Asta Literature Retrieval: Pathophysiology and clinical mechanisms of STRA6-related syndromic microphthalmia. Core disease mechanisms, molecular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Animal and cellular models of microphthalmia

• Authors: Philippa Harding, D. Cunha, M. Moosajee
• Year: 2021
• Venue: Therapeutic Advances in Rare Disease
• URL: https://www.semanticscholar.org/paper/4d2e4dcc85cec0b36a5e8dc218ea73bed92976b1
• DOI: 10.1177/2633004021997447
• PMID: 37181112
• PMCID: 10032472
• Citations: 9
• Summary: By understanding the causes of microphthalmia, researchers can develop treatments to prevent or reduce the severity of this condition and establish genotype–phenotype correlations to provide patients with the appropriate prognosis, multidisciplinary care and informed genetic counselling.
• Evidence snippets:
• Snippet 1 (score: 0.486) > Microphthalmia is a rare developmental eye disorder affecting 1 in 7000 births. It is defined as a small (axial length ⩾2 standard deviations below the age-adjusted mean) underdeveloped eye, caused by disruption of ocular development through genetic or environmental factors in the first trimester of pregnancy. Clinical phenotypic heterogeneity exists amongst patients with varying levels of severity, and associated ocular and systemic features. Up to 11% of blind children are reported to have microphthalmia, yet currently no treatments are available. By identifying the aetiology of microphthalmia and understanding how the mechanisms of eye development are disrupted, we can gain a better understanding of the pathogenesis. Animal models, mainly mouse, zebrafish and Xenopus, have provided extensive information on the genetic regulation of oculogenesis, and how perturbation of these pathways leads to microphthalmia. However, differences exist between species, hence cellular models, such as patient-derived induced pluripotent stem cell (iPSC) optic vesicles, are now being used to provide greater insights into the human disease process. Progress in 3D cellular modelling techniques has enhanced the ability of researchers to study interactions of different cell types during eye development. Through improved molecular knowledge of microphthalmia, preventative or postnatal therapies may be developed, together with establishing genotype–phenotype correlations in order to provide patients with the appropriate prognosis, multidisciplinary care and informed genetic counselling. This review summarises some key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future. Plain language summary Animal and Cellular Models of the Eye Disorder, Microphthalmia (Small Eye) Microphthalmia, meaning a small, underdeveloped eye, is a rare disorder that children are born with. Genetic changes or variations in the environment during the first 3 months of pregnancy can disrupt early development of the eye, resulting in microphthalmia. Up to 11% of blind children have microphthalmia, yet currently no treatments are available. By understanding the genes necessary for eye development, we can determine how disruption by genetic changes or environmental factors can cause this condition. This helps us understand why microphthalmia

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

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.437) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[3] Proteomic Analysis of Aqueous Humor Identified Clinically Relevant Molecular Targets for Neovascular Complications in Diabetic Retinopathy

