neuropsychiatric symptoms, a neuropsychiatric and/or neurologic evaluation should be granted to every patient with DD, at least at the time of the diagnosis, with a follow-up to be determined based on the clinical features. Darier's disease also appears to be associated with cardiac problems.
  • Snippet 3 (score: 0.417) > Variants in ATP2A2 correlate with an impaired function of the isoform b of the sarco/endoplasmic reticulum ATPase protein (SERCA2), a calcium pump distributed throughout the endoplasmic reticulum (ER). > The functional deregulation of SERCA2 activity leads to altered intracellular calcium (Ca 2+ ) homeostasis and the post-translational misfolding of neosynthesized proteins, resulting in ER stress induction. Abnormal intracellular Ca 2+ signaling appears to correlate with a loss of desmosomal junctions in basal cells with a subsequent acantholysis and cleavage of the epidermal suprabasal layer. This aberrant skin phenotype highlights the importance of the distinct regulation of the process of keratinization, which must be highly and properly preserved to maintain the protective function of the epidermal barrier, as the body's first line of defense against the external environment. > Although the disease is associated with a clear disruption of the normal process of keratinization and multilayered stratification of the epidermis, the correlation between SERCA2b malfunction and the molecular mechanism triggering the manifestation of the disease is still unknown. > Our main objective is to provide a broad perspective on the molecular and systemic aspects involved in disease pathogenesis, discussing empirical findings from the literature and clinical therapeutic implications. > Therefore, this review offers in-depth analyses of the different cardiac, neurological, and metabolic manifestations that may occur with the typical skin manifestations of Darier's disease, investigating all possible molecular pathways involved in the altered skin phenotype. In addition, we aim to highlight any existing gaps in current knowledge and propose further insights into research studies to better understand the pathophysiological mechanisms underlying the disease.
  • Snippet 4 (score: 0.416) > Darier′s disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, which encodes the SERCA2 protein, an endoplasmic reticulum ATPase Ca2+ transporter. These mutations impair the intracellular calcium homeostasis leading to increased protein misfolding, endoplasmic reticulum (ER) stress response, and the activation of the unfolded protein response (UPR), culminating in keratinocyte apoptosis and anomalies in interfollicular epidermal stratification. Clinically, the disease is characterized by the presence of skin lesions with hyperkeratotic papules and an increased susceptibility to inflammatory reactions, bacterial and viral infections. The histological hallmarks include acantholysis, dyskeratosis, and increased apoptotic keratinocytes, referred to as “corp ronds”. The SERCA2b isoform is expressed not only in the epidermis but it is present ubiquitously in all tissues, suggesting that its alteration may have multi-organ effects. The review aims to provide a broad overview of the pathology, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression. Beginning with an examination of the cellular alterations, our work then shifts to exploring their impact in an organ-specific context, providing insights into new potential therapeutic strategies tailored to clinical manifestations.

[2] [Clinical, therapeutic and pathophysiological aspects of Darier's disease].

[3] 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
  • Citations: 2
  • 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: 0.422) > 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.

