Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Erythrokeratodermia Variabilis. Core disease mechanisms, molecular and cel...

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

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP)

• Authors: A. Terrinoni, G. Sala, Ernesto Bruno, Consuelo Pitolli, M. Minieri et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3042ff40f9af1eac025ccb7cdc2e98af65eafc50
• DOI: 10.3390/ijms241813962
• PMID: 37762265
• PMCID: 10530436
• Citations: 8
• Influential citations: 1
• Summary: This study analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV), and demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.
• Snippet 2 (score: 0.454) > Eritrokeratodermia variabilis (EKV, OMIM 133200) is another peculiar disease that is caused by defects in the process of keratinization. EKV is a rare, congenital, epithelial disease with early onset, characterized by remitting-relapsing erythematous patches associated with plaques of hyperkeratosis, sometimes massive (hystrix-like), stationary, or migratory [13]. The EKV disease has been associated with mutations in connexin genes GJB3 (Cx31) [14] and GJB4 (CX30.3) [15,16]. Recently, a variant of this disease has been identified, caused by mutations in connexin gene GJA1 (Cx43) [17]. Since it has not been recognized as a distinct entity, the new definition of erythrokeratodermia variabilis et progressiva (EKVP) has now been used to include the GJA1 variant. The accurate prevalence of EKVP is unknown, but it is estimated to be less than 1:200.000, being primarily inherited as an autosomal dominant connexin-dependent disease. Despite its dominant transmission, few cases of recessive transmission have been reported [18][19][20][21]. > The clinical features of EKVP present some overlap with other forms of ichthyoses such as lamellar ichthyosis or epidermolytic hyperkeratosis. Indeed, EKVP can be included within the ichthyosis group of mendelian disorders of cornification (MeDOC) [8], although its clinical phenotype is not characterized by generalized scaling of the epidermis and/or erythema. In addition, EKVP presents histologically with a thinner stratum corneum in respect of the other types of ichthyoses. > Although some of the genetic bases of EKVP have been discovered, the mechanism by which the reported mutations in connexin genes give rise to the general phenotype of the disease is still unclear.

[2] 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: 0.451) > 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.

[3] The genetic and molecular basis of a connexin-linked skin disease

• Authors: Sergiu A. Lucaciu, Dale W Laird
• Year: 2024
• Venue: Biochemical Journal
• URL: https://www.semanticscholar.org/paper/ec98115afd0d803d04f3ed9af4991faa8eebc2a5
• DOI: 10.1042/BCJ20240374
• PMID: 39513663
• PMCID: 11668363
• Citations: 5
• Summary: Evidence suggests that connexin variants associated with EKVP elicit a plethora of molecular defects including impaired gap junction (GJ) formation, dysregulated hemichannel and/or GJ channel function, cytotoxicity, dominant disruption of co-expressed connexins, and/or altered turnover kinetics.
• Evidence snippets:
• Snippet 1 (score: 0.440) > Indeed, loricrin gene variants cause a range of phenotypic presentations, including PSEK-like keratodermas, thus the field adopted the terminology of 'loricrin keratoderma' to distinguish this disorder from other similar presenting diseases with distinct molecular etiologies [45]. Furthermore, since as early as 1991, it has been proposed that EKV and PSEK may represent different clinical manifestations of the same condition [46], since the main clinical difference between EKV and PSEK is that EKV lesions are well-demarcated and migratory, while PSEK lesions are nonmigratory and symmetric [34]. It has been argued that the available clinical evidence does not support the existence of a non-migratory PSEK phenotype, rather the migratory erythemas in EKV are sometimes static and increasing in size, resembling the PSEK phenotype [34]. Once evidence emerged that the same GJB4 variant (Cx30.3-G12D) may cause phenotypes consistent with a diagnosis of either EKV or PSEK in the same family, van Steensel and colleagues proposed adopting the new nomenclature of erythrokeratodermia variabilis et progressiva (EKVP) to encompass both the variable and progressive nature of the lesions [34,47]. For simplicity, we will use the term EKVP throughout this paper to collectively refer to these variable clinical manifestations, except in situations where the clinical phenotype demands distinguishing between EKVP and other erythrokeratodermas. > Here, we set out to review the known and putative underlying molecular causes of EKVP associated with connexin gene variants, what is known about the underlying pathogenic mechanisms, the landscape of treatment options, and the pressing questions that need to be addressed.
• Snippet 2 (score: 0.395) > Note: the helical NTD inserts into the aqueous pore and is not embedded in the lipid bilayer. (D) Six connexins oligomerize to form a single membrane-spanning channel termed a HC (aka, connexon), with an aqueous pore connecting the cytoplasm and extracellular milieu. > (E) Compatible HCs on opposing cell membranes can dock to form unique double membrane-spanning intercellular channels called GJ channels. The aqueous pore in these channels directly connect the cytoplasm of the adjoined cells. Both types of channels permit the passage of small metabolites and ions up to 1 kDa in size. Created using BioRender. > The crucial roles of these keratinocyte connexins within the epidermis are highlighted by gene ablation/ attenuation studies and the association between connexin-encoding gene mutations and skin disease [25,26]. Variants in the genes encoding five of these keratinocyte connexins are clinically linked to at least seven cutaneous disorders with varying severity including some life-shortening conditions [25,26]. However, not all gene variants result in skin phenotypes, as Cx26 gene variants are the most common cause of sensorineural hearing loss that can occur with or without skin manifestations in a variant-dependent manner [26,27]. Similarly, the vast majority of Cx43 variants cause oculodentodigital dysplasia (ODDD), a rare congenital condition impacting various systems that rarely present with skin phenotypes [26,28,29]. > Erythrokeratodermia variabilis (EKV) first described by da Costa in 1925 [30] is a rare hereditary skin disorder characterized by well-demarcated lesions consisting of fixed hyperkeratotic plaques and transient migratory erythematous patches that tend to progressively worsen with age [31]. This classical EKV phenotype is sometimes referred to as EKV of Mendes da Costa, while a similar clinical presentation with distinct circinate erythematous lesions is termed EKV Cram-Mevorah [32,33].

[4] Topical Treatments for Rare Genetic Dermatological Diseases: A Narrative Review

• Authors: B. Oliveira, Ana Torres, Eduardo Ricci-Júnior, I. F. Almeida, M. Monteiro
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/dffc2b1f6280306c0db43e826542f92a4d31b340
• DOI: 10.3390/ph18111762
• PMID: 41305004
• PMCID: 12655290
• Summary: A comprehensive review of the topical treatments of EB, ichthyosis, HHD, DD, erythrokeratodermias, porokeratosis, ILVEN, and piebaldism highlighted the potential of off-label use of topical therapies as cost-effective alternatives in the treatment of rare genetic skin disorders.
• Evidence snippets:
• Snippet 1 (score: 0.430) > Erythrokeratodermias are a group of rare genodermatoses characterized by the presence of hyperkeratotic plaques associated with areas of erythema (Figure 1). These conditions exhibit both clinical and genetic heterogeneity and are classified into two main subtypes: Progressive Symmetrical Erythrokeratoderma (PSEK) and Erythrokeratoderma Variabilis (EKV) [42,43]. > PSEK begins in childhood and presents as non-migratory, symmetrical, erythematous, hyperkeratotic plaques. These lesions range in color from reddish orange to brown and show marked peripheral erythema. A typical sign is the symmetry of the lesions, which affect the knees, elbows, hands, and feet [43]. Genetically, PSEK shows considerable phenotypic variability and is predominantly congenital in an autosomal dominant manner. > Although its pathophysiology is not fully understood, mutations in the LOR gene, located on chromosome 1q21, have been identified in some cases. The LOR gene involves loricrin, a structural protein of the cornified cell envelope, a highly resistant protective layer formed in epidermal cells during keratinization. Loricrin plays a fundamental role in the skin barrier, being one of the main proteins that contribute to skin rigidity and impermeability. It is also involved in the formation of keratohyalin granules, structures found in the granular layer of the epidermis that assist in organizing and compacting proteins during the cornification process [43,44]. > EKV is distinguished by the combination of two types of skin lesions: fixed, welldemarcated, symmetrical hyperkeratotic plaques that persist in specific areas, and transient, migratory erythema that shifts location over the course of hours or days. These manifestations may occur simultaneously or alternate throughout an individual's lifetime. The disease typically begins in childhood, although late-onset cases have been reported. Facial involvement, especially on the cheeks is common, as is the involvement of flexural areas such as the axillae, groin, neck, and trunk [42]. EKV exhibits marked phenotypic variability, even among members of the same family.