• Authors: J. Oh, Seong Joon Ahn, Jaehun Jung, Tae Wan Kim, Kwang Pyo Kim
• Year: 2025
• Venue: Molecular & Cellular Proteomics : MCP
• URL: https://www.semanticscholar.org/paper/c18f63557d9e05b0b56490117c2f763ce1973276
• DOI: 10.1016/j.mcpro.2025.100953
• PMID: 40118382
• PMCID: 12131854
• Citations: 10
• Summary: It is identified that the pathological factors driving DR progression have a much greater impact than age, a previously known variable, in shaping the proteomic landscape of AH and underscores the potential of AH proteomics in uncovering predictive biomarkers and elucidating the molecular pathogenesis of DR and its complications.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Using MS-based proteomic analyses, our study characterized the AH proteome in patients with DR and its clinically important neovascular complications. The AH, composed of a complex mixture of proteins, growth factors, and electrolytes, plays a crucial role in maintaining a homeostatic microenvironment in the anterior segment structures of the eye. Abnormalities in the composition of AH can impact the surrounding intraocular tissues and contribute to ocular pathophysiology. Therefore, the AH proteome provides valuable insights into the molecular mechanisms underlying intraocular diseases. > In this study, we focused on exploring the differential expression of proteins among the NPDR, PDR, and NVG patient groups, with the aim of identifying biomarkers associated with the progression from NPDR to PDR and from PDR to NVG. The validation process confirmed the significance of the selected potential biomarker candidates obtained from the proteomic analysis. These candidates exhibited distinct expression patterns across different stages of DR, and their potential diagnostic value was supported by receiver operating characteristic curve analysis. Importantly, the stage-specific proteins identified through NMF clustering and open target analysis provided insights into the molecular changes associated with each stage of the disease and highlighted potential key proteins involved in the pathogenesis of serious neovascular complications of DR. > Particularly, our study contributes to the growing understanding of the molecular mechanisms underlying the progression of DR, with a specific focus on NVG. Recent studies on DR have underscored the importance of phenotyping to identify disease-specific biomarkers and therapeutic targets (24,25). Likewise, advances in glaucoma research highlight the importance of patient stratification to develop tailored management strategies (26,27), which are particularly valuable for severe subtypes such as NVG. By focusing on the unique molecular profile of PDR with and without NVG, we address an unmet clinical need, complementing existing studies while providing novel insights into potential biomarkers and therapeutic targets for NVG, which remains a particularly challenging condition to manage.

[4] A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

• Authors: Luz D. Orozco, Leah A. Owen, Jeffrey W. Hofmann, A. Stockwell, Jianhua Tao et al.
• Year: 2023
• Venue: Cell Genomics
• URL: https://www.semanticscholar.org/paper/71e90acd3f74f2163e658d934e4e35f993725a47
• DOI: 10.1016/j.xgen.2023.100302
• PMID: 37388919
• PMCID: 10300496
• Citations: 40
• Influential citations: 2
• Summary: A molecular atlas at different stages of age-related macular degeneration uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, FRZB and TLE2, as mechanistic players in disease.
• Evidence snippets:
• Snippet 1 (score: 0.421) > Deciphering mechanisms driving AMD onset and progression has been a major challenge. The diversity of risk factors and their interactions, the heterogeneous disease presentation and progression, and the lack of appropriate in vivo and in vitro models are obstacles to translational research in multifactorial ophthalmic diseases. For AMD, the nature of the disease and the inaccessibility of the affected tissues compounds these barriers to molecular characterization. The macula is a uniquely primate, intricate structure <6 mm in diameter. AMD phenotypes such as drusen and GA lesions are confined to this region and are only found in humans. To date, animal models do not recapitulate the full spectrum of phenotypes observed in the human condition. Furthermore, the patchiness of AMD lesions results in spatial variability of cellular dysfunction within the macula. Last but not least, the retina and RPE/choroid quickly undergo degradation postmortem, posing a logistical challenge for human sample banking. > To overcome these obstacles, here we used a multifaceted approach to investigate the epigenetic and transcriptional mechanisms underlying AMD. To address the issue of disease heterogeneity, tissues used for bulk analyses were carefully chosen from a collection of phenotyped human ocular tissue, where the controls showed little or no signs of drusen, and the disease tissues were delineated by clinical staging criteria. This is important, as we observed that at least 30% of presumed ''normal'' donors >60 years of age showed disease pathophysiology. 2 Lack of well-characterized phenotypes can introduce artifacts in downstream molecular experiments. The attention to postmortem interval (PMI) time, in tandem with rigorous phenotyping and dissecting procedures, is critical for data quality. As we and others have demonstrated, transcriptomic and epigenetic changes can be a reflection of long PMI rather than of underlying disease mechanisms. 2,49 To better understand the cellular complexity in AMD eyes, we employed single-cell genomics to complement and validate our bulk-tissue approach; our single-cell approach provides cell type information, and our bulk tissue provides a more complete molecular landscape. While many single-cell genomics studies of the human eye are publicly available, these

