HFE gene knockout produces mouse model of  hereditary hemochromatosis

Zhou, Xiao Yan; Tomatsu, Shunji; Fleming, Robert E.; Parkkila, Seppo; Waheed, Abdül; Jiang, Jinxing; Fu, Ying; Brunt, Elizabeth M.; Ruddy, David A.; Prass, Cynthia E.; Schatzman, Randall C.; O’Neill, Rosemary; Britton, Robert S.; Bacon, Bruce R.; Sly, William S.

doi:10.1073/pnas.95.5.2492

Cited by 489 publications

(329 citation statements)

References 26 publications

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“…Both mouse studies and, to a lesser extent, human studies indicate that, although heterozygous persons do show detectably higher levels of iron loading, their iron loading is not close to what would be expected for a haplotype insufficiency. 10,11 The protein levels of Hfe in Hfe ϩ/Ϫ mice as well as in the AAV-Hfe-transduced mice remain to be determined. HFE and TfR2 form a complex when expressed in tissue culture cells, leading to the hypothesis that they interact to form a sensor to detect the degree of Tf saturation.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Gao

Chen

Domenico

et al. 2010

Blood

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Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrinreceptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes. (Blood. 2010;115(16):3374-3381) IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disease of iron metabolism characterized by increased intestinal iron absorption and hepatic iron overload. 1 HH is caused by mutations in genes encoding proteins involved in iron homeostasis, including the HH protein, HFE 2 ; hemojuvelin 3 ; hepcidin 4 ; transferrin-receptor 2 (TfR2) 5 ; and ferroportin. 6 Accumulation of excessive iron results in hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, arrhythmias, diabetes, arthritis, and hypogonadotropic hypogonadism. 7 HH type 1, the most common form of HH, is caused by a missense mutation in HFE resulting in a C282Y (numbering system includes the first 23 amino acid signal peptide) substitution and accounts for 85% of HH. 2 HFE encodes an atypical major histocompatibility complex class I protein. Like the major histocompatibility complex class I proteins, HFE is a membrane protein that consists of a signal sequence, ␣1-␣3 domains followed by a transmembrane domain, and a short cytoplasmic domain. HFE also forms a heterodimeric complex with ␤2-microglobulin. 8 The C282Y mutation in HFE disrupts a disulfide bond in the ␣3 domain, leading to misfolding, lack of association with ␤2-microglobulin, and failure to traffic to the cell surface. 9 The Hfe knockout mouse (Hfe Ϫ/Ϫ ) also develops iron overload, confirming that the HFE-C282Y mutation confers loss of rather than gain of function. 10 Although the importance of HFE in iron regulation is apparent in patients with HH and murine models, 10,11 the underlying mechanism by which HFE regulates iron metabolism is only beginning to be understood.Type 3 HH is caused by a variety o...

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Gao

Chen

Domenico

et al. 2010

Blood

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“…18 Abnormal LH pulsatile secretion may be associated with male infertility and could disrupt the regulatory role of both the Sertoli and Leydig cells, resulting in abnormal spermatogenesis. 19 To investigate the role of HFE in the regulation of iron homeostasis, Zhou et al 20 generated a knockout mouse model of HH by targeted disruption of the murine HFE gene. This study revealed that the HFE protein was involved in the regulation of iron homeostasis and that mutations in this gene were responsible for HH.…”

Section: Discussionmentioning

confidence: 99%

An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population

Yu¹,

Wang²,

Xin³

et al. 2012

Asian J Androl

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Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe, and excess iron is associated with the impairment of spermatogenesis. The aim of this study is to investigate the association between three mutations (C282Y, H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population. Two groups of Chinese men were recruited: 444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility. The HFE gene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The experimental results demonstrated that no C282Y or S65C mutations were detected. Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio50.801, 95% confidence interval50.452-1.421, x 2 50.577, P50.448). The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P50.896, P50.404 and P50.05, respectively). Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction.

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“…This Warburg metabolic pathway has therefore been proposed as a general anabolic principle of activated and proliferating cells, while glucose breakdown through oxidative phosphorylation is a characteristic of differentiated or resting cells – not only for tumours, but also in normal tissue and the immune system 26, 27. Indeed, in murine GM‐CSF‐DC (see below), Toll‐like receptor stimulation promotes increased anabolic glycolysis rather than oxidative phosphorylation, which is crucial for DC activation, survival and function in the face of increased membrane‐forming demands due to secretory processes or migration 28, 29, 30, 31. However, when 1,25‐OH‐VD3 is given to human monocytes undergoing GM‐CSF differentiation to create tolerogenic DC (as outlined above), an early transcriptional programme is started that engages oxidative phosphorylation 32, 33, 34.…”

Section: Vd3 In Metabolic Imprinting Of DCmentioning

confidence: 99%

Vitamin D immunoregulation through dendritic cells

2016

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SummaryVitamin D (VD3) has been linked to immunological processes, and its supplementation may have a role in treatment or prevention of diseases with underlying autoimmune or pro‐inflammatory states. As initiators of the immune responses, dendritic cells (DC) are a potential target of VD3 to dampen autoimmunity and inflammation, but the role of DC in VD3‐mediated immunomodulation in vivo is not understood. In addition to being targets of VD3, DC can provide a local source of bioactive VD3 for regulation of T‐cell responses. Here we review existing studies that describe the tolerogenic potential of VD3 on DC, and discuss them in the context of current understanding of DC development and function. We speculate on mechanisms that might account for the potent but poorly understood tolerogenic activities of VD3 and the role of DC as both targets and sources of this hormone.

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HFE gene knockout produces mouse model of hereditary hemochromatosis

Cited by 489 publications

References 26 publications

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population

Vitamin D immunoregulation through dendritic cells

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