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

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.

A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

“…Importantly, the levels of Zn and Fe were not altered in whole blood, suggesting a specific requirement for Slc39a8 in maintaining Mn levels ( SI Appendix , Fig. S2 ), consistent with previous reports in human carriers of SLC39A8 A391T ( 9 , 30 ). Next, we measured Mn in tissue and observed reduced levels of Mn in the liver ( SI Appendix , Fig.…”

“…However, for other traits, there may be different tissue-specific mechanisms underlying disease risk associated with SLC39A8 A391T. For example, human brain MRI studies have shown that SLC39A8 A391T carriers show lower Mn deposition in putamen and white matter tracts but higher deposition in globus pallidus and substantia nigra ( 30 ). Globus pallidus and substantia nigra play an important role in degenerative neurological disorders including Parkinson’s disease ( 58 ).…”

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

“…The hallmark of occupational exposure through inhalation is neurotoxicity manifesting as parkinsonism and dystonia (manganism, or Mn intoxication) 85 , 86 . Neurotoxicity is an aspect of the Mendelian syndromes caused by loss of function of all three of the hepatic manganese transporters; interestingly, GWAS has also identified a common missense variant in SLC39A8 as a risk factor for schizophrenia and many other diseases 88 , 89 ; altered function of glycosyltransferases due to manganese overload in the neurons is a proposed mechanism for neurological manifestations of this variant 90 . Because manganese is excreted through the liver into the bile, increased circulating manganese secondary to liver damage may be a contributing factor to the neurological manifestations of chronic acquired hepatocerebral degeneration (CAHD) 91 – 93 .…”

Mammalian brain glycoproteins exhibit diminished glycan complexity compared to other tissues

“…Blood samples were collected following CO 2 euthanasia and decapitation in a microtainer tube (BD, #365967), and plasma was separated by centrifugation and stored at −80 °C until use. Plasma N-glycan profiling was performed as described previously 73 . In brief, 5 µL of mouse plasma was lyophilized, resuspended in 20 μL 1X Rapid PNGase F buffer (NEB #P0710S), and denatured at 70 °C for 15 min After cooling to room temperature, 1 μL of Rapid PNGase F was added, and incubated at 50 °C for 60 min C18 Sep-Pak columns (50 mg, Waters, #WAT054955) were preconditioned with one column volume of methanol, 5% acetic acid, 1-propanol, and 5% acetic acid and placed in 1.5 mL tubes.…”