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Hereditary Hyperekplexia

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Hyperekplexia. Core disease mechanisms, molecular and cellular...

2026-05-10
Asta MONDO:0021022 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Hyperekplexia. 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] A Novel Dominant Hyperekplexia Mutation Y705C Alters Trafficking and Biochemical Properties of the Presynaptic Glycine Transporter GlyT2*

  • Authors: C. Giménez, G. Perez-siles, Jaime Martínez-Villarreal, Esther Arribas-González, E. Jiménez et al.
  • Year: 2012
  • Venue: The Journal of Biological Chemistry
  • URL: https://www.semanticscholar.org/paper/f78196744b4d80d8b28460c2906665029f69ccc9
  • DOI: 10.1074/jbc.M111.319244
  • PMID: 22753417
  • Citations: 41
  • Influential citations: 1
  • Summary: This study revealed a new dominant GlyT2 mutation pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom, and functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > Background: Hyperekplexia or startle disease is caused by defects in glycinergic transmission. Results: A new mutation pY705C in the glycine transporter GlyT2 alters protein trafficking and H+ and Zn2+ transport modulation. Conclusion: Multiple pathogenic mechanisms may contribute to the complex phenotype of individuals with the Y705C mutation. Significance: This is the first common dominant mutation associated with hyperekplexia affecting the presynaptic glycine transporter GlyT2. Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl−-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311–Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H+ and Zn2+ dependence of glycine transport that may affect the function of glycinergic neurotrans

[2] 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: 0.419) > 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.

[3] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

  • Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
  • Year: 2024
  • Venue: International Journal For Multidisciplinary Research
  • URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
  • DOI: 10.36948/ijfmr.2024.v06i03.19194
  • Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.417) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[4] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

  • Authors: O. Tsukamoto
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
  • DOI: 10.3390/ijms21010226
  • PMID: 31905684
  • PMCID: 6982115
  • Citations: 16
  • Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
  • Evidence snippets:
  • Snippet 1 (score: 0.414) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[5] Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia

  • Authors: Fei-xia Zhan, Chaoyan Zhang, Shige Wang, Zeyu Zhu, Guang Chen et al.
  • Year: 2020
  • Venue: Journal of Clinical Neurology (Seoul, Korea)
  • URL: https://www.semanticscholar.org/paper/a8d84d4ba70e71f44456d7da28f847e0464f2f7a
  • DOI: 10.3988/jcn.2020.16.2.230
  • PMID: 32319239
  • PMCID: 7174104
  • Citations: 9
  • Summary: Hyperekplexia is a treatable disease, and clonazepam is the drug of choice, and the possible pathogenic mechanisms are discussed to enhance the understanding and recognition of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.413) > Background and Purpose Hyperekplexia (HPX), a rare neurogenetic disorder, is classically characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli and followed by a shortly general stiffness. Glycine receptor alpha 1 (GLRA1) is the major pathogenic gene of the disease. We described the clinical manifestations of genetically confirmed HPX patients and made a literature review of GLRA1-related HPX to improve the early recognition and prompt the management of the disorder. Methods Extensive clinical evaluations were analyzed in 4 Chinese HPX patients from two unrelated families. Next generation sequencing was conducted in the probands. Sanger sequence and segregation analysis were applied to confirm the findings. Results All four patients including 3 males and 1 female presented with excessive startle reflex, a cautious gait and recurrent falls. Moreover, startle episodes were dramatically improved with the treatment of clonazepam in all cases. Exome sequencing revealed 2 homozygous GLRA1 mutations in the patients. The mutation c.1286T>A p.I429N has been previously reported, while c.754delC p.L252* is novel. Conclusions HPX is a treatable disease, and clonazepam is the drug of choice. By studying and reviewing the disorder, we summarized the phenotype, expanded the genotype spectrum, and discussed the possible pathogenic mechanisms to enhance the understanding and recognition of the disease. Early awareness of the disease is crucial to the prompt and proper administration, as well as the genetic counseling.

[6] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[7] 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: 4
  • 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: 0.408) > 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.

