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The schizophrenia-associated variant in SLC39A8 alters N-glycosylation in the mouse brain

ABSTRACT: The schizophrenia-associated variant in SLC39A8 alters N-glycosylation in the mouse brain

PROVIDER: PRJNA764904 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15992466.fastq.gz	Fastqsanger.gz
	SRR15992467.fastq.gz	Fastqsanger.gz
	SRR15992468.fastq.gz	Fastqsanger.gz
	SRR15992469.fastq.gz	Fastqsanger.gz
	SRR15992470.fastq.gz	Fastqsanger.gz

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Similar Datasets

The schizophrenia-associated variant in SLC39A8 alters N-glycosylation of critical proteins in the mouse brain

Project description:A missense mutation (A391T) in the manganese transporter SLC39A8 is strongly associated with schizophrenia through GWAS, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a mouse knock-in model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. N-linked glycosylation was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, one third of all detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia such as cell adhesion molecules and neurotransmitter receptors. These findings provide a mechanistic link between a risk allele and biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia.

2022-03-08 | PXD021632 | Pride

The schizophrenia-associated variant in SLC39A8 alters N-glycosylation in the mouse brain

Project description:In this experiment we performed RNAseq from two different bran regions of wild-type and mice containing the A391T missense mutation in SLC39A8.

2021-09-23 | GSE184516 | GEO

The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain.

Project description:A missense mutation (A391T) in SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. Glycosylation of Asn residues in glycoproteins (N-glycosylation) was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one-third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia, such as cell adhesion molecules and neurotransmitter receptors that are expressed across all cell types. These findings provide a mechanistic link between a risk allele and potentially reversible biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development.

| S-EPMC9106890 | biostudies-literature

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation.

Project description:A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.

| S-EPMC7403432 | biostudies-literature

Transcriptome analyses of intestine-specific Slc39a8-KO mice

Project description:Purpose: To identify genes whose expression was altered in the intestinal epithelial cells (IECs) of Slc39a8-KO mice. Methods: Poly(A) RNA-seq Results: We identified four genes that showed changes in their expression in the Slc39a8-KO IECs.

2024-04-05 | GSE192695 | GEO

Expression data of E12.5 Slc39a8 knockout (KO) embryo heart and wild type (WT) control

Project description:Slc39a8 KO mouse embryo hearts exhibit ventricle noncompaction phenotype which becomes evident at E12.5. The goal of this experiment is to identify genes that are differentially expressed between Slc39a8 KO and WT, which may be underlying the phenotype.

2017-10-10 | GSE103673 | GEO

Neuronal SLC39A8 deficiency impairs cerebellar development and function by dysregulating brain Mn homeostasis

Project description:RNAseq was performed using cerebellum tissue of WT and neuron-specific slc39a8-KO mice

2024-08-01 | GSE217704 | GEO

Functional Schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes

Project description:Functional Schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes

| PRJNA1099689 | ENA

Functional Schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes

Project description:Recent collaborative genome wide association studies (GWAS) have identified >200 independent loci contributing to risk for schizophrenia (SCZ). The genes closest to these loci have diverse functions, supporting the potential involvement of multiple relevant biological processes; yet there is no direct evidence that individual variants are functional or directly linked to specific genes. Nevertheless, overlap with certain epigenetic marks suggest that most GWAS-implicated variants are regulatory. Based on the strength of association with SCZ and the presence of regulatory epigenetic marks, we chose one such variant near TSNARE1 and ADGRB1, rs4129585, to test for functional potential and assay differences that may drive the pathogenicity of the risk allele. We observed that the variant-containing sequence drives reporter expression in relevant neuronal populations in zebrafish. Next, we introduced each allele into human induced pluripotent cells and differentiated 4 isogenic clones homozygous for the risk allele and 5 clones homozygous for the non-risk allele into neural precursor cells. Employing RNA-seq, we found that the two alleles yield significant transcriptional differences in the expression of 109 genes at FDR <0.05 and 259 genes at FDR <0.1. We demonstrate that these genes are highly interconnected in pathways enriched for synaptic proteins, axon guidance, and regulation of synapse assembly. Exploration of genes near rs4129585 suggests that this variant does not regulate TSNARE1 transcripts, as previously thought, but may regulate the neighboring ADGRB1, a regulator of synaptogenesis. Our results suggest that rs4129585 is a functional common variant that functions in specific pathways likely involved in SCZ risk.

2024-06-12 | GSE263894 | GEO

Zinc transporter ZIP8 (SLC39A8) overexpression effect on primary mouse articular chondrocytes

Project description:Gene expression profiling of primary mouse articular chondrocyte infected with recombinant adenovirus expressing the zinc transporter ZIP8 (SLC39A8) protein. In this study, we have attempted to explore the effects of ZIP8 overexpression on mouse transcriptome and have identified numerous genes which are involved in osteoarthritis pathogenesis.

2017-10-10 | GSE104795 | GEO

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