Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2761 - 2774

Published: April 23, 2024

Abstract SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe profound impairments other conditions. To advance understanding of clinical phenotypes their relationship function, 81 patients (36 female, 44%, median age 5.4 years) 69 unique SCN2A variants were systematically phenotyped assessed. Participants recruited through FamileSCN2A Foundation. Primary phenotype (epilepsy neonatal onset, n = 27; infant 18; later onset 24; without seizures, 12) was strongly correlated a non-seizure severity index (P 0.002), which based on presence gross motor, fine communication abilities, gastrostomy tube dependence diagnosis cortical visual impairment scoliosis. Non-seizure greatest neonatal-onset group least 0.002). Children lowest indices still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score 49.5 (>3 standard deviations below norm-referenced mean test). Epileptic spasms significantly more common infant-onset (67%) than (22%) or later-onset (29%) epilepsy 0.007). also variant < 0.0001); gain-of-function mixed predominated shifting moderate loss complete groups. Exploratory cluster analysis identified five groups, representing: (i) primarily loss-of-function low indices; (ii) mostly but higher (iii) late-onset only, (mostly zero) severe/complete variants. Two exclusively clusters distinguished from each largely scores secondarily function. The between primary emphasizes role developmental factors differential expression effects depends combination at seizure (primary phenotype) As precision therapies for towards trials, knowledge disease will be valuable identifying appropriate these trials selecting efficient outcomes.

Language: Английский

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A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks

Genes & Development, Journal Year: 2024, Volume and Issue: 38(1-2), P. 11 - 30

Published: Jan. 1, 2024

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, known pre-mRNA splicing factor, mutated some ALS patients. Here, two human cell models were generated to investigate how mutation the C-terminal low-complexity domain (LCD) can cause changes thousands transcripts that collectively are DNA damage response, cilium organization, and translation. We show D262V mutant protein binds new binding sites on differentially spliced from genes ALS. demonstrate ALS-linked alters normal RNA-dependent protein–protein interactions. Furthermore, cells expressing exhibit aggregation phenotype, markedly reduced growth rates, stress granule kinetics, aberrant neuronal processes. This study provides insight into single amino acid factor alter RNA networks

Language: Английский

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MicroRNA-mediated regulation of nonsense-mediated mRNA decay factors: Insights into microRNA prediction tools and profiling techniques

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Journal Year: 2024, Volume and Issue: 1867(2), P. 195022 - 195022

Published: March 2, 2024

Language: Английский

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Alternative Splicing Alterations in Patients With Amyotrophic Lateral Sclerosis: Link to the Disruption of TAR DNA‐Binding Protein 43 kDa Functions

Neurology and Clinical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

ABSTRACT Background Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that causes degeneration of both upper and lower motor neurons. TAR DNA‐binding protein 43 kDa (TDP‐43) mislocalized in the neurons patients with ALS. TDP‐43 regulates RNA metabolism, including alternative splicing. Although dysregulation splicing by supposed to have key role ALS pathology, nature aberrant tissues has not been well studied. Aim To screen for alterations find those linked pathology. Methods Postmortem human tissue samples were collected from brain banks subjected sequencing polymerase chain reaction analyses. Results We identified 16 novel genes exhibited significant changes. In addition, TDP‐43‐deficient SH‐SY5Y cells, five similar patterns, indicating part altered regulated TDP‐43. Conclusion further studies on pathological significance these changes are needed, they potential serve as therapeutic targets treatment

Language: Английский

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Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 11, 2025

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later of life, when age-related changes are occurring. To identify molecular early course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) neurons performed longitudinal bulk transcriptomics proteomics on brains at six time points across lifespan compared data to healthy control flies as well human post-mortem brain datasets. We found that translational energy metabolism pathways were downregulated αSyn earliest timepoints; comparison with aged suggests elevated accelerates associated normal aging. Unexpectedly, single-cell analysis a mid-disease stage revealed upregulate protein synthesis nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches animal models can thus help elucidate cascades underlying neurodegeneration vs. aging co-pathologies.

