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
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...
October 15, 2020: JCI Insight