[5] Metabolomic Profile of Posner–Schlossman Syndrome: A Gas Chromatography Time-of-Flight Mass Spectrometry-Based Approach Using Aqueous Humor

• Authors: Haiyan Wang, R. Zhai, Qian Sun, Ying-Jie Wu, Zhujian Wang et al.
• Year: 2019
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/dfdc6207615d8b15471e627ccba5763ca72c366b
• DOI: 10.3389/fphar.2019.01322
• PMID: 31780941
• PMCID: 6855217
• Citations: 13
• Summary: Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) technology-based non-targeted metabolomics approach was adopted to measure comprehensive metabolic profiles of aqueous humor samples obtained from patients with PSS with an aim to demonstrate the underlying pathophysiology, identify potential biomarkers specific to PSS, and develop effective treatment strategies.
• Evidence snippets:
• Snippet 1 (score: 0.419) > The Posner–Schlossman syndrome (PSS) is a disease with clinically recurrent unilateral anterior uveitis with markedly elevated intraocular pressure (IOP) and subsequent progression to optic neuropathy. Retrospective studies have reported increased annual incidence of PSS, especially in China. While currently, the clinical management of PSS is still challenging. Metabolomics is considered to be a sensitive approach for the development of novel targeted therapeutics because of its direct elucidation of pathophysiological mechanisms. Therefore, we adopted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) technology-based non-targeted metabolomics approach to measure comprehensive metabolic profiles of aqueous humor (AH) samples obtained from patients with PSS, with an aim to demonstrate the underlying pathophysiology, identify potential biomarkers specific to PSS, and develop effective treatment strategies. A comparative analysis was used to indicate the distinct metabolites of PSS. Pathway analysis was conducted using MetaboAnalyst 4.0 to explore the metabolic reprogramming pathways involved in PSS. Logistic regression and receiver-operating characteristic (ROC) analyses were employed to evaluate the diagnostic capability of selected metabolites. Comparative analysis revealed a clear separation between PSS and control groups. Fourteen novel differentiating metabolites from AH samples obtained from patients with PSS were highlighted. Pathway analysis identified 11 carbohydrate, amino acid metabolism and energy metabolism pathways as the major disturbed pathways associated with PSS. The abnormal lysine degradation metabolism, valine–leucine–isoleucine biosynthesis, and citrate circle were considered to weigh the most in the development of PSS. The ROC analysis implied that the combination of glycine and homogentisic acid could serve as potential biomarkers for the discrimination of control and PSS groups. In conclusion, these results revealed for the first time the identity of important metabolites and pathways contributing to the development/progression of PSS, enabled the better understanding of the mechanism of PSS, and might lead to the development of metabolic biomarkers and novel therapeutic strategies to restrict the development/progression of PSS.

[6] Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

• Authors: Yuxiang Hu, S. Qi, H. Zhuang, Qiao Zhuo, Yu Liang et al.
• Year: 2023
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/f7b32962e2856b2fb22d1cfae85a77376702b618
• DOI: 10.3389/fimmu.2023.1163739
• PMID: 37025993
• PMCID: 10071000
• Citations: 3
• Summary: This study demonstrates that the occurrence of CNV might be associated with the dysfunction of immune and inflammatory processes and that IFN-β could serve as a potential therapeutic target.
• Evidence snippets:
• Snippet 1 (score: 0.418) > However, although these drugs can help to partially restore vision and delay disease progression, they cannot cure wet AMD (6). Thus, there is a considerable need to clarify the mechanisms underlying the onset of secondary CNV during the course of AMD and, in turn, to identify potential targets for the treatment of AMD. > Previous studies have demonstrated that the onset and progression of CNV are mediated by various regulatory factors (11,12). However, many molecular components of the pathophysiology of CNV remain unknown, especially in the adult population. Proteomic analysis is considered one of the most advanced exploratory research methods that can be used to discover new protein biomarkers of clinical significance (13). Multiple studies have employed proteomic analysis to study AMD (14). Furthermore, RNA transcriptome analysis of human AMD in donor eyes revealed that multiple pathogenic pathways (e.g., angiogenesis, extracellular matrix remodeling, inflammation, and immune responses) were perturbed in retinal pigment epithelium (RPE) cells (15, 16). Although proteomics and transcriptomics have improved general knowledge regarding CNV, more systematic studies of the relationship between proteomes and transcriptomes may reveal novel molecular alterations in CNV biology. > In the present research, we constructed a laser-induced CNV mouse model and then combined proteomic and transcriptomic (i.e., proteotranscriptome) analyses to identify the core genes, biological processes, and signaling pathways involved in the onset of CNV. In addition, we focused on the functions of interferon-b (IFN-b) and related potential therapy for CNV.

