Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice

• Published in: Nature genetics Vol. 39; no. 8; pp. 1025 - 1032
• Main Authors: Andrews, Nancy C, Wang, Fudi, Paradkar, Prasad N, Custodio, Angel O, McVey Ward, Diane, Fleming, Mark D, Campagna, Dean, Roberts, Kristina A, Boyartchuk, Victor, Dietrich, William F, Kaplan, Jerry
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2007; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cellular biology; Chromosomes; Chromosomes, Mammalian; Crosses, Genetic; Diagnosis; Female; Gene Function; Gene mapping; Genetic aspects; Genetic diversity; Genetic variation; Genetics; Human Genetics; Iron; Iron - metabolism; Iron metabolism disorders; letter; Liver - metabolism; Macrophages - metabolism; Male; Mammals; Mice; Mice, Inbred Strains; Physiological aspects; Protein Transport; Quantitative Trait Loci; Risk factors; RNA, Small Interfering; Rodents; Trafficking; United States
• DOI: 10.1038/ng2059
• ISSN: 1061-4036

We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus.