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 2

Zip8 393T-KI male mice exhibit increased susceptibility to chemically induced colitis.

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Zip8 393T-KI male mice exhibit increased susceptibility to chemically in...
(A) Initial body weight of Zip8 393T-KI homozygous mice at 11.5–13 weeks of age was higher compared with that of WT and heterozygous mice. n = 16–20 male mice/genotype. (B) Zip8 393T-KI heterozygous and homozygous mice exhibited increased and more sustained weight loss in DSS-induced colitis model. Statistical analysis by linear regression (day 7–14). Slopes are equal between groups, but intercepts were significantly different between WT and Zip8 393T-KI heterozygous and homozygous mice (P < 0.0001), with no difference between Zip8 393T-KI heterozygous and homozygous mice (P = 0.9498). (C) Percentage of mice with rectal bleeding at day 5 and/or 6 was numerically higher in the heterozygous and homozygous mice (nonsignificant, χ2 test). (D) Day 14 histology was consistent with more inflammation in Zip8 393T-KI homozygous mice, with crypt elongation, crypt branching (top right), and expansion of lamina propria immune infiltrate and squamous metaplasia (bottom right). Scale bar: 400 μm; 200 μm (right). Images are representative of n = 5–7 mice/genotype. (E) Zip8 393T-KI heterozygous and homozygous mice had increased Il6 mRNA, consistent with ongoing inflammation. Relative expression was graphed and normalized to Gapdh mRNA. n = 4–7 male mice/genotype. Statistical analysis by 1-way ANOVA with Kruskal-Wallis and Dunn’s multiple comparisons tests when 3 or more groups compared (A and E).