[7] 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: 0.417) > 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.

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

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.417) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[9] Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

• Authors: Ling-hui Qu, Xin Jin, Y. Long, Jia-yun Ren, Chuang-huang Weng et al.
• Year: 2020
• Venue: Bioscience Reports
• URL: https://www.semanticscholar.org/paper/a82d96818d129b6a03065b51851df3a190f4d706
• DOI: 10.1042/BSR20193536
• PMID: 31904091
• PMCID: 6974426
• Citations: 5
• Summary: These findings provide a basis for investigating genotype–phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.
• Evidence snippets:
• Snippet 1 (score: 0.417) > Abstract Background: The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. Methods: In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families. Results: We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. Conclusions: These findings provide a basis for investigating genotype–phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.

[10] 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: 0.416) > 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.

[11] Insights Into Cockayne Syndrome Type B: What Underlies Its Pathogenesis?

• Authors: Ricardo Afonso-Reis, Cristiana R Madeira, D. Brito, C. Nóbrega
• Year: 2025
• Venue: Aging Cell
• URL: https://www.semanticscholar.org/paper/1b86ba09359d5e2f0ff083dd037d872b4faec812
• DOI: 10.1111/acel.70136
• PMID: 40536083
• PMCID: 12266758
• Citations: 3
• Summary: It is proposed that CS‐B pathogenesis arises from a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction, and it is argued that these molecular features influence each other, rather than acting as isolated mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.415) > Cockayne Syndrome complementation group B is a complex disorder with diverse underlying molecular mechanisms that contribute for its highly debilitating and multisystemic phenotype. Years of research focusing on the physiological role of ERCC6 have provided extensive knowledge regarding different processes and cellular pathways dependent on ERCC6. Most accumulated knowledge regarding ERCC6 function is related to its crucial role in TC-NER. Nevertheless, significant advances have been made associating ERCC6 with several other mechanisms that are essential for proper cell functioning. This has helped bridge the gap in the knowledge in the pathological context of Cockayne Syndrome. Currently, ERCC6 has been identified to play an important role in distinct DNA repair mechanism, responsible for tackling different type of DNA damage. These mechanisms include TC-NER, BER, and DSB repair where ERCC6 is essential for the recruitment of repair machinery, and ICL repair where ERCC6 modulates effector repair factors. Notably, ERCC6 function is not limited to DNA repair. In fact, ERCC6 is implicated in transcription by remodeling chromatin of relevant regions, modulating RNAP I and II and cooperating with transcription factors and co-factors. Additionally, mitochondrial processes such as mtDNA maintenance, mitochondrial transcription and structural organization also rely on ERCC6. The key role ERCC6 plays in all these cellular processes, highlights the importance of ERCC6 for proper cell functioning. Ultimately, ERCC6 dysfunction leads to extremely deleterious consequences to the cell, which culminates in cellular malfunction and cell death. > Premature aging is a hallmark of progeroid syndromes, such as Cockayne Syndrome. Therefore, a relation between normal aging and Cockayne syndrome pathophysiology may be established to explore the potential mechanisms driving CS progression. Considering the cellular processes ERCC6 is involved in a physiological context, in this review we have organized CS-B pathophysiology into main three molecular features. These features include DNA damage accumulation, transcriptional dysregulation and mitochondrial dysfunction. Importantly, we consider that these features do not act as isolated pathways but rather influence one another, through a mechanism interplay. This interplay has the potential to exacerbate dysfunction of affected features or induce dysfunction of an otherwise functional feature.

