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

Robert G. Mealer; Bruce G. Jenkins; Chia Yen Chen; Mark J. Daly; Tian Ge; Sylvain Lehoux; Thorsten Marquardt; Christopher D. Palmer; Julien H. Park; Patrick J. Parsons; Robert Sackstein; Sarah E. Williams; Richard D. Cummings; Edward M. Scolnick; Jordan W. Smoller

doi:10.1038/s41598-020-70108-9

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

Robert G. Mealer
, Bruce G. Jenkins
, Chia Yen Chen
, Mark J. Daly
, Tian Ge
, Sylvain Lehoux
, Thorsten Marquardt
, Christopher D. Palmer
, Julien H. Park
, Patrick J. Parsons
, Robert Sackstein
, Sarah E. Williams
, Richard D. Cummings
, Edward M. Scolnick
, Jordan W. Smoller

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

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.

Original language	English
Article number	13162
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-70108-9
State	Published - 1 Dec 2020
Externally published	Yes

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Mealer, R. G., Jenkins, B. G., Chen, C. Y., Daly, M. J., Ge, T., Lehoux, S., Marquardt, T., Palmer, C. D., Park, J. H., Parsons, P. J., Sackstein, R., Williams, S. E., Cummings, R. D., Scolnick, E. M., & Smoller, J. W. (2020). The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation. Scientific Reports, 10(1), Article 13162. https://doi.org/10.1038/s41598-020-70108-9

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title = "The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation",

abstract = "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.",

author = "Mealer, \{Robert G.\} and Jenkins, \{Bruce G.\} and Chen, \{Chia Yen\} and Daly, \{Mark J.\} and Tian Ge and Sylvain Lehoux and Thorsten Marquardt and Palmer, \{Christopher D.\} and Park, \{Julien H.\} and Parsons, \{Patrick J.\} and Robert Sackstein and Williams, \{Sarah E.\} and Cummings, \{Richard D.\} and Scolnick, \{Edward M.\} and Smoller, \{Jordan W.\}",

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AU - Mealer, Robert G.

AU - Jenkins, Bruce G.

AU - Chen, Chia Yen

AU - Daly, Mark J.

AU - Ge, Tian

AU - Lehoux, Sylvain

AU - Marquardt, Thorsten

AU - Palmer, Christopher D.

AU - Park, Julien H.

AU - Parsons, Patrick J.

AU - Sackstein, Robert

AU - Williams, Sarah E.

AU - Cummings, Richard D.

AU - Scolnick, Edward M.

AU - Smoller, Jordan W.

PY - 2020/12/1

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N2 - 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.

AB - 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.

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JO - Scientific Reports

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

Abstract

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