[8] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

  • Authors: Nagwa Gaboon, B. Banaganapalli, K. Nasser, M. Razeeth, Mosab S. Alsaedi et al.
  • Year: 2019
  • Venue: Saudi Journal of Biological Sciences
  • URL: https://www.semanticscholar.org/paper/f1f1341fd61e31f39a5129e7c80ff67cd0b6fb0f
  • DOI: 10.1016/j.sjbs.2019.10.001
  • PMID: 31889854
  • PMCID: 6933272
  • Citations: 17
  • Influential citations: 1
  • Summary: Genetic defects in RMND1 gene alters the mitochondrial energy metabolism leading to the accumulation of ceramide, and subsequently promote dysregulated apoptosis and tissue necrosis in kidneys, this study suggests.
  • Evidence snippets:
  • Snippet 1 (score: 0.407) > One of the recently identified nuclear genes involved in mitochondrial respiratory chain deficiencies is RMND1 (Required for Meiotic Nuclear Division protein 1) (Garcia-Diaz et al., 2012;Janer et al., 2012). It has been demonstrated that various novel and common recessive mutations in RMND1 are associated with multiple phenotypes characterized by delayed maturation of vision, developmental delay, dilated cardiomyopathy, deafness and neurological defects (Gupta et al., 2016), renal tubular acidosis type 4 presented as hyponatraemia and hyperkalaemia and cystic/hypoplastic kidneys (Ng et al., 2016). Likewise, complex clinical spectrum of patients with RMND1 mutations is emerging with infantile encephalomyopathy with lactic acidosis (Garcia-Diaz et al., 2012;Casey et al., 2016) to a less severe form of developmental delay, hypotonia, renal disease and congenital sensorineural deafness (Janer et al., 2015). Therefore, molecular screening of RMND1 gene will help identify the inheritance mode of causative genetic mutations in patients with renal and or neurological defects. > MIDs have complex etiologies with underlying cross talk of inter and intra molecular signaling. Hence, metabolomic studies on these patients could provide a better understanding of the interconnectivity between genetic and molecular networks (Davies, 2018). Metabolomic profiling examines the metabolic changes in body fluids driven from cellular processes to understand the onset and pathogenesis of disease phenotype (Abbiss et al., 2019). Metabolomics analyzes metabolites by either targeted or untargeted approaches. The untargeted approach involves hypothesis free surveying of hundreds of thousands of small molecule metabolites for discovering novel mechanisms or pathways, whereas the targeted one refers to measuring predefined sets of metabolites, typically focusing on a few pathways of interest (Kalim and Rhee, 2017). The specific relationship between inherited mutations in mitochondrial proteins and their functional impacts in terms of metabolic defects in chronic kidney disease (CKD) is not yet well characterized.

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

  • Authors: I. Condò
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
  • DOI: 10.3390/ijms23126525
  • PMID: 35742964
  • PMCID: 9223693
  • Citations: 18
  • Influential citations: 2
  • Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[10] 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: 0.401) > 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.

[11] The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes

  • Authors: A. Tokolyi, E. Persyn, A. Nath, K. Burnham, J. Marten et al.
  • Year: 2025
  • Venue: Nature Genetics
  • URL: https://www.semanticscholar.org/paper/5435e12fd796fca6db2c0ce1844b6fc252d2d73e
  • DOI: 10.1038/s41588-025-02096-3
  • PMID: 40038547
  • PMCID: 11906350
  • Citations: 14
  • Summary: This study mapped blood gene expression and splicing quantitative trait loci and uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans (https://IntervalRNA.org.uk). > The majority of genetic variants associated with common diseases and other complex traits identified through genome-wide association studies (GWAS) lie in nonprotein-coding sequences 1 . Consequently, the molecular mechanisms that underpin many of these genotype-phenotype associations are unclear. Molecular quantitative trait locus (QTL) mapping studies, which identify genetic determinants of transcript, protein or metabolite abundance, can address this knowledge gap by identifying the molecular intermediaries that mediate genetically driven disease risk. These studies can provide specific hypotheses for functional validation experiments 2,3 . > Molecular QTL data can be used for a range of biomedical applications. For example, they have the potential to identify and validate new therapeutic targets and pathways, inform about the biological mechanisms of drug action and safety, highlight new therapeutic indications and reveal clinically relevant biomarkers [4][5][6] . > Many previous studies have carried out QTL mapping within a single molecular domain such as gene or protein expression [7][8][9][10][11][12] .

