Relating enhancer genetic variation across mammals to complex phenotypes using machine learning

Science, Journal Year: 2023, Volume and Issue: 380(6643)

Published: April 27, 2023

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent functionally conserved despite low sequence conservation. We developed Tissue-Aware Conservation Inference Toolkit (TACIT) associate candidate with species' using predictions from machine learning models trained on specific tissues. Applying TACIT motor cortex parvalbumin-positive interneuron neurological revealed dozens enhancer-phenotype associations, including brain size-associated interact genes implicated in microcephaly or macrocephaly. provides a foundation for identifying associated evolution any convergently evolved phenotype large group aligned genomes.

Language: Английский

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Trigeminal neuralgia

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: May 30, 2024

Language: Английский

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Central and peripheral contributions of T-type calcium channels in pain

Molecular Brain, Journal Year: 2022, Volume and Issue: 15(1)

Published: May 2, 2022

Abstract Chronic pain is a severely debilitating condition that reflects long-term sensitization of signal transduction in the afferent pathway. Among key players this pathway are T-type calcium channels, particular Ca v 3.2 isoform. Because their biophysical characteristics, these channels ideally suited towards regulating neuronal excitability. Recent evidence suggests contribute to excitability neurons all along ascending and descending pathways, within primary neurons, spinal dorsal horn pain-processing midbrain cortex. Here we review contribution function each populations how they dysregulated chronic conditions. Finally, discuss molecular pharmacology potential role as therapeutic targets for pain.

Language: Английский

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A multi-ancestry genetic study of pain intensity in 598,339 veterans

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1075 - 1084

Published: March 1, 2024

Language: Английский

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CaV3.2 calcium channels contribute to trigeminal neuralgia

Pain, Journal Year: 2022, Volume and Issue: 163(12), P. 2315 - 2325

Published: April 20, 2022

Trigeminal neuralgia (TN) is a rare but debilitating disorder characterized by excruciating facial pain, with higher incidence in women. Recent studies demonstrated that TN patients present mutations the gene encoding Ca V 3.2 T-type calcium channel, an important player peripheral pain pathways. We characterize role of channels at 2 levels. First, we examined biophysical properties CACNA1H variants found patients. Second, investigated animal model trigeminal neuropathic pain. Whole-cell patch-clamp recordings from 4 different mutants expressed tsA-201 cells (E286K pore loop domain I, H526Y, G563R, and P566T I-II linker) identified loss function activation E286K mutation gain G563R mutations. Moreover, inactivation was observed H526Y Cell surface biotinylation revealed no difference channel trafficking among variants. The mutant also caused firing transfected ganglion neurons. In female male mice, constriction infraorbital nerve induced thermal heat hyperalgesia. Block Z944 resulted antihyperalgesia. effect absent -/- indicating molecular target antihyperalgesic effect. Finally, enzyme-linked immunosorbent assay analysis increased expression spinal subnucleus caudalis. Altogether, study demonstrates

Language: Английский

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Trigeminal neuralgia and genetics: A systematic review

Molecular Pain, Journal Year: 2021, Volume and Issue: 17

Published: Jan. 1, 2021

Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed systematic study asking prevalence familial trigeminal neuralgia, which genes that have been identified human TN studies animal models pain. MedLine, Embase, Cochrane Library Web Science were searched from inception to January 2021. 71 included review. Currently, few provide information TN; available evidence indicates 1–2% cases form. The propose following be possible contributors development TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene SLC6A4. Their role still needs addressed. experimental suggest an emerging pain, though may more relevant for neuropathic than per se. In summary, this review suggests important factors pathogenesis previously assumed.

Language: Английский

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Intranasal CRMP2-Ubc9 inhibitor regulates NaV1.7 to alleviate trigeminal neuropathic pain

Pain, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 26, 2023

Abstract Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that results part from increased SUMOylation collapsin response mediator protein 2 (CRMP2), leading an CRMP2/Na interaction and functional activity 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 mediated by the SUMO-conjugating enzyme Ubc9. further demonstrated effectively reduces dorsal root ganglia alleviated inflammatory Here, used a comprehensive array approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, behavioral analyses, assess implications regulation (TG) neurons. confirmed expression Scn9a Dpysl2 UBE2I within TG Furthermore, found between 1.7, with being SUMOylated these ganglia. Disrupting uncoupled interaction, impeded diffusion on plasma membrane, subsequently diminished activity. Compound also led reduction neuron excitability. Finally, when intranasally administered rats constriction injury infraorbital nerve, significantly decreased nociceptive behaviors. Collectively, our findings underscore critical role regulating neurons, emphasizing importance indirect modulation

Language: Английский

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Rare variant analyses in large-scale cohorts identified SLC13A1 associated with chronic pain

Pain, Journal Year: 2023, Volume and Issue: 164(8), P. 1841 - 1851

Published: March 21, 2023

Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in chronic patients have identified hundreds of common pathogenic variants, yet they only explained portion individual variance pain. With the advances next-generation sequencing technologies, it now feasible to conduct rarer variants large-scale databases. Here, we performed gene-based rare variant analyses 200,000 human subjects UK biobank whole-exome database for investigating 9 different states and validated our findings 3 other Our SLC13A1 gene coding sodium/sulfate symporter associated back multisite at genome-wide level headache, knee, neck shoulder nominal level. Seven loss-of-function were within locus potentially contributing development pain, 2 them individually These then tested replication biobanks, strongest evidence was found rs28364172 as an contributor. Transcriptional Slc13a1 rodents showed substantial regulation its expression dorsal root ganglia sciatic nerve neuropathic assays. results stress importance sulfate homeostasis nervous system critical role preventing states, thus suggesting new therapeutic approaches treating personalized manner, especially people mutations gene.

Language: Английский

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Progress in animal models of trigeminal neuralgia

Archives of Oral Biology, Journal Year: 2023, Volume and Issue: 154, P. 105765 - 105765

Published: July 12, 2023

Language: Английский

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MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response

The Journal of Headache and Pain, Journal Year: 2023, Volume and Issue: 24(1)

Published: Jan. 14, 2023

Abstract Background While new genetic analysis methods are widely used in the clinic, few researchers have focused on trigeminal neuralgia (TN) with familial clustering (≥ 2 TN patients one kindred family). Previous literature suggests that (FTN) may be associated inherited factors. To date, next-generation sequencing studies been reported for FTN. This study investigated pathogenic mechanism of FTN by using whole-exome (WES) technology, which enhance our understanding human pathophysiology. Method We performed WES 7 probands from families Sanger was two control groups (FTN family members group and nonfamilial subject group) to potentially identify FTN-related gene mutations. In where carried mutations, ribonucleic acid (RNA) related members, as well were analysed RNA (RNA-seq) confirm differential expression. Results Seven derived 3 Chinese families. identified MARS1 mutation c.2398C > A p.(Pro800Thr) Family 1. confirmed 14/26 [53.8%] 1 member group, while none subjects had this mutation. RNA-seq showed higher expression Fosl1 (Fos-like antigen 1) NFE2 (Nuclear factor, erythroid 2) than group. genes integrated stress response (ISR). Conclusion mutations cause chronic activation ISR, contribute ISR pathophysiological changes FTN, cause/accelerate peripheral nerve degeneration. The findings can enrich knowledge role molecular genetics humans.

Language: Английский

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