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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE184516 | GEO | 2021/09/23

REPOSITORIES: GEO

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

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

| PRJNA764904 | ENA

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

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

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

Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans.

Project description:Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0 × 10(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution.

| S-EPMC4681542 | biostudies-literature

RNA-seq analysis of Slc39a8(neo/neo) versus wild-type mice: yolk sac, placenta and fetal liver, kidney, lung, heart and cerebellum

Project description:Slc39a8 encodes ZIP8, a ubiquitous divalent cation/bicarbonate symporter expressed in pluripotent mouse embryonic stem cell; ZIP8 influxes Zn2+, Mn2+ and Fe2+. Slc39a8(neo/neo) knockdown mice globally exhibit 10-15% of wild-type ZIP8 mRNA and protein levels, and show a pleiotropic phenotype of stunted growth, neonatal lethality, multi-organ dysmorphogenesis, and dysregulated hematopoiesis manifested as severe anemia. Herein we performed transcriptomics of GD13.5 yolk sac and placenta, and GD16.5 liver, kidney, lung, heart and cerebellum, comparing Slc39a8(neo/neo) with wild-type. Meta-data analysis of differentially-expressed genes revealed 29 unique genes from all tissues –– having enriched GO categories associated with hematopoiesis and hypoxia and KEGG categories of complement, response to infection, and the coagulation cascade –– consistent with dysregulated hematopoietic stem cell fate. Based on transcription factor (TF) profiles in the JASPAR database, and searching for TF-binding sites enriched by Pscan, numerous genes encoding zinc-finger TFs and associated with hematopoietic stem cell functions were identified. We conclude that, in this mouse model, deficient ZIP8-mediated Zn2+ transport affects zinc-finger (e.g. GATA proteins) and other transcription-factors (e.g. TAL1) predominantly in yolk sac, strongly supporting the observed dysmorphogenesis and anemia phenotype.

2018-07-01 | GSE111080 | GEO

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