[12] Insights into Muscle Degeneration from Heritable Inclusion Body Myopathies

  • Authors: S. Krause
  • Year: 2015
  • Venue: Frontiers in Aging Neuroscience
  • URL: https://www.semanticscholar.org/paper/89a3262d2815a7a07284bcb48d9a39f76ce0e582
  • DOI: 10.3389/fnagi.2015.00013
  • PMID: 25729363
  • PMCID: 4325924
  • Citations: 14
  • Influential citations: 1
  • Summary: Several intriguing clues from monogenic defects in heritable IBMs contributing to the molecular basis of muscle loss will be discussed with special emphasis on inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) and GNE myopathy.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > In conclusion, it will be essential to continue studying fundamental cellular pathways underlying muscular hypertrophy and atrophy to advance the discovery of promising targets for the development of causative and safe therapies for skeletal muscle disorders. > An encouraging approach is a novel strategy to promote muscle maintenance and delay muscular atrophy by utilizing an antibody, which modulates the activin type II receptor (ActRII) response (Lach-Trifilieff et al., 2014). The wide therapeutic spectrum holds promise to treat a variety of progressive neuromuscular conditions regardless of the underlying molecular defect. Another example of a non-disease specific treatment option is the molecular chaperone 4-phenylbutyrate (4-PBA), an FDA-approved substance to treat children suffering from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding and preventing misfolded protein accumulation and aggregation. Recently, convincing evidence was provided that 4-PBA might be also functional to resolve protein aggregates in vitro and in vivo and to improve grip strength in a mouse model for plectinopathy, a hereditary protein aggregate myopathy (Winter et al., 2014). > In summary, recent history of gene identification in hereditary inclusion body myopathies has fostered enthusiasm to facilitate detailed understanding of molecular disease mechanisms in these familial disorders. However, the involved genes show an unprecedented functional diversity. > Therefore, a plethora of key mechanisms underlying disease onset in hereditary IBMs remain to be elucidated at the molecular and physiological level, some of which may be also relevant for the etiology of sarcopenia. Neglected aspects that may be specific to the discussed hIBMs include regulation of RNA transcription and processing, cellular senescence, angiogenesis, and Z -disk architecture. > Understanding the deleterious combination of disease mechanisms in detail will be an important goal for future research to establish targeted intervention strategies and to prevent sarcopenia in those at risk to develop disease-associated or age-related muscle loss. Additionally and regardless of the underlying defect, it will be important for affected patients to immediately translate current broad understanding of muscle wasting and general advances to improve muscle function into safe, approved therapy.

[13] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

  • Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
  • Year: 2024
  • Venue: Molecular Biotechnology
  • URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
  • DOI: 10.1007/s12033-024-01133-6
  • PMID: 38565775
  • PMCID: 11928429
  • Citations: 74
  • Influential citations: 2
  • Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[14] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[15] Novel Approaches to Studying SLC13A5 Disease

  • Authors: Adriana S. Beltran
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
  • DOI: 10.3390/metabo14020084
  • PMID: 38392976
  • PMCID: 10890222
  • Citations: 2
  • Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[16] 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: 0.384) > 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.

[17] 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: 10
  • 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: 0.384) > 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.

[18] 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: 0.384) > 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.

[19] Chromatin modifiers in neurodevelopment

  • Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
  • Year: 2025
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
  • DOI: 10.3389/fnmol.2025.1551107
  • PMID: 40469903
  • PMCID: 12133960
  • Citations: 2
  • Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[20] 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: 0.383) > 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.

Notes

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