[5] Role of Transcriptomics in Precision Oncology

• Authors: Ruby Srivastava
• Year: 2024
• Venue: Reports of Radiotherapy and Oncology
• URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
• DOI: 10.5812/rro-142195
• Citations: 4
• Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
• Evidence snippets:
• Snippet 1 (score: 0.399) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[6] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.394) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[7] Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data

• Authors: Kinza Rian, Marta R. Hidalgo, C. Çubuk, M. M. Falco, C. Loucera et al.
• Year: 2021
• Venue: Computational and Structural Biotechnology Journal
• URL: https://www.semanticscholar.org/paper/af786ba590cb9db62ff31318c785685ade68bfd9
• DOI: 10.1016/j.csbj.2021.05.022
• PMID: 34136096
• PMCID: 8170118
• Citations: 10
• Summary: This work presents the implementation of a mechanistic model of cell signaling for the interpretation of transcriptomic data as an R/Bioconductor package, a Cytoscape plugin and a web tool with enhanced functionality which includes building interpretable predictors, estimation of the effect of perturbations and assessment of the effects of mutations in complex scenarios.
• Evidence snippets:
• Snippet 1 (score: 0.387) > Mechanistic models of signaling pathways provide a natural bridge from variations in genotype (at the scale of gene activity or integrity) to variations in phenotype (at the scale of cells, tissues or organisms) [1]. They are built over graphs that represent the biological knowledge of the complex functional relationships among proteins within the cell, as described in repositories such as KEGG [2], Reactome [3], WikiPathways [4], or other more specialized, such as Disease Maps [5]. Specifically, they provide a conceptual framework for the interpretation of gene expression or genomic variation data and their consequences over downstream processes and phenotypic responses, such as cell proliferation and death, which are particularly relevant for studying disease progression or drug response [6]. Mechanistic models have successfully been used to understand the disease mechanisms behind different cancers [7,8] (including neuroblastoma [9,10] and glioblastoma [11]) rare diseases [12,13], complex diseases such as diabetes [14] or obesity [15], the mechanisms of action of drugs [16] or gender-specific effects of drugs in cancer [17]. In addition to diseases, other scenarios have been studied, such as the molecular mechanisms of death and the post-mortem ischemia of a tissue [18] or the effects of nanoplastics on embryos and human induced pluripotent stem cells [19]. > One of the most important aspects of mechanistic models is that they convey the notion of causality and can, therefore, be used to predict the downstream consequences of perturbations of specific conditions [20]. Thus, the possibility of simulating the effect of a drug allowed a systematic in silico drug repurposing experiment in Fanconi Anemia [21] in which some of the drugs predicted were further validated [22]. Also recently, all the targeted drugs currently in clinical trials for testing treatment and prevention of COVID-19 [23] were predicted by means of a mechanistic model [24] of the COVID-19 disease map [25]. application of mechanistic modeling show how the simulation of drug inhibitions at single-cell level uncovers the molecular basis of the generation of resistance to

[8] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 15
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.381) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[9] 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: 12
• 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: 0.381) > 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

[10] 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: 0.380) > 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.

[11] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

• Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
• Year: 2021
• Venue: Molecular Genetics & Genomic Medicine
• URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
• DOI: 10.1002/mgg3.1809
• PMID: 34519438
• PMCID: 8580094
• Citations: 12
• Influential citations: 2
• Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[12] Molecular genetic basis of epidermolysis bullosa

• Authors: Y. Kotalevskaya, V. Stepanov
• Year: 2023
• Venue: Vavilov Journal of Genetics and Breeding
• URL: https://www.semanticscholar.org/paper/720cbefbd0435504a6ed670ccf4f491dfbd3f143
• DOI: 10.18699/VJGB-23-04
• PMID: 36923479
• PMCID: 10009482
• Citations: 8
• Influential citations: 2
• Summary: The study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the Disease.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB.

[13] Novel insights into the evolution and structural characterization of dyskerin using comprehensive bioinformatics analysis.