[12] Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells

• Authors: D. Gurda, L. Handschuh, Weronika Kotkowiak, H. Jakubowski
• Year: 2015
• Venue: Amino Acids
• URL: https://www.semanticscholar.org/paper/0e9ac31119ab67e72fdaa6e9cc442fa7ed2f4642
• DOI: 10.1007/s00726-015-1956-7
• PMID: 25802182
• PMCID: 4458266
• Citations: 93
• Influential citations: 3
• Summary: It is found that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
• Evidence snippets:
• Snippet 1 (score: 0.414) > lead to the accumulation of Hcy and its metabolites in the blood-hyperhomocysteinemia (HHcy)-which is an independent risk factor for cardiovascular disease (CVD) and causes endothelial dysfunction, a hallmark of atherosclerosis (Dayal and Lentz 2008). However, molecular mechanisms underlying the pathophysiology of HHcy are not fully understood (Jakubowski 2011(Jakubowski , 2013;;Perla-Kajan et al. 2007). One hypothesis states that metabolic conversion of Hcy to Hcythiolactone initiates a pathway that leads to pathologies associated with HHcy (Jakubowski 1997a(Jakubowski , 1999(Jakubowski , 2007)). Hcy-thiolactone is chemically reactive and modifies ε-amino groups of protein lysine residues, which generates immunogenic and toxic N-homocysteinylated protein (N-Hcy-protein) (Jakubowski 2008(Jakubowski , 2013;;Jakubowski et al. 2000). > In humans and mice, HHcy leads to the accumulation of Hcy-thiolactone and N-Hcy-protein, in addition to Hcy (Chwatko et al. 2007;Jakubowski et al. 2008Jakubowski et al. , 2009)). We and other investigators have shown that HHcy induces changes in gene expression in mouse models that are associated with atherothrombotic disease (Devlin et al. 2005;DiBello et al. 2010;Ingrosso et al. 2003;Kim et al. 2011;Pogribny et al. 2008;Sharma et al. 2006;Suszynska-Zajczyk et al. 2014a, b, c, d). However, it is not known what mechanism(s) are involved and which metabolite-Hcy itself, Hcy-thiolactone, or N-Hcy-protein-is responsible for changes in gene expression. > The key to understanding mechanisms by which HHcy disrupts normal cellular function and ultimately causes disease is to identify genes whose expression is affected by individual Hcy metabolites.

[13] Identification of Key Genes and Pathways in Persistent Hyperplastic Primary Vitreous of the Eye Using Bioinformatic Analysis

