HFE: A Genetic Determinant of Olfactory Mn Absorption and Toxicity

Harvard School Of Public Health, Boston MA

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Abstract

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.