• Authors: C. Cerrudo, D. M. Mengual Gómez, D. Gomez, P. Ghiringhelli
• Year: 2015
• Venue: Journal of proteome research
• URL: https://www.semanticscholar.org/paper/c8becabfeb8bdbc8ed150b3de31ac69a4cc5a8f9
• DOI: 10.1021/pr500956k
• PMID: 25540932
• Citations: 7
• Influential citations: 1
• Summary: This work predicted protein domains and compared sequences and structures to detect the universe of dyskerin-like proteins and identified conserved features of shared domains in the three superkingdoms, confirming that there is a strong structural conservation.
• Evidence snippets:
• Snippet 1 (score: 0.377) > Rocchi et al. have recently created a homology model of human dyskerin by using a template crystal structure from Saccharomyces cerevisiae (PDB ID: 3U28), which has a sequence identity of 73% with the human dyskerin sequence. 9However, the structures of eukaryotic dyskerins remain poorly understood. > A number of related genetic diseases are caused by defects in the telomere maintenance machinery.These disorders, often called telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease.Defects in genes involved in telomere maintenance result in a large overlapping spectrum of symptoms.The best known of these diseases is dyskeratosis congenital disorder (DKC), 10 aplastic anemia, Hoyeraal− Hreidarsson syndrome, idiopathic pulmonary fibrosis, 11 and cancer.The symptoms of these disorders are extensive, and the age of onset is highly variable; however, the disorders share similar underlying molecular mechanisms and have overlapping, incompletely penetrant phenotypes.Recently, an increasing number of reports have identified syndromes that do not include the classic symptoms but are still caused by mutations in core telomere maintenance proteins such as Revesz syndrome and Coats plus syndrome. 12Despite this heterogeneity it is important to go a bit deeper in the role of dyskerin in cancer due to the incidence and mortality of this disease and the fact that dyskerin has been explored for the development of drugs to selectively or preferentially kill cancer cells.A pioneer study has reported dyskerin expression to be increased in several human cancer types, especially in breast cancers. 13In accord with the known biological functions of the protein, breast cancers with low dyskerin expression contained lower levels of pseudouridine and telomerase RNA than those with high expression.Moreover, cancers with high expression generally exhibited worse histopathological features and prognosis.In line with these findings, DKC1 overexpression is associated with prostate cancer progression. 14Also, DKC1 is downregulated in sporadic chronic lymphocytic leukemia. 15

[14] Significance and Mechanisms Analyses of RB1 Mutation in Bladder Cancer Disease Progression and Drug Selection by Bioinformatics Analysis

• Authors: Dingguo Zhang, Jinjun Tian, Qier Xia, Zhenyu Yang, B. Gu
• Year: 2021
• Venue: Bladder Cancer
• URL: https://www.semanticscholar.org/paper/6038af24d56f6d9c5eeb1572c64dd5acd6aa62f2
• DOI: 10.3233/BLC-200368
• PMID: 38994537
• PMCID: 11181786
• Citations: 7
• Summary: The significance of RB1 mutation in disease progression and drug selection in bladder cancer was suggested by the results, and multiple genes and pathways related to such a program were identified.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Early and comprehensive intervention might be important for such patients to live longer. > Nowadays, molecular pathological diagnosis and individualized medicine testing can help doctors select target drugs according to the characteristics of the patient's tumor cells, including bladder cancer. Different patients may have tumor cells with different pathways activated in their bodies, which results in different molecular and pathological characteristics. These are the main mechanisms for disease progression and drug resistance in many tumors, which is also the basis of individualized treatment. Analyzing the activation of different pathways can help us understand the characteristics of different subtypes of tumors, and might help us explore potential personalized treatment at the same time. If a certain pathway is specifically activated in certain subtype patients, the drugs targeted this pathway might be more effective in such patients. Through these analyses, we can find out the potential mechanisms of drug resistance and clinical phenotypes that are associated with RB1 mutation, and provide some theoretical basis and directions for further research and verification. This might be quite preliminary and only have some theoretical functions. To explore these issues deeply, the gene expression data was analyzed in depth to find the key pathways and core genes associated with RB1 mutation. Results of GSEA analysis suggested that RB1 mutation were mainly associated with DNA repair, multiple cancer related pathways, cell proliferation and division, and metabolism. Previous researches have shown that defects in DNA repair contributed the disease progression of bladder cancer and influenced the treatment, especially in MIBC. Genomic alterations in the DNA repairassociated genes could render tumors sensitive to cisplatin-based chemotherapy for MIBC [20]. RB1 regulates the cell cycle. In RB1 mutated tumors, our findings showed that many processes involved in cell proliferation were enriched. RB1 mutation could result in abnormal regulation of cell cycle and cell division proliferation, which lead to continuous cell growth and tumor progression. Therefore, besides the three drugs above, other drugs, such as Docetaxel (Taxotere) which effectively induces G2M arrest and apoptosis might be more sensitive in patients with RB1 mutation [21]. > Next, we searched for DEGs and performed functional enrichment analysis on them. The results show a total of 999 DEGs. Enrichment analysis suggested that DEGs in RB1 mutated bladder cancer patients implicated with multiple cellular programs.

