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

Scientific reports 2020 Aug 04

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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.

Citation

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. The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation. Scientific reports. 2020 Aug 04;10(1):13162