Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease
Laxmi Sunuwar, Azra Frkatović, Sodbo Sharapov, Qinchuan Wang, Heather M. Neu, Xinqun Wu, Talin Haritunians, Fengyi Wan, Sarah Michel, Shaoguang Wu, Mark Donowitz, Dermot McGovern, Gordan Lauc, Cynthia Sears, Joanna Melia
Laxmi Sunuwar, Azra Frkatović, Sodbo Sharapov, Qinchuan Wang, Heather M. Neu, Xinqun Wu, Talin Haritunians, Fengyi Wan, Sarah Michel, Shaoguang Wu, Mark Donowitz, Dermot McGovern, Gordan Lauc, Cynthia Sears, Joanna Melia
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Research Article Gastroenterology Genetics

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.

Authors

Laxmi Sunuwar, Azra Frkatović, Sodbo Sharapov, Qinchuan Wang, Heather M. Neu, Xinqun Wu, Talin Haritunians, Fengyi Wan, Sarah Michel, Shaoguang Wu, Mark Donowitz, Dermot McGovern, Gordan Lauc, Cynthia Sears, Joanna Melia

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Figure 1

Zip8 393T-KI mice exhibit abnormal Mn homeostasis.

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Zip8 393T-KI mice exhibit abnormal Mn homeostasis. (A) Whole blood Mn wa...
(A) Whole blood Mn was reduced in Zip8 393T-KI homozygous mice (–18.9%, P = 0.0395). n = 11–13 male mice/genotype, 9–14 weeks of age, fasted. (B) Liver Mn was reduced in Zip8 393T-KI heterozygous and homozygous mice. (C) Kidney Mn was reduced in Zip8 393T-KI heterozygous and homozygous mice. (D) Relative Mn levels were comparable between WT and Zip8 393T-KI mice across additional tissue types. n = 3–7 male mice/genotype, 8–10 weeks of age (B–D). (E) Biliary Mn was increased in Zip8 393T-KI homozygous mice compared with WT mice. n = 4 male mice/genotype, 8–10 weeks of age, fasted. (F) There was no difference in liver Slc39a8 mRNA across genotypes. Relative expression, normalized to Gapdh mRNA. n = 3 male mice/genotype, 8–10 weeks of age. (G) Zip8 localized to the bile canalicular membrane in a pattern similar to that of Mdr1 in WT and Zip8 393T-KI homozygous mice. Confocal images are representative of at least 3 animals/genotype. Scale bars: 5 μm. Whole blood (A) and bile Mn (E) were measured by atomic absorption spectroscopy; tissue Mn was measured by ICP-MS and normalized to wet tissue weight (B–D). Mean ± SEM. Statistical analysis by 1-way ANOVA with Kruskal-Wallis and Dunn’s multiple comparisons tests when 3 or more groups were compared (A–C and F); unpaired, 1-sided t test was used for comparison of 2 groups (D and E).