[4] Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment

  • Authors: Matthew Hunt, Nuoqi Wang, Naricha Pupinyo, P. Curman, Monica Torres et al.
  • Year: 2024
  • Venue: EMBO Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/f7c5a64ae39d0e6828204398238aafde68ee7c02
  • DOI: 10.1038/s44321-024-00104-3
  • PMID: 39060641
  • PMCID: 11392931
  • Citations: 9
  • Summary: Dantrolene, an approved ryanodine receptor antagonist, improved various pathophysiological hallmarks of Darier disease in in vitro models of the disease, demonstrating the potential applicability of the drug as a novel therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > Referee #1 (Comments on Novelty/Model System for Author): > In Darier disease the keratinocytes are skin cells that are mostly affected by the loss of function mutations of the SERCA pump. However, the authors selected HEK cells and for some of the experiments patient-derived fibroblasts as a working model. I do not fully understand why were keratinocytes not used at least for some of the experiments. Confirming the findings in an animal model of DD plus and minus Dantrelone would increase the clinical relevance of the study. Since Danrelone is in clinical use, the authors might want to search patient databases for individuals treated with dantralone and evaluate how this might have affected gene expression or protein abundance in the skin or in outer organs. This might be helpful in enhancing the relevance of the mechanisms identified in HEK cells. > Answer: We would like to thank the reviewer for investing time in reviewing our manuscript. With regards to the first point made, we would like to clarify that we used HEKa cells, which are primary keratinocyte cells, either with pharmacological or genetic SERCA2 inhibition. With regards to the point about animal models of DD, we did not use one as there are no validated animal models currently established which recapitulate the pathophysiology of DD (the knockout mice have a completely different phenotype, they get skin cancer instead of the typical DD rash). Instead, we have performed new experiments in patient derived keratinocytes (Figures 2-5). And finally, with regards to the point about patient databases, we have been unable to find any case reports about the use of Dl in DD patients, and so believe there not to be any. In this manuscript the authors propose Dantrolene sodium (D1) as potential drug in treating patients with Darier disease caused by mutations in the SERCA pump (ATP2A2). Indeed, this is an interesting subject as novel cures for DD as well as Hailey-Hailey disease (HHD) are very much needed. However, the study needs significant improvement and additional experimental investigation in order to prove if Dantrolene can be used in treating DD and HHD. > I have several suggestions and comments: 1.

[5] Mimicking Darier Disease In Vitro: A Human Epidermal Organoid Approach

  • Authors: Rishika Agarwal, E. Parente, S. Müller, Elisabeth A Kappos, T. Dittmar et al.
  • Year: 2025
  • Venue: Experimental Dermatology
  • URL: https://www.semanticscholar.org/paper/0cff72056be786d60104dee8f8dfb62845dc9b5d
  • DOI: 10.1111/exd.70191
  • PMID: 41466489
  • PMCID: 12749551
  • Summary: It is demonstrated that epidermal organoids derived from patients with Darier disease are a valuable model for studying DD and provide a platform to study complex genetic epidermal disorders and personalised drug screening.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > Darier disease (DD) is a rare genetic disorder caused by mutations in the ATP2A2 gene, resulting in calcium dysregulation and impaired keratinocyte adhesion. Due to the paucity of suitable models, understanding the molecular mechanisms of DD has been challenging. In this study, we developed a human epidermal organoid model derived from DD patient keratinocytes to investigate the molecular and phenotypic features of the disease. The model recapitulates key aspects of DD pathology, including acantholysis, desmosomal dysfunction and barrier disruption, with mislocalisation of desmosomal proteins. Furthermore, the transcriptomic landscape of DD organoids reflected broad perturbations in epidermal structure. Enrichment of pathways associated with epidermal development, cell adhesion, cell migration and keratinocyte differentiation underscored the multifaceted disruption of epithelial integrity and homeostasis that defines DD pathology. Our work demonstrates that epidermal organoids derived from patients with Darier disease are a valuable model for studying DD. They provide a platform to study complex genetic epidermal disorders and personalised drug screening.

[6] 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: 39
  • 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: 0.412) > 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.

[7] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

  • Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
  • Year: 2014
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
  • DOI: 10.3389/fcell.2014.00037
  • PMID: 25364744
  • PMCID: 4207010
  • Citations: 27
  • Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
  • Snippet 2 (score: 0.397) > In such scenario a biomarker needs to serve as proxy of key mechanistic factors characterizing and driving a disease on a patient-specific level, combined with educating on the specific interference of disease mechanism with drug mechanism of action. For capturing these constraints a detailed molecular map of a clinical phenotype and its interference with a drug mechanism of action is needed, and here integration of Omics profiling adds to identifying such mechanisms (Fechete et al., 2011;Mühlberger et al., 2012). > An a priori stratification of patients based on an appropriately chosen biomarker panel reflecting the pathophysiology of a given patient (group) allowing to determine a match with a specific drug's mechanism of action appears as promising approach. As recently discussed by Himmelfarb et al. fresh approaches are critical in finding therapies to kidney disease benefiting patients, outlining the importance of improving the translational aspect in clinical research (Himmelfarb and Tuttle, 2013). Here, omics technologies have added significantly to the data landscape characterizing chronic kidney disease, however, in a first instance mainly expanding the candidate set of apparently relevant processes and pathways, going in hand with a large number of biomarker candidates, which individually hamper clinically relevant assessment on disease progression (Fechete et al., 2011;Hellemons et al., 2012). > Integrative approaches in the realm of Systems Biology have been proposed for reaching a consensus description of chronic kidney disease pathophysiology, including molecular models of DN as well as of the reno-cardial axis (He et al., 2012;Komorowsky et al., 2012;Mayer et al., 2012;Heinzel et al., 2013). Still, a translation process needs to be followed, joining disease pathophysiology, stratification markers allowing enrichment strategies, combined with on a molecular mechanistic level matching drugs for allowing precision medicine (Mirnezami et al., 2012). In this work we exemplify such procedure on DN being the major clinical presentation leading to end stage renal disease.

