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