• Authors: D. M. Thomas, C. Kannabiran, D. Balasubramanian
• Year: 2021
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/590b9d8ba80ae0e43134cce7329e7da927fb434f
• DOI: 10.3389/fmed.2021.690594
• PMID: 34485332
• PMCID: 8409525
• Citations: 17
• Summary: A comprehensive analysis using bioinformatics to identify the key genes and molecular pathways associated with PHPV, and to evaluate potential therapeutic agents for disease management revealed 14 potential genes, 4 major pathways, 7 drug gene targets, and 26 candidate drugs that could provide the basis of novel targeted therapies for targeted treatment and management of PHPV.
• Evidence snippets:
• Snippet 1 (score: 0.411) > Depending on the ocular pathology of PHPV, the limbal and pars plicata incisions are the two most frequent surgical incision methods (24). The most common criteria for surgical intervention are severe media opacities due to cataract or retrolental membranes, progressive anterior chamber shallowing due to cataract, uncontrolled glaucoma or secondary ocular hypotony related to ciliary process dragging, vitreous hemorrhage, and retinal detachment following vitreoretinal traction (5,25). In cases with advanced pathology, such as acute optic nerve hypoplasia, severe retinal detachment, or microphthalmia, surgery is not a preferred choice since post-operative vision is often low (24). Non-surgical management is currently used in non-progressive conditions and patients with noncentral opacity that does not cause any visual impairment. If a non-surgical alternative is used, diligent follow-up should be carried out to detect any potential risks, such as cataract progression or glaucoma (26). The disease's heterogeneity continues to render PHPV diagnosis and treatment challenging. > Since PHPV is a rare disease, understanding the mechanisms that constitute a group of phenotypes is often restricted by small sampling sizes. Therefore, comprehending the molecular mechanisms underlying the expression of the mutated gene, which leads to improper vascular remodeling and the formation of PHPV is often individual-specific and critical for diagnosis, prevention, and therapeutic management. The assessment and analysis of molecular pathways and genetic variant analysis using conventional variant detection FIGURE 2 | Summary of the study design and methodology flowchart. Text mining was conducted using pubmed2ensembl to identify genes associated with persistent hyperplastic primary vitreous (PHPV). GeneCodis was used to detect genes enriched in Gene Ontology (GO) biological process terms and KEGG pathways. STRING and MCODE software were used to construct a protein-protein interaction network and identify modules. The GO biological process terms and KEGG pathways were analyzed using DAVID, ClueGO, and ShinyGo. The drug list was compiled based on the gene-drug interaction using the drug-gene interaction database (DGIdb).

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

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.410) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[15] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

• Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
• Year: 2024
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
• DOI: 10.3389/fmed.2024.1425038
• PMID: 39135718
• PMCID: 11317438
• Citations: 1
• Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[16] Clinical and Molecular Aspects of C2orf71/PCARE in Retinal Diseases

• Authors: Maddalen Zufiaurre-Seijo, J. Garcia-Arumi, A. Duarri
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/40826eee3452ecc763b0b4fc661e205ed443e9ec
• DOI: 10.3390/ijms241310670
• PMID: 37445847
• PMCID: 10341768
• Citations: 5
• Summary: This study summarizes the current understanding of C2orf71-related retinal diseases, including their clinical manifestations and an unclear genotype-phenotype correlation, and discusses molecular and functional studies on the photoreceptor-specific ciliary PCARE, focusing on the Photoreceptor cell and its ciliary axoneme.
• Evidence snippets:
• Snippet 1 (score: 0.407) > In this review, we discussed C2orf71/PCARE-related human retinal ciliopathies and the respective models, focusing on their function, localization, and interactors. We have emphasized the importance of PCARE localization into multiple cilia compartments, where several proteins express differently, frequently interacting with proteins from neighboring or similar compartments. A consistent examination of tissue expression patterns is essential for determining the significance of this gene in the retina and other relevant cell types and whether similar mechanisms and signaling pathways are involved. A comparative functional investigation of distinct pathogenic mechanisms will be possible by standardizing the data acquired for each mutation. At various stages of RP54 or CRD degeneration, the histology of the retina, with a focus on the photoreceptor layer, must be documented. Electron microscopy in longitudinal and cross-sectional sections of the junction between the inner and outer segments might be useful in identifying structural defects induced by PCARE mutations. Understanding how mutations in this particular ciliary gene lead to diverse clinical symptoms is required for linking clinical diagnosis with molecular identification. Moreover, establishing better C2orf71 patient-derived in vitro models, such as human retinal organoids, would open new approaches to studying relevant pathogenic mechanisms and structural defects and offer the possibility of developing novel and efficient therapies. Still, some questions remain. For instance, what factors contribute to variation in genotype-phenotype correlations? Why is there this variability in the age of onset? May the PCARE protein have other tissue-specific functions? And if so, why is it not described as syndromic RP or CRD? Targeting the photoreceptor cilium and ciliary genes may be a possible strategy for the treatment or prevention of retinal ciliopathies, given the important function of the photoreceptor cilium and the significant number of ciliary gene mutations that have been found in various retinal disorders. Particularly for gene augmentation and antisense-oligo nucleotide-based therapies, considerable progress has been made in refining the drug formulation and delivery techniques. Today, more research is being conducted on drugs targeting the proteostasis network to create more broadly applicable cures.