[8] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 15
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.407) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[9] Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

  • Authors: Cameron L. McKnight, Y. C. Low, D. Elliott, D. Thorburn, Ann E. Frazier
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/bf41f9d980522896fcd2284bd630fbb418e55941
  • DOI: 10.3390/ijms22147730
  • PMID: 34299348
  • PMCID: 8306397
  • Citations: 21
  • Summary: Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modell...
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Mitochondrial disease hPSC models provide a system to study disease gene-or mutation-related pathomechanisms in tissues relevant to the clinical phenotype. Ultimately, the long-term goal of these models would be to identify a phenotype in a clinically relevant cell type that could be used to validate efficacy of targeted treatments, or for use in highthroughput treatment trials [94][95][96] (Figure 2). > There are now a wide range of endpoints that have been validated in terminally differentiated cell types to investigate the underlying cellular mechanisms of disease and efficiently identify targetable pathways. Many of these approaches can also be adapted to suit different cell types and even organoids at scale. The tissue specific nature of mitochondrial diseases means that mitochondrial function post-differentiation can be distinct to that from the undifferentiated stem cells or original fibroblast line, often greatly exaggerating any underlying defects [97]. Additionally, detailed transcriptomic and proteomic analyses can elucidate cellular compensation mechanisms and potential target pathways to inform downstream treatment studies [98,99]. Other approaches include microscopic visualization of key cellular features to determine a mutation's impact on cell structure or function [100]. For cardiomyocytes and neurons, electrophysiology can provide highly sensitive data to identify even subtle functional changes [101]. Calcium imaging can be particularly informative in the context of mitochondrial diseases, since calcium handling is a key role of mitochondria [102,103].

[10] Discovering cell types underlying rare disease phenotypes using scRNA-seq data from non-diseased tissues

  • Authors: Jorge Novoa, F. Pazos, M. Chagoyen
  • Year: 2025
  • Venue: bioRxiv
  • URL: https://www.semanticscholar.org/paper/c038b1472f7b42b58e9068eae4b0b0bf3970657e
  • DOI: 10.64898/2025.12.09.693155
  • Summary: Applied across diverse tissues and phenotypes, Cell4Rare was validated against literature-based associations and highlights the potential of computational analyses of non-diseased scRNA-seq data to uncover the cellular basis of rare disease phenotypes, paving the way for improved diagnostics and therapeutic strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.405) > Rare diseases, despite their individual low prevalence, collectively affect millions worldwide and pose persistent challenges for both diagnosis and treatment. The majority of these conditions have a genetic basis, with mutations that disrupt molecular and cellular pathways, ultimately manifesting as distinct and often severe phenotypes. Experimental approaches such as CRISPR-Cas9 gene editing, animal models, patient-derived iPSCs, and in vitro functional assays have become indispensable tools for validating the pathogenicity of specific variants and establishing the molecular and cellular pathways disrupted (MacArthur et al., 2014). These strategies provide critical insights into disease etiology by enabling the direct interrogation of gene function and phenotype. However, they are often limited by high costs, extended timelines, and scalability challenges-particularly in the context of rare diseases, where patient samples and resources are scarce. These limitations underscore the urgent need for robust, scalable computational tools that make use of the more abundant healthy omics data to facilitate the discovery and understanding of rare disease-causing mechanisms. > A major obstacle in rare disease research is determining the specific cellular contexts in which pathogenic genetic variants exert their effects. This is especially challenging given that many rare disease-associated genes are broadly expressed across tissues but lead to phenotypes that are restricted to a small subset of cell types (Feiglin et al., 2017). Pinpointing these relevant cellular targets is crucial for understanding disease mechanisms and for designing effective, targeted therapies. Recent advances in single-cell transcriptomics, along with growing databases of genotype-phenotype associations, offer an unprecedented opportunity to study gene activity at cellular resolution. Yet, for most rare diseases-many of which have pediatric onset-single-cell data from affected individuals remain unavailable, making traditional case-control approaches impractical. > In this context, computational methods that extract mechanistic insights from single-cell data derived from non-diseased tissues offer a valuable alternative. These approaches can help infer the cellular consequences of genetic alterations and guide the selection of the most relevant experimental systems for downstream validation.

