Dataset Information

Skipping of FCER1G Exon 2 Is Common in Human Brain But Not Associated with the Alzheimer's Disease Genetic Risk Factor rs2070902.

ABSTRACT:

Background

Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer's disease (AD) may provide insights into treatments that could reduce AD risk.

Objective

Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2.

Methods

AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR.

Results

The protein encoded by FCER1G, FcRγ, is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon 2 (D2-FCER1G) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype.

Conclusions

In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902.

SUBMITTER: Feldner AC

PROVIDER: S-EPMC10741965 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Skipping of <i>FCER1G</i> Exon 2 Is Common in Human Brain But Not Associated with the Alzheimer's Disease Genetic Risk Factor rs2070902.

Feldner Alyssa C AC Turner Andrew K AK Simpson James F JF Estus Steven S

Journal of Alzheimer's disease reports 20231130 1

<h4>Background</h4>Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer's disease (AD) may provide insights into treatments that could reduce AD risk.<h4>Objective</h4>Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of <i>FCER1G</i> exon 2.<h4>Methods</h4>AD and non-AD brain samples were analyzed for <i>FCER1G</i> expression by genotyping, immunohistochemistry, immunofluore ...[more]

PMID: 38143775

Similar Datasets

Project description:BackgroundAt least 90% of human genes are alternatively spliced. Alternative splicing has an important function regulating gene expression and miss-splicing can contribute to risk for human diseases, including Alzheimer's disease (AD).MethodsWe developed a splicing decision model as a molecular mechanism to identify functional exon skipping events and genetic variation affecting alternative splicing on a genome-wide scale by integrating genomics, transcriptomics, and neuroimaging data in a systems biology approach. In this study, we analyzed RNA-Seq data of hippocampus brain tissue from Alzheimer's disease (AD; n = 24) and cognitively normal elderly controls (CN; n = 50) and identified three exon skipping events in two genes (RELN and NOS1) as significantly associated with AD (corrected p-value < 0.05 and fold change > 1.5). Next, we identified single-nucleotide polymorphisms (SNPs) affecting exon skipping events using the splicing decision model and then performed an association analysis of SNPs potentially affecting three exon skipping events with a global cortical measure of amyloid-β deposition measured by [18F] Florbetapir position emission tomography (PET) scan as an AD-related quantitative phenotype. A whole-brain voxel-based analysis was also performed.ResultsTwo exons in RELN and one exon in NOS1 showed significantly lower expression levels in the AD participants compared to CN participants, suggesting that the exons tend to be skipped more in AD. We also showed the loss of the core protein structure due to the skipped exons using the protein 3D structure analysis. The targeted SNP-based association analysis identified one intronic SNP (rs362771) adjacent to the skipped exon 24 in RELN as significantly associated with cortical amyloid-β levels (corrected p-value < 0.05). This SNP is within the splicing regulatory element, i.e., intronic splicing enhancer. The minor allele of rs362771 conferred decreases in cortical amyloid-β levels in the right temporal and bilateral parietal lobes.ConclusionsOur results suggest that exon skipping events and splicing-affecting SNPs in the human hippocampus may contribute to AD pathogenesis. Integration of multiple omics and neuroimaging data provides insights into possible mechanisms underlying AD pathophysiology through exon skipping and may help identify novel therapeutic targets.

Project description:Exon skipping (ES), the most common alternative splicing event, has been reported to contribute to diverse human diseases due to the loss of functional domains/sites or frameshifting of the open reading frame (ORF) and noticed as therapeutic targets. Accumulating transcriptomic studies of aging brains show the splicing disruption is a widespread hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Here, we built ExonSkipAD, the ES annotation database aiming to provide a resource/reference for functional annotation of ES events in AD and identify therapeutic targets in exon units. We identified 16 414 genes that have ~156 K, ~ 69 K, ~ 231 K ES events from the three representative AD cohorts of ROSMAP, MSBB and Mayo, respectively. For these ES events, we performed multiple functional annotations relating to ES mechanisms or downstream. Specifically, through the functional feature retention studies followed by the open reading frames (ORFs), we identified 275 important cellular regulators that might lose their cellular regulator roles due to exon skipping in AD. ExonSkipAD provides twelve categories of annotations: gene summary, gene structures and expression levels, exon skipping events with PSIs, ORF annotation, exon skipping events in the canonical protein sequence, 3'-UTR located exon skipping events lost miRNA-binding sites, SNversus in the skipped exons with a depth of coverage, AD stage-associated exon skipping events, splicing quantitative trait loci (sQTLs) in the skipped exons, correlation with RNA-binding proteins, and related drugs & diseases. ExonSkipAD will be a unique resource of transcriptomic diversity research for understanding the mechanisms of neurodegenerative disease development and identifying potential therapeutic targets in AD. Significance AS the first comprehensive resource of the functional genomics of the alternative splicing events in AD, ExonSkipAD will be useful for many researchers in the fields of pathology, AD genomics and precision medicine, and pharmaceutical and therapeutic researches.