Impaired Iron Transport Activity of Ferroportin 1 in Hereditary Iron Overload

McGregor, J A; Shayeghi, Majid; Vulpe, Chris D.; Anderson, Gregory J.; Pietrangelo, Antonello; Simpson, Robert J.; McKie, Andrew T.

doi:10.1007/s00232-005-0768-1

Cited by 35 publications

(33 citation statements)

References 24 publications

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“…Female mice produce more hepcidin mRNA and have higher iron levels in liver and spleen than male mice [17]; this could also account for sex-associated differences in the function of normal or abnormal ferroportin as an iron exporter. Altogether, the molecular basis by which ferroportin Q248H affects iron metabolism is unclear, expression of Q248H in Xenopus oocytes decreased the efficiency of iron export, but did not alter ferroportin regulation by hepcidin [18].…”

Section: Discussionmentioning

confidence: 99%

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Rivers

Barton²,

Gordeuk

et al. 2007

Blood Cells, Molecules, and Diseases

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The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to selfCorrespondence: Dr. James C. Barton G105, 2022 Brookwood Medical Center Drive Birmingham, AL 35209 Telephone 205-877-2888 FAX 205-877-2039 ironmd@dnamail.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF. NIH Public Access

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Section: Discussionmentioning

confidence: 99%

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Rivers

Barton²,

Gordeuk

et al. 2007

Blood Cells, Molecules, and Diseases

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“…It has been a source of debate whether haploinsufficiency would explain Fpn disease or whether the disease results from a dominant-negative effect. While studies have supported the view that Fpn is a multimer 9,13,24 and that the mutant allele can affect the behavior of the wild-type allele, other studies have suggested that Fpn is monomeric. 10,12,25 All human Fpn mutations are missense mutations.…”

Section: Discussionmentioning

confidence: 99%

The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease

Zohn

Domenico

Pollock

et al. 2007

Blood

105

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IntroductionHereditary hemochromatosis is a common disorder in humans, characterized by iron overload resulting in tissue injury and ultimately organ failure. Typically, hemochromatosis exhibits an autosomal-recessive pattern of inheritance and is associated with mutations in HFE, hemojuvelin, hepcidin, or transferrin receptor 2. 1,2 Targeted deletion of these genes in the mouse results in hemochromatosis, providing mouse models for most forms of the disease. Hemochromatosis type IV, also referred to as ferroportin (Fpn) disease, results from mutations in the iron transporter ferroportin. Fpn is the only known iron exporter in mammalian cells and is present on the surface of macrophages, intestinal enterocytes, hepatocytes, and placental cells. [3][4][5] The level of cell surface Fpn is regulated by its interaction with hepcidin, a peptide secreted by the liver in response to iron stores and inflammation. Hepcidin binds to Fpn, inducing its internalization and degradation, thus regulating the export of iron from cells to plasma. 6 Mutations in Fpn lead to iron-overload disease but, in contrast to other forms of hemochromatasis, ferroportin disease exhibits an autosomal-dominant pattern of inheritance. 7 The disorder has different presentations depending on the Fpn mutation. Mutations leading to Fpn that is not internalized by hepcidin result in iron accumulation in hepatocytes and high transferrin saturation. 8,9 Mutations leading to Fpn that is not appropriately targeted to the cell surface result in iron accumulation in Kupffer cells and low transferrin saturation. [9][10][11] The mechanism by which the disease mutations exert a dominant effect is unclear. Some groups that study the disease suggest that it results from haploinsufficiency, 10,12 whereas others suggest that the disorder results from a dominantnegative effect of the mutant allele. 9,13 Importantly, all human mutations are missense mutations and mice that are heterozygous for a targeted deletion of Fpn do not show the disease. 14 Treatment for hemochromatosis aims to decrease iron load by repeated phlebotomy and this treatment works well for most patients. Many patients with ferroportin disease, however, become anemic with phlebotomy, highlighting the need for a mouse model to develop better treatments.We report here on a missense mutation in mouse Fpn that results in a disorder that is identical to classic human ferroportin disease. We show that macrophages isolated from mutant mice have no Fpn on their cell surface and that expression of Fpn constructs containing the missense mutation (H32R) affects the behavior of wild-type Fpn. These results show that Fpn disease is due to a dominant-negative effect of the mutant allele and provide the first mouse model for this disorder. Materials and methods Generation of mutant mice and identification of Fpn mutationThe ffe mouse line was identified in a screen for recessive ethylnitrosourea (ENU)-induced mutations that cause morphologic abnormalities at embryonic day (E) 12.5. [15][16][17] The ffe mutation...

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“…A common deletion (162delVal), has been found in unrelated families (78,115,116 ). Other sequence variations are private, with the exception of the Q248H substitution, which has been detected in populations of African descent but for which contribution to African iron overload is a matter of debate (117)(118)(119)(120)(121). Recent studies have shown that most SLC40A1 sequence variants are unresponsive to hepcidin-mediated internalization (5,122,123 ).…”

Section: Hemochromatosis Attributable To Tfr2 Deficiencymentioning

confidence: 99%

Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches

et al. 2006

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Since the discovery of the hemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron-overload diseases. At least 4 main types of hereditary hemochromatosis (HH) have been identified. Surprisingly, genes involved in HH encode for proteins that all affect pathways centered around liver hepcidin synthesis and its interaction with ferroportin, an iron exporter in enterocytes and macrophages. Hepcidin concentrations in urine negatively correlate with the severity of HH. Cytokine-mediated increases in hepcidin appear to be an important causative factor in anemia of inflammation, which is characterized by sequestration of iron in the macrophage system. For clinicians, the challenge is now to diagnose HH before irreversible damage develops and, at the same time, to distinguish progressive iron overload from increasingly common diseases with only moderately increased body iron stores, such as the metabolic syndrome. Understanding the molecular regulation of iron homeostasis may be helpful in designing innovative and reliable DNA and protein tests for diagnosis. Subsequently, evidence-based diagnostic strategies must be developed, using both conventional and innovative laboratory tests, to differentiate between the various causes of distortions of iron metabolism. This review describes new insights in mechanisms of iron overload, which are needed to understand new developments in diagnostic medicine.

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Impaired Iron Transport Activity of Ferroportin 1 in Hereditary Iron Overload

Cited by 35 publications

References 24 publications

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study

The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease

Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches

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