Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Genos Glycoscience Research Laboratory, Zagreb, Croatia.
JCI Insight. 2020 Oct 15;5(20):140978. doi: 10.1172/jci.insight.140978.
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.
ZIP8 是一种金属转运蛋白，在锰 (Mn) 稳态中发挥作用。ZIP8 中的一个常见遗传变异（rs13107325；A391T）在 GWAS 中确定的多效性 SNP 中排名前十；A391T 与精神分裂症、肥胖症、克罗恩病的风险增加以及血液 Mn 减少有关。在这里，我们使用 CRISPR/Cas9 介导的基因敲入 (KI) 生成了 ZIP8 A391T 的小鼠模型 (Zip8 393T-KI 小鼠)。Zip8 393T-KI 小鼠重现了 SNP 与血液 Mn 的关联，血液 Mn 减少。存在受限的异常组织 Mn 稳态，肝脏和肾脏 Mn 减少，胆汁 Mn 增加，为 Zip8 功能减弱提供了体内证据。在化学诱导的结肠炎模型中受到挑战时，雄性 Zip8 393T-KI 小鼠表现出增强的疾病易感性。在基于人群的队列中，ZIP8 391-Thr 与减少的三触角血浆 N-聚糖种类相关，以定义一种假定与 Mn 依赖性糖基转移酶活性相关的基因型特异性糖表型。这种糖表型在克罗恩病患者队列中得以维持。这些数据以及 ZIP8 391-Thr 与多种疾病的关联表明，Mn 稳态在复杂人类疾病中具有被低估的作用。