[17] 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: 0.406) > 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

[18] Proteogenomic characterization of MiT family translocation renal cell carcinoma

• Authors: Y. Qu, Xiaohui Wu, Aihetaimujiang Anwaier, Jinwen Feng, Wenhao Xu et al.
• Year: 2022
• Venue: Nature Communications
• URL: https://www.semanticscholar.org/paper/988de9f78d8ccfd7f0630a61c9c0fe14b53b18ba
• DOI: 10.1038/s41467-022-34460-w
• PMID: 36470859
• PMCID: 9722939
• Citations: 44
• Influential citations: 4
• Summary: The comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues reveals dysregulation of DNA repair, mTOR signalling and metabolic processes and identifies mTOR signaling pathway as a potential therapeutic target.
• Evidence snippets:
• Snippet 1 (score: 0.406) > Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication. The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.

[19] Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

• Authors: Anna J. Esser, Srijan Mukherjee, I. A. Dereven’kov, S. Makarov, D. Jacobsen et al.
• Year: 2022
• Venue: iScience
• URL: https://www.semanticscholar.org/paper/84dc9a5341805b0d8a66dcc8fd59f1c03e92538f
• DOI: 10.1016/j.isci.2022.104981
• PMID: 36105582
• PMCID: 9464900
• Citations: 18
• Summary: Current knowledge on the cblC disease, structure–function relationships of the MMACHC protein, the genotypic and phenotypic spectra in humans, experimental disease models, and promising therapies are covered.
• Evidence snippets:
• Snippet 1 (score: 0.404) > The complex molecular consequences of MMACHC mutations that lead to cblC disease remain enigmatic. Huemer et al. proposed iScience Review and impaired non-enzymatic protein functions . Whether metabolites in plasma such as Hcy and MMA are disease-causing mediators, or bystander biomarkers remains unclarified (Hannibal and Blom, 2017). For instance, Hcy is a known risk factor for arteriosclerosis and thrombotic events and Hcy lowering treatment can prevent vascular complications in cblC patients. However, other manifestations do not respond to Hcy normalization and are not sufficiently explained by the direct toxicity of metabolites. > Research over the last decade uncovered significant functional versatility of the MMACHC protein, including the biochemical characteristics of its mutants, in vitro oxidative stress owing to futile redox cycling, dysregulation of gene expression, and proteomic changes in seemingly unrelated biochemical pathways. iPSCs that could be differentiated into organ-relevant cell types promise to give insights into tissue-specific alterations in cellular cobalamin trafficking, signaling, proliferation, and differentiation, and biochemical response to drugs. Refined animal models may help to further understand the role of the MMACHC gene during organogenesis and the fundaments of the striking clinical heterogeneity. Pathogenesis and treatment response may be investigated in the scope of specific organs as well as their systemic interactions for specific pathogenic mutations. Approximately 1,000 patients worldwide have been diagnosed with cblC disease in the last 50 years . International cooperation is essential to obtain representative and adaptable insights in light of the limited case numbers. Guidelines provide best-practice orientation for a more standardized and comparable management. Despite improvements regarding timely diagnosis, early treatment and overall survival, neurological, and ophthalmological dysfunctions remain unsolved. The incorporation of cblC disease biomarkers into newborn screening will support the earliest possible interventions and facilitate the initiation of prospective studies. Prenatal diagnosis and prenatal treatment trials may play a central role in learning how to prevent in utero damage and long-term sequelae. Synthetic cobalamin derivatives that can bypass MMACHC-driven processing may be useful to treat genotypes where residual MMACHC protein expression and/or enzymatic activity

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

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 25
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.404) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

Notes

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