[15] Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34)

• Authors: P. Bourque, J. Warman-Chardon, D. Lelli, L. Laberge, Carly Kirshen et al.
• Year: 2018
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/45cefba2abf5bfb40cebb10bff8a2c4ee695de40
• DOI: 10.1212/NXG.0000000000000263
• PMID: 30065956
• PMCID: 6066365
• Citations: 31
• Influential citations: 6
• Summary: The majority of patients with EK have no pathogenic mutations in the GJB genes or LOR, and there is significant overlap in the clinical and genetic features of the “variabilis” and “progressiva” forms of EK.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Erythrokeratodermia (EK) is a rare skin disorder, likely genetic and usually present from infancy.1 There is patchy symmetrical involvement over the body surface, manifested in progressive figurate plaques of hyperkeratosis and more transient areas of erythema. There is significant overlap in the clinical and genetic features of the “variabilis” and “progressiva” forms of EK. Restricted cutaneous syndromes of EK have been described associated with mutations in the connexin (GJB3, GJB4, and GJA1) and loricrin (LOR) genes. The majority of patients with EK, however, have no pathogenic mutations in the GJB genes or LOR.

[16] Molecular Genetics of Keratinization Disorders – What’s New About Ichthyosis

• Authors: J. Uitto, L. Youssefian, A. Saeidian, H. Vahidnezhad
• Year: 2020
• Venue: Acta Dermato-Venereologica
• URL: https://www.semanticscholar.org/paper/bf6faf053470c47d9da1767b5e76ef97ac78c431
• DOI: 10.2340/00015555-3431
• PMID: 32147742
• PMCID: 9128965
• Citations: 27
• Influential citations: 2
• Summary: Some of the recent progress made in understanding the molecular genetics of keratinization disorders are highlighted, and selected, recently characterized cases are presented as representative of different forms of heritable ichthyosis.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Erythrokeratoderma manifests with hyperkeratotic, often transient and migratory erythematous and figurate plaques with sharply demarcated borders typically developing in early childhood (Fig. 7). It has been historically divided into two main categories: (a) erythrokeratodermia variabilis et progressiva; and (b) progressive symmetric erythrokeratoderma. However, these two presentations are currently listed on the OMIM catalogue under a single disease entry (OMIM #133200). There are a number of other presentations with erythrokeratoderma (59). Erythrokeratoderma can be inherited either in an autosomal dominant or an autosomal recessive pattern. The autosomal dominant forms have been associated with mutations in the gap junction-related genes (GJB2, GJB3, GJB4, and GJA1) as well as in LOR, encoding loricrin, a cornified envelope protein (53)(54)(55)59). Autosomal recessive erythrokeratoderma has been associated with mutations in ABHD5, ELOVL4 and KDSR. More recently, the genotypic spectrum of erythrokeratoderma has been extended by application of NGS using ichthyosis-associated gene sequencing panels which identified mutations in addition to those previously identified genes, also in PNPLA1 in families with the autosomal recessive form of erythrokeratoderma (Fig. 7) (10). These studies provide evidence in support of the notion that erythrokeratoderma can be a manifestation associated with multiple types of ichthyosis with different gene defects (60). Consequently, erythrokeratoderma may not be a distinct genetic entity but rather a manifestation of multiple ichthyosis-related genetic diseases that can occur with or without a more typical ichthyosis presentation.

[17] 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: 6
• 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: 0.375) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report 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) [

[18] 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: 0.375) > 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.

Notes

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