HFE: A Genetic Determinant of Olfactory Mn Absorption and Toxicity

描述(申请人提供)：HFE基因的遗传变异是成人遗传性血色素沉着症(HH)的主要原因，HH是北美高加索人群中最常见的孟德尔遗传病。错义变异体C282Y和H63D促进肠道吸收和进行性组织铁沉积。HH也与其他二价金属的代谢紊乱有关，人们认为这些影响是由于二价金属转运蛋白(DMT1)的失调引起的。我们实验室的工作表明，锰可以通过一种涉及DMT1的机制直接穿过嗅觉上皮进入中枢神经系统。因此，我们推测C282Y和/或H63D HFE等位基因携带者可能更容易通过嗅觉途径接触锰，从而可能损害嗅觉功能。我们的模型进一步表明，HFe/-基因敲除小鼠通过嗅觉系统增加了对54MN的吸收，这些动物对导致嗅觉受损的锰暴露更敏感。这个试点项目将测试HFE作为嗅觉锰吸收和毒性的遗传决定因素的假设。 公共卫生相关性：HFE基因的遗传变异是成人遗传性血色素沉着症(HH)的主要原因，HH是北美高加索人群中最常见的孟德尔遗传病。错义变异体C282Y和H63D促进肠道吸收和进行性组织铁沉积。我们的假设是，HFE是嗅觉锰吸收和毒性的遗传决定因素。为了验证这一假设，我们将研究HFE相关性血色病的小鼠模型，以测试吸入的锰的吸收是否发生改变，以及HFe是否因此增加了对嗅觉-嗅觉损伤的敏感性。

DESCRIPTION (provided by applicant): Genetic variants of the HFE gene are the leading cause of adult onset hereditary hemochromatosis (HH), the most common Mendelian genetic disease in the North American Caucasian population. The missense variants C282Y and H63D promote increased intestinal absorption and progressive tissue deposition of iron. HH has also been associated with derangements in the metabolism of other divalent metals, and it is thought these effects arise due to malregulation of divalent metal transporter (DMT1). Work in our laboratory has demonstrated that manganese can enter the central nervous system directly across the olfactory epithelium by a mechanism that involves DMT1. We therefore hypothesize that carriers of C282Y and/or H63D HFE alleles may be more susceptible to manganese exposure through the olfactory pathway, and consequently may have impaired olfactory function. Our model further suggests that Hfe-/- knockout mice would have increased 54Mn absorption through the olfactory system and that these animals would be more sensitive to manganese exposures causing impaired olfaction. This pilot project will test the hypothesis that HFE acts as a genetic determinant of olfactory manganese absorption and toxicity. PUBLIC HEALTH RELEVANCE: Genetic variants of the HFE gene are the leading cause of adult onset hereditary hemochromatosis (HH), the most common Mendelian genetic disease in the North American Caucasian population. The missense variants C282Y and H63D promote increased intestinal absorption and progressive tissue deposition of iron. Our hypothesis is that HFE acts as a genetic determinant of olfactory manganese absorption and toxicity. To test this hypothesis, we will study a mouse model of HFE-associated hemochromatosis to test whether absorption of inhaled manganese is altered, and whether HFE therefore promotes a greater susceptibility to damage to olfaction - the sense of smell.