[11] Molecular characterization of the circadian clock in patients with Parkinson’s disease–CLOCK4PD Study protocol

  • Authors: M. Yalçin, A. Peralta, C. Bentes, Cristiana Silva, T. Guerreiro et al.
  • Year: 2024
  • Venue: PLOS ONE
  • URL: https://www.semanticscholar.org/paper/f87121fcb57f42d6940fa5a15a53dc3ceb313f51
  • DOI: 10.1371/journal.pone.0305712
  • PMID: 39028707
  • PMCID: 11259294
  • Citations: 3
  • Summary: This study aims to characterize expression profiles of circadian genes obtained from saliva samples in PD patients and controls, and correlate reflected changes in CR of measured genes with distinct PD phenotypes (diffuse malignant and mild/motor-predominant).
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > Using the comprehensive clinical data collected, we plan to carry out additional subgroup analysis to determine clinical features that might influence the CR.Data from this study will contribute to a comprehensive characterization of CR differences in individuals with PD with respect to healthy controls, and will be correlated to additional data collected from questionnaires, diaries and activity tracking.Our study further aims to explore alterations in PD subgroup of patients with diffuse malignant and intermediate/mild-motor predominant phenotype.For this sub-group analysis ambulatory PSG data is additionally planned to be collected, which will allow for further characterization of sleep metrics.and can be correlated to gene expression changes.We further plan to carry out a sub-group analysis with respect to followup clinical assessment, which will take place 1-year after recruitment to correlate gene expression changes with disease progression, which can be used as a predictor of disease phenotype. > PD progression is reported to be dependent on the disruption in molecular pathways associated to mitochondrial dysfunction, impaired protein degradation and aggregation, oxidative stress, inflammation, apoptosis and cell death [92,93] in which the circadian system is involved.In our recent study [26] we observed similar gene expression changes (up-or-downregulation) due to the knockout of core-clock genes (BMAL1, PER2, NR1D1) and PD patients versus healthy controls.Both conditions showed striking changes in genes involved in immunity and inflammation, extracellular matrix organization and focal adhesion, oxidase activity and endocytosis, axonal guidance and structure, cell cycle and growth, autophagy, cell death and mitochondrial function, providing further evidence of the possible role for the dysregulation of the circadian clock in PD related mechanisms of neurodegeneration.In the course of this study, as an exploratory analysis we will use NanoString 1 multiplex system to characterize alterations in CR expression of genes involved in several of these neuropathology-related pathways (770 genes) to identify new targets.For this purpose, we plan to short-list a group of patients with a longer and shorter disease duration and compare to age-matched non-PD controls.

[12] 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: 30
  • 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: 0.396) > 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.

[13] Renal ciliopathies: promising drug targets and prospects for clinical trials

  • Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
  • Year: 2023
  • Venue: Expert Opinion on Therapeutic Targets
  • URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
  • DOI: 10.1080/14728222.2023.2218616
  • PMID: 37243567
  • Citations: 12
  • Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[14] 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: 4
  • 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: 0.394) > 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.

[15] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 13
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[16] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

  • Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
  • Year: 2022
  • Venue: Frontiers in Medical Technology
  • URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
  • DOI: 10.3389/fmedt.2022.810315
  • PMID: 35281671
  • PMCID: 8907708
  • Citations: 7
  • Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [see (13)].

Notes

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

Reference Validation

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Table (click to expand)
Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 32
On topic 18
Off topic 0

All extracted references resolved successfully.