| Title: | The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation |
| Journal: | Scientific Reports |
| Published: | 4 Aug 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32753748/ |
| DOI: | https://doi.org/10.1038/s41598-020-70108-9 |
| URL: | https://www.nature.com/articles/s41598-020-70108-9.pdf |
Publication 7497
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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.15 Authors
- 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
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