Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Cernunnos-XLF deficiency. Core disease mechanisms, molecular and cellular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

• Authors: F. Cipe, Ç. Aydoğmuş, A. Babayigit Hocaoglu, M. Kilic, Gulfem Kaya et al.
• Year: 2014
• Venue: Case Reports in Pediatrics
• URL: https://www.semanticscholar.org/paper/ecb61a50f501de25067696c2f95c1c93424dd690
• DOI: 10.1155/2014/614238
• PMID: 24511403
• PMCID: 3910469
• Citations: 25
• Influential citations: 3
• Summary: In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.
• Evidence snippets:
• Snippet 1 (score: 0.459) > Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.

[2] Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

• Authors: J. Procházková, J. Loizou
• Year: 2015
• Venue: Immunology
• URL: https://www.semanticscholar.org/paper/db00a7eb5e12821ad4bbf47c02e778a417d7ecea
• DOI: 10.1111/imm.12547
• PMID: 26455503
• PMCID: 4988471
• Citations: 17
• Summary: The mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.419) > primordial dwarfism. 69 The alterations found, substantially decrease XRCC4 protein levels leading to reduced cellular ligase IV activity and ionizing radiation-induced DNA double-strand break repair defects. However, none of the patients show signs of immune deficiency so far. 69 Moreover, another three patients from a consanguineous family and one unrelated patient with mutations in XRCC4 were identified. Similarly, the clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, in the absence of a recognizable immunological phenotype. 70 A homozygous mutation resulting in a premature stop codon and very low levels of XRCC4 transcript was found in two patients with progressive neurological defects, confirming the importance of DNA repair and XRCC4 in the brain. 71 Another mutation that destabilizes XRCC4 protein, leading to proteasomemediated degradation, was also identified recently. 72 Intriguingly, patient cells are radiosensitive and display a severe DSB repair defect but the patient only manifests with neurological defects without immune deficiency. 72 Exome sequencing of two siblings with microcephaly and gonadal failure, identified another mutation leading to an in-frame deletion of 23 amino acids, so expanding the spectrum of XRCC4 mutations. 73 In addition, Aprataxin, involved in DNA single-strand break repair, was recently shown to interact with XRCC4. Cells lacking Aprataxin show increased levels of DNA breaks and the human disease characterized by Aprataxin deficiency is associated with progressive cerebellar degeneration, ataxia and oculomotor apraxia. This condition resembles other human diseases caused by deficiency in NHEJ pathway proteins but so far, immune deficiency was not described in these patients. [74][75][76] XLF deficiency > The XRCC4-like factor (XLF, also called Cernunnos) shares sequence homology and structure similarity with XRCC4. 77 Indeed, cells depleted for XLF display increased radiosensitivity and a defect in NHEJ. 77 In addition, XLF was suggested to have overlapping functions with H2AX and 53BP1 in the assembly of DSB response factors on chromatin during V

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

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

[4] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

• Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
• Year: 2024
• Venue: Metabolites
• URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
• DOI: 10.3390/metabo14100515
• PMID: 39452896
• PMCID: 11509386
• Citations: 2
• Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
• Evidence snippets:
• Snippet 1 (score: 0.365) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[5] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.363) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

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

• Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
• DOI: 10.1002/jimd.70065
• PMID: 40714961
• PMCID: 12301291
• Citations: 3
• Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.359) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[7] Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine

• Authors: D. D’Amario, A. Gowran, F. Canonico, Elisa Castiglioni, D. Rovina et al.
• Year: 2018
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/096308b81a68a01f81baf515ae43a6a4321bac2c
• DOI: 10.3390/jcm7090291
• PMID: 30235804
• PMCID: 6162458
• Citations: 28
• Influential citations: 1
• Summary: This comprehensive review will focus on the pertinent clinical aspects of cardiac disease in muscular dystrophy while also providing a detailed consideration of the known and developing concepts in the pathophysiology of dystrophic cardiomyopathy and forthcoming therapeutic options.
• Evidence snippets:
• Snippet 1 (score: 0.358) > protein-coupled receptors [52]. Myofibres lacking dystrophin are consequently sensitive to mechanical damage and have dysregulated cellular signalling which ultimately lead to cell death and consequent loss of tissue function. Increased intracellular calcium concentration, dysregulation of nitric oxide synthase (NOS), mitochondrial malfunction, inadequate anti-oxidant response, and several genetic modifiers are all implicated in the molecular pathophysiology of MD-CM [53][54][55][56] (see Figure 2). Overall, the causal mechanisms defining the final MD cardiac phenotype likely involve nuanced activation of known and novel pathophysiological pathways acting collectively on different cell types [57]. It becomes obvious that new, more powerful, and predictive patient-specific models are required to effectively address the unanswered questions concerning MD-CM pathophysiology and to identify novel therapies that might impact causal factors. Undoubtably, the recapitulation of certain fundamental hallmarks of MD-CM e.g., specific DMD mutation, lack of dystrophin expression, increased intracellular calcium [58][59][60][61][62][63][64][65][66][67][68][69] obtained with patient-specific cardiomyocytes derived from pluripotent stem cells will make significant additions, beyond the structural hypothesis of increased sensitivity to stretch-induced damage, to our knowledge of the pathomechanisms. A schematic depicting the pathological signalling resulting from mutations in the dystrophin gene. Muscular dystrophy mutations cause dystrophin protein deficiency ranging from no expression to the generation of semi-functional truncated isoforms which result in clinically severe (e.g., Duchenne) or milder (e.g., Becker) forms of muscular dystrophies respectively.

[8] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.357) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[9] 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: 0.356) > 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].

[10] 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: 0.354) > 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.

[11] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

• Authors: Debopam Samanta
• Year: 2025
• Venue: Children
• URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
• DOI: 10.3390/children12040481
• PMID: 40310132
• PMCID: 12025602
• Citations: 19
• Influential citations: 1
• Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
• Evidence snippets:
• Snippet 1 (score: 0.353) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[12] Cernunnos defect in an Iranian patient with T− B+ NK + severe combined immunodeficiency: A case report and review of the literature

• Authors: M. Jamee, Nasrin Khakbazan Fard, Shahrzad Fallah, Zahra Golchehre, Mazdak Fallahi et al.
• Year: 2022
• Venue: Molecular Genetics & Genomic Medicine
• URL: https://www.semanticscholar.org/paper/50350d2524eceac39e88c1a8315d65ff9d53dde5
• DOI: 10.1002/mgg3.1990
• PMID: 35656589
• PMCID: 9356558
• Citations: 5
• Summary: A new patient with Cernunnos deficiency is presented and the clinical, immunological, and molecular features of reported patients in the literature are summarized.
• Evidence snippets:
• Snippet 1 (score: 0.351) > In conclusion, Cernunnos deficiency should be considered as a differential diagnosis in patients with microcephaly, growth retardation, recurrent infections, T-cell defects, and hypogammaglobulinemia. Normal B-cells should not rule out the diagnosis, as patients may display T − B + NK + phenotype.

[13] Expanding the clinical spectrum of Cernunnos/XLF deficiency: a literature review of a rare cause of severe combined immunodeficiency including a novel case

• Authors: G. Kabadayı, Ö. Atay, D. Baysal Bakır, H. Yağmur, Esma Tuğba Kasikci Mermer et al.
• Year: 2025
• Venue: BMC Immunology
• URL: https://www.semanticscholar.org/paper/e77dc46a74cf31405ff3a5a6aa65fb27c9da6578
• DOI: 10.1186/s12865-025-00774-9
• PMID: 41225329
• PMCID: 12613498
• Summary: A novel infant with Cernunnos/XLF deficiency is described, underscoring the value of early recognition and the critical role of genetic testing and hematopoietic stem cell transplantation, and expanding the clinical spectrum of this rare disease.
• Evidence snippets:
• Snippet 1 (score: 0.351) > Expanding the clinical spectrum of Cernunnos/XLF deficiency: a literature review of a rare cause of severe combined immunodeficiency including a novel case

[14] 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: 0.349) > 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.

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

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
• DOI: 10.1186/s13395-020-00240-7
• PMID: 32727611
• PMCID: 7389686
• Citations: 24
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.348) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

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

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.348) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[17] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

• Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 4
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.347) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[18] 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: 0.346) > : 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.

[19] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 9
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.345) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[20] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 92
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.343) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

Notes

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