Language: Английский

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Genomics of diffusion-imaging integrating GWAS, exome data and single-cell sequencing unravels lifespan determinants of cerebral small vessel disease

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Peak width of skeletonized mean diffusivity (PSMD) is an emerging automated diffusion imaging marker showing clinically relevant changes in cerebral small vessel disease (cSVD), a leading cause stroke and dementia with no mechanism-based treatment. We conducted genome-wide association study PSMD 58,403 participants from 24 population-based cohorts (89% European, 10% East-Asian, 1% African-American), identifying 31 independent common variant associations. Additionally, whole-exome sequencing analysis 32,957 yielded associations single burden rare coding variants four novel genes. Mendelian randomization supported causal higher blood pressure larger values, increased risk stroke, especially intracerebral hemorrhage. Strikingly, genetic susceptibility to white matter hyperintensities, established MRI-marker cSVD, was associated early childhood older age, prominent lifespan effects for VCAN SMG6. Leveraging unique brain single-cell resources we showed temporal the cell-type specificity these genes developing overall enrichment loci expressed fetal endothelial cells. Finally, through extensive integration multi-omics resources, provide precious leads gene prioritization accelerate drug discovery cSVD.

Language: Английский

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RNA‐binding proteins in pain

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2024, Volume and Issue: 15(2)

Published: March 1, 2024

Abstract RNAs are meticulously controlled by proteins. Through direct and indirect associations, every facet in the brief life of an mRNA is subject to regulation. R NA‐ b inding p roteins (RBPs) permeate biology. Here, we focus on their roles pain. Chronic pain among largest challenges facing medicine requires new strategies. Mounting pharmacologic genetic evidence obtained pre‐clinical models suggests fundamental for a broad array RBPs. We describe diverse that span RNA modification, splicing, stability, translation, decay. Finally, highlight opportunities expand our understanding regulatory interactions contribute signaling. This article categorized under: Interactions with Proteins Other Molecules > Protein‐RNA Interactions: Functional Implications Translation Regulation Disease Development

Language: Английский

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ZMAT2 condensates regulate the alternative splicing of TRIM28 to reduce cellular ROS accumulation, thereby promoting the proliferation of HCC cells

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 20, 2024

Dysregulation of splicing factor expression plays a crucial role in the progression hepatocellular carcinoma (HCC). Our research found that level ZMAT2 was increased HCC, promoting proliferation HCC cells. RNAseq data indicated absence induced skipping exon mRNA, while RIPseq further revealed mRNA binding motifs ZMAT2. A comprehensive analysis and indicateed played maturation process TRIM28 mRNA. Knocking down led to deletion 25 bases 11 TRIM28, ultimately resulting nonsense-mediated decay (NMD). could regulate reduce accumulation ROS cells, thereby their proliferation. also discovered capable undergoing phase separation, formation liquid droplet condensates within Additionally, it able form protein-nucleic acid with In summary, this study is first reveal condensates, regulating The leads upregulated reduced accumulation, accelerating

Language: Английский

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Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

Language: Английский

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Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated transcriptome in human cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 8, 2024

The helicase UPF1 acts as the central essential factor in human nonsense-mediated mRNA decay (NMD) and is involved various other degradation processes. Given its multifunctionality, distinguishing between mRNAs regulated directly indirectly by remains a critical challenge. We engineered two different conditional degron tags into endogenous cell lines to probe consequences of rapid depletion. inhibits NMD within hours strongly stabilizes substrates, which can be classified groups based on their expression kinetics. Extended depletion results massive transcript isoform alterations, partially driven secondary effects. define high-confidence UPF1-regulated core set transcripts, consists mostly substrates. NMD-regulated genes are brain development integrated stress response, among biological In summary, systems rapidly inhibit NMD, providing valuable insights roles across experimental systems.

Language: Английский

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