Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

Wen, Lai; Vann, David R.; Doulias, Paschalis‐Thomas; Wang, Tao; Landesberg, Gavin; Li, Xueli; Ricciotti, Emanuela; Scalia, Rosario; He, Miao; Hand, Nicholas J.; Rader, Daniel J.

doi:10.1172/jci90896

Cited by 138 publications

(155 citation statements)

References 52 publications

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“…Relative abundance of A2G1S1, a monosialo-monogalacto bi-antennary N-glycan with permethylated m/z of 2227, is consistently elevated in plasma/serum across multiple CDGs (34), and was the only N-glycan reported as significantly elevated by Rader and colleagues in A391T homozygotes (28). Both subject A and subject B show increased A2G1S1 at baseline that decreased following Mn treatment (A 2.246% -> 0.652% with Mn; B 1.650% -> 0.622% with Mn; CC 0.439%) (Supp.…”

Section: Slc39a8-cdg Patients Have Increased Precursor N-glycans and mentioning

confidence: 89%

“…The plasma N-glycome is increasingly explored as a potential biomarker in a variety of settings including depression (52-54), pregnancy (55), IBD (56), Down syndrome (57), inflammation and metabolic health (58), and post-surgical changes (59). Given the repeated association of SLC39A8 with glycosylation defects in prior studies (25)(26)(27)(28)38), and the exquisite sensitivity of certain glycosyltransferases for Mn as an irreplaceable co-factor, we focused our study on glycosylation changes in A391T carriers.…”

Section: Discussionmentioning

confidence: 99%

“…Serum protein N-glycans analyzed by MALDI-TOF in these mice was suggestive of impaired N-glycosylation. Analysis of plasma N-glycans in human rs13107325 homozygous minor allele carriers (n=12) showed a slight but significant increase in one N-glycan precursor (monosialo-monogalacto-biantennary glycan, abbreviated A2G1S1), though a complete N-glycan analysis was not reported (28).…”

mentioning

confidence: 98%

“…Importantly, a marker of impaired glycosylation and some clinical phenotypes such as seizure activity improved following supplementation with glycosylation precursors (galactose and uridine) or Mn (25,27). A recent study by Rader and colleagues showed that SLC39A8 regulated Mn homeostasis through uptake from bile in inducible-and liver-specific-knockout mice (28). Serum protein N-glycans analyzed by MALDI-TOF in these mice was suggestive of impaired N-glycosylation.…”

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confidence: 98%

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

Mealer

Jenkins

Chen

et al. 2019

Preprint

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A common missense variant (rs13107325 (C->T), A391T) in SLC39A8, a gene encoding a transporter of divalent cations including manganese (Mn), is convincingly associated with schizophrenia and has pleiotropic effects on several additional brain-related phenotypes.Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum Mn and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified Mn-related changes in human carriers of the SLC39A8 missense allele. Analysis of structural brain MRI scans from the UK Biobank showed a dose-dependent change in the ratio of T2w to T1w signal in several brain regions, presumably from altered transport of paramagnetic cations including Mn. We confirmed a specific reduction of serum Mn and showed through comprehensive profiling reduced complexity and branching of the plasma protein N-glycome in both heterozygous and homozygous minor allele carriers. N-glycome profiling of two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that hypofunction of the common missense variant exists on a spectrum with potential for reversibility.Characterizing the functional impact of this variant may enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.

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Section: Slc39a8-cdg Patients Have Increased Precursor N-glycans and mentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 98%

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

Mealer

Jenkins

Chen

et al. 2019

Preprint

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“…Further qRT-PCR analysis on single-cell populations isolated by fluorescence-activated cell sorting (FACS) demonstrated that Slc39a8 was expressed in cardiac endothelial cells of E12.5 hearts (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/ JCI96993DS1). To study the role of Slc39a8 in cardiac ventricular morphogenesis, we generated Slc39a8 -/-mice by removing the third exon of the Slc39a8 gene (26). Slc39a8 mRNA was efficiently deleted in the Slc39a8 -/-hearts ( Figure 1C).…”

Section: Slc39a8 Is Expressed In the Developing Heart And Regulates Zmentioning

confidence: 99%

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Wen¹,

Li²,

Cheng³

et al. 2018

Journal of Clinical Investigation

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Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

et al. 2019

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Key Points Question Is there any genetic variant associated with adolescent brain development that can inform psychopathology of schizophrenia? Findings In this imaging genetics study of brain structure, a significant association between a missense mutation in SLC39A8 (a gene previously associated with schizophrenia) and gray matter volume in putamen was discovered and replicated using 10 411 healthy participants from 5 independent studies. Compared with healthy control individuals, such association was significantly weakened in both patients with schizophrenia and unaffected siblings. Meaning Common genetic variant indicates an involvement of neuronal ion transport in both pathophysiology of schizophrenia and structural development of putamen.

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Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

Cited by 138 publications

References 52 publications

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

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

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

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