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The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation.
Mealer, Robert G; Jenkins, Bruce G; Chen, Chia-Yen; Daly, Mark J; Ge, Tian; Lehoux, Sylvain; Marquardt, Thorsten; Palmer, Christopher D; Park, Julien H; Parsons, Patrick J; Sackstein, Robert; Williams, Sarah E; Cummings, Richard D; Scolnick, Edward M; Smoller, Jordan W.
Affiliation
  • Mealer RG; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. rmealer@partners.org.
  • Jenkins BG; The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, MA, USA. rmealer@partners.org.
  • Chen CY; National Center for Functional Glycomics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. rmealer@partners.org.
  • Daly MJ; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Ge T; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Lehoux S; The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, MA, USA.
  • Marquardt T; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Palmer CD; The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, MA, USA.
  • Park JH; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Parsons PJ; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Sackstein R; The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, MA, USA.
  • Williams SE; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • Cummings RD; National Center for Functional Glycomics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Scolnick EM; Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Münster, Germany.
  • Smoller JW; Laboratory of Inorganic and Nuclear Chemistry, Wadsworth Center, New York State Department of Health, Albany, NY, USA.
Sci Rep ; 10(1): 13162, 2020 08 04.
Article in En | MEDLINE | ID: mdl-32753748
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Brain / Cation Transport Proteins / Manganese Type of study: Etiology_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: Sci Rep Year: 2020 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Brain / Cation Transport Proteins / Manganese Type of study: Etiology_studies / Risk_factors_studies Limits: Female / Humans / Male Language: En Journal: Sci Rep Year: 2020 Document type: Article Affiliation country: Estados Unidos