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

Abstract

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.

Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis

“… 9 , 40 The LIF score is no longer used since the medical and MRI physics community is more familiar with T1 for the assessment of inflammation and fibrosis across all specialties including cardiology and neurology. 11 , 18 , [41] , [42] , [43] , [44] , [45] In this GWAS study, the cT1 values reported are standardised across the MRI scanner model and field strength, showing very high repeatability and reproducibility. 46 …”

Replication of 15 loci involved in human plasma protein N-glycosylation in 4802 samples from four cohorts

“…We speculate that alterations in SLC9A9 function might affect sialylation of bisected (addition of bisected GlcNAc) glycans via modulation of Golgi pH. Interestingly, strong defects in another solute carrier, a manganese transporter SLC38A9 (Mn 2+ cations are important cofactors for normal Golgi functioning (Breton et al 2006)), lead to a congenital disorder of glycosylation (Park et al 2015), while the common missense variant rs13107325 in this gene was found to be associated with weak changes in the plasma protein N-glycome (Mealer et al 2019). In Sharapov et al (Sharapov et al 2019), rs13107325 was associated with the percentage of trisialylated structures, although this association did not reach genome-wide significance (nominal P = 6×10 -5 ).…”

N‐glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency

“…Groups included (a) controls (33 healthy adults homozygous for the major allele (C) at rs13107325 of SLC39A8), (b) parents of P1 and P2 who are heterozygous mutations carriers, and (c) patients P1, P2 as well as two previously described cases of SLC39A8-CDG also analyzed by MALDI-TOF by our group. 19 Experimental analyses were performed at least in duplicates and results are presented as mean with SEM. Statistical analyses were performed on GraphPad Prism Version 8.0 (GraphPad Software, San Diego, California).…”

“…We recently published the first MALDI-TOF MS N-glycome profiles of two SLC39A8-CDG cases who also had abnormal transferrin IEF, identifying glycosylation abnormalities that were reversed after a year of manganese supplementation. 19 Here, we describe two patients who show no detectable abnormalities as assessed by conventional glycosylation analysis. By contrast, we identified changes in the serum N-glycome profiling by MALDI-TOF consistent with our prior studies on SLC39A8-CDG.…”