Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease

Abstract

ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn’s disease, and reduced blood Mn. Here, we used CRISPR/ Cas9 -mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn’s disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.

Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

“…SLC39A8: the SLC39A8 A391T variant was not reported in the fine-mapping paper, as its genetic region was not included in the ImmunoChip design. Because this variant has been published in several papers as an IBD variant with genetic and functional evidence [58][59][60] , we assign this variant as "Known causal candidate". TYK2: the TYK2 A928V was not reported in the fine-mapping paper 5 , likely due to a lack of power.…”

Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library

“…[7,[13][14][15][16] In contrast, the function of ZIP8 is not yet fully defined. However, it has been shown to be key to maintaining whole body manganese homeostasis, its genetic variants have been linked to a wide variety of human pathologies, including schizophrenia, scoliosis, obesity or Crohn's disease, [17][18][19] and lately it has gained great interest as a therapeutic target for the treatment of cartilage and joint diseases. [20][21][22] Although little information is available on their structure, divalent metal transporters possess well defined pockets that should be suitable for inhibition by small molecules, as recently shown by the structural characterization of a competitive inhibitor of DMT1 in complex with a bacterial analog of the transporter.…”

Behavioral phenotyping of Zip8 393T-KI mice for in vivo study of schizophrenia pathogenesis

“…ZIP8 is highly conserved across species 10 with 85% sequence conservation across the entire mouse and human gene with 100% conservation around site 391 (murine equivalent is site 393). We 11 and others 12 have taken advantage of this interspecies sequence homology and CRISPR-Cas9 genome editing to generate a knock-in (KI) mouse model of ZIP8 A391T (murine Zip8 A393T). The Zip8 393T-KI mouse phenocopies ZIP8 391Tassociated human phenotypes, including reduced blood Mn, enhanced susceptibility to intestinal inflammation, and altered N-glycosylation [11][12][13] .…”

“…We 11 and others 12 have taken advantage of this interspecies sequence homology and CRISPR-Cas9 genome editing to generate a knock-in (KI) mouse model of ZIP8 A391T (murine Zip8 A393T). The Zip8 393T-KI mouse phenocopies ZIP8 391Tassociated human phenotypes, including reduced blood Mn, enhanced susceptibility to intestinal inflammation, and altered N-glycosylation [11][12][13] . The genotypic effect is enhanced in male KI mice, supported by observations in the human population 11,14 .…”

“…The Zip8 393T-KI mouse phenocopies ZIP8 391Tassociated human phenotypes, including reduced blood Mn, enhanced susceptibility to intestinal inflammation, and altered N-glycosylation [11][12][13] . The genotypic effect is enhanced in male KI mice, supported by observations in the human population 11,14 . Work-to-date with specific relevance to schizophrenia has suggested ZIP8 A391T may alter glutamate signaling, the neuroinflammatory response, and brain N-glycosylation 13,15 .…”