Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

Lawless, Matthew W.; Mankan, Arun K.; White, Mary; O’Dwyer, Michael J.; Norris, Suzanne

doi:10.1186/1471-2121-8-30

Cited by 42 publications

(36 citation statements)

References 70 publications

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“…Laboratory studies have identified the endoplasmic reticulum stress response as a potential shared pathway by which these two diseases could synergistically enhance cellular injury. 18 In this study, a novel A271S HFE mutation was also found in one a-1-antitrypsin deficiency case with heart failure and cardiac iron deposition. The systemic iron accumulation suggests that the mutation may have functioned in a similar manner to that of other HFE mutations in increasing iron deposition.…”

Section: Discussionmentioning

confidence: 85%

HFE mutations in α-1-antitrypsin deficiency: an examination of cirrhotic explants

et al. 2010

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Increased iron deposition is often seen in liver explants with a-1-antitrypsin deficiency, but it remains unclear if this is a nonspecific effect of end-stage liver disease or if individuals with a-1-antitrypsin deficiency and excess iron are at increased risk for HFE mutations. To further examine this question, 45 liver explants with a-1-antitrypsin deficiency and 33 control livers with chronic hepatitis C were examined for histological iron accumulation, graded on a scale of 0 to 4 þ , and HFE mutations. Interestingly, the a-1-antitrypsin cirrhotic livers showed a bimodal distribution of iron accumulation, with peaks at grades 1 and 3. In contrast, hepatitis C cirrhotic livers showed a unimodal distribution with a peak at grade 2. HFE mutations in livers with a-1-antitrypsin deficiency were as follows: C282Y ¼ 2%, H63D ¼ 42%. H63D mutations were more frequent in a-1-antitrypsin deficiency cases than in controls (42 vs 27%), but was not statistically significant, P ¼ 0.17. However, there was a significant association with HFE mutations in a-1-antitrypsin deficiency livers with grade 3 þ or 4 þ iron, P ¼ 0.02. In contrast, livers with hepatitis C showed a similar frequency of HFE mutations as the general population: C282Y ¼ 15%, H63D ¼ 27%. A rare S65C mutation and a novel A271S mutation were also found in this study; the latter patient had 4 þ iron in the liver and later developed heart failure with cardiac iron. In conclusion, total H63D mutations were high (42%) in cirrhotics with a-1-antitrypsin deficiency and there was a significant association between HFE mutations and high levels of iron accumulation.

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Section: Discussionmentioning

confidence: 85%

HFE mutations in α-1-antitrypsin deficiency: an examination of cirrhotic explants

et al. 2010

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“…In fact, at least seven missense mutations causing disease were reported at the HFE exon 4 (which codes for the α3 domain of the protein) including the major p.Cys282Tyr mutation, making this exon a hot spot for mutations. In the case of this mutation, the tyrosine for cysteine substitution disrupts the formation of the disulfide bond that physiologically occurs between Cys225 and Cys282 residues and that is essential for HFE association with β2-microglobulin [1,16,17]. Therefore, the p.Cys282Tyr-mutated HFE protein is unable to bind to the chaperone β2-microglobulin and to be transported to cell surface where it would interact with TfR1 and TfR2 in order to regulate hepcidin expression.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G NC)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5′-UTR of HAMP gene (c. -25GN A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.

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“…46,47 The HFE C282Y mutation could contribute to this process either by accelerating or differentially activating UPR branches linked to tumor cell resistance. 48 Finally, we cannot completely rule out that other mechanisms, such as linkage disequilibrium with other genetic variants at risk on chromosome 6p, 49 were the HFE gene is located, might explain the association between C282Y heterozygosis, risk of ovarian cancer and survival.…”

Section: Discussionmentioning

confidence: 99%

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis

Gannon

Medelci

Page

et al. 2010

Intl Journal of Cancer

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Cancer cells require large amounts of micronutrients, particularly iron, for their rapid growth and frequent divisions. Cellular iron uptake is regulated by the transferrin receptor and the hemochromatosis protein (HFE) system. Two frequent mutations in the HFE gene, H63D and C282Y, are associated with hemochromatosis type I, an inherited iron overload disease and, possibly, with cancer. In this study, we evaluated the frequency of the H63D and C282Y mutations in a cohort of 677 consecutive cases of woman with gynecological pathologies. Cases included 80 women with tumor-free pathologies normal ovary (NOV), 124 with benign ovarian tumors (BOV), 96 with epithelial ovarian cancer (EOC) tumors of low malignant potential (LPM), 264 with invasive tumors of the ovary (TOV) and 113 with endometrial cancer. We found that the C282Y allele frequency in EOC patients was higher than that in the control NOV group (5.8% vs. 1.3%, p < 0.001) and was associated with an increased risk of ovarian cancer (OR = 4.88; 95% CI 1. 15-20.61; p = 0.018). The effect of the two HFE mutations on patient survival was also analyzed.Kaplan-Meier analyses did not find any significant association between the H63D allele and patient survival. However, EOC patients with at least one C282Y allele had a decreased overall survival compared to those with no C282Y allele (p = 0.001). These results indicate that the C282Y mutation may increase the risk of developing ovarian cancer and may be further associated with poor outcomes. Keywords CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptIron is an essential trace element that can be carcinogenic through a variety of mechanisms including acting as an essential nutrient for proliferating tumor cells, 1 catalyzing the formation of mutagenic hydroxyl radicals, 2 and by suppressing the host immune response. 3,4 In the past decades, several genes were identified as being central to the maintenance of iron homeostasis. 5 One such gene is HFE, a major histocompatibility class I-like (MHC-I-like) molecule, that, when mutated, may cause hereditary hemochromatosis (HH). 6 HH is a common genetic disorder in Caucasian populations that is characterized by high levels of iron absorption from diet, which results in the presence of high circulating iron levels and iron accumulation in the body. 7 As with other MHC-I molecules, HFE needs to associate with β2-microglobulin (β2m) for its appropriate expression at the cell surface. 8 The two most common mutations in HFE are C282Y, a guanine-to-adenine transition leading to a cysteine-to-tyrosine change and H63D, a cysteine-to-guanine transition causing a histidineto-aspartic acid change. 6 HFE associates with the major protein responsible for cellular iron uptake, namely the transferrin receptor (TfR), 9 also called CD71. The association of HFE with TfR at the cell surface lowers TfR affinity for the circulating iron-transporter transferrin, thereby limiting iron uptake and thus directly implicating HFE in the modulation of cellular iron level...

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Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses

Cited by 42 publications

References 70 publications

HFE mutations in α-1-antitrypsin deficiency: an examination of cirrhotic explants

HFE mutations in α-1-antitrypsin deficiency: an examination of cirrhotic explants

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis

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