scholarly journals From Environment to Genome and Back: A Lesson from HFE Mutations

2020 ◽  
Vol 21 (10) ◽  
pp. 3505
Author(s):  
Raffaela Rametta ◽  
Marica Meroni ◽  
Paola Dongiovanni
Keyword(s):  
Dietary Habits ◽  
Epigenetic Modification ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Phenotypic Expression ◽  
Bioactive Molecules ◽  
Hfe Gene ◽  
Human Populations ◽  
Environmental Pressures ◽  
Hfe Mutations

The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities.

scholarly journals From Environment to Genome and Back: A Lesson from HFE Mutations

2020 ◽  
Author(s):  
Raffaella Rametta ◽  
Marica Meroni ◽  
Paola Dongiovanni
Keyword(s):  
Dietary Habits ◽  
Epigenetic Modification ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Phenotypic Expression ◽  
Bioactive Molecules ◽  
Hfe Gene ◽  
Human Populations ◽  
Environmental Pressures ◽  
Hfe Mutations

The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities.

scholarly journals Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients

2013 ◽  
Vol 88 (4) ◽  
pp. 530-540 ◽  
Author(s):  
Fatima Mendonca Jorge Vieira ◽  
Maria Cristina Nakhle ◽  
Clarice Pires Abrantes-Lemos ◽  
Eduardo Luiz Rachid Cancado ◽  
Vitor Manoel Silva dos Reis
Keyword(s):  
Hepatitis C ◽  
Alcohol Abuse ◽  
Porphyria Cutanea Tarda ◽  
Hereditary Hemochromatosis ◽  
Control Group ◽  
Hfe Gene ◽  
Precipitating Factors ◽  
Serological Tests ◽  
Hfe Mutations ◽  
Precipitating Factor

BACKGROUND: Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES: Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. METHODS: An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. RESULTS: Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. CONCLUSIONS: Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients

Hereditary Hemochromatosis Since Discovery of the HFE Gene

2001 ◽  
Vol 47 (7) ◽  
pp. 1147-1156 ◽  
Author(s):  
Elaine Lyon ◽  
Elizabeth L Frank
Keyword(s):  
Molecular Genetic ◽  
Hereditary Hemochromatosis ◽  
Phenotypic Expression ◽  
Protein Product ◽  
Population Screening ◽  
The Body ◽  
Hfe Gene ◽  
Molecular Testing ◽  
Disease Mechanism ◽  
Biochemical Tests

Abstract Background: Hereditary hemochromatosis is an inherited disorder of iron metabolism that is characterized by excessive iron deposition in major organs of the body. Chronic increased iron absorption leads to multiorgan dysfunction. Since the discovery of the gene responsible for the majority of cases, research has progressed rapidly to identify the gene product, the effects of mutations, and the implications for different populations. The protein product of the HFE gene is a transmembrane glycoprotein, termed HFE, that modulates iron uptake. Mutations in the HFE protein compromise its function and produce disease symptoms. Two mutations, C282Y and H63D, have been linked to the majority of disease cases. Approach: We reviewed the recent literature for the molecular basis of hereditary hemochromatosis. Genotypic information was combined with biochemical and clinical phenotypic information to achieve a better understanding of the disease mechanism. Content: This review provides a comprehensive discussion of known mutations in the HFE gene and their phenotypic expression. Diagnostic criteria using molecular genetic techniques in conjunction with traditional biochemical tests are provided. Current methods and limitations of molecular testing are examined in detail. A strategy for population screening and an algorithm for diagnosis that incorporates molecular testing are presented. Treatment by therapeutic phlebotomy and the use of blood obtained from hemochromatosis patients are discussed. Summary: Although the disease mechanism has not been completely elucidated, phenotypic and penetrance data are becoming available. Controversy still exists concerning the role of genetic testing in diagnosis and population screening.

Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1859-1859
Author(s):  
Patricia Aguilar-Martinez ◽  
Severine Cunat ◽  
Fabienne Becker ◽  
Francois Blanc ◽  
Marlene Nourrit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Exon 2 ◽  
High Iron ◽  
Iron Parameters

Abstract Introduction: Homozygozity for the p.Cys282Tyr (C282Y) mutation of the HFE gene is the main genotype associated with the common form of adult hereditary hemochromatosis. C282Y carriers do not usually develop iron overload, unless they have additional risk factors such as liver diseases, a dysmetabolic syndrome or an associated genetic defect. The commonest is the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele. However, a few rare HFE mutations can be found on the 6th chromosome in trans, some of which are of clinical interest to fully understand the disorder. Patients and Methods: We recently investigated four C282Y carrier patients with unusually high iron parameters, including increased levels of serum ferritin (SF), high transferrin saturation (TS) and high iron liver content measured by MRI. They were males, aged 37, 40, 42, 47 at diagnosis. Two brothers (aged 40 and 42) were referred separately. The HFE genotype, including the determination of the C282Y, H63D and S65C mutations was performed using PCR-RFLP. HFE sequencing was undertaken using the previously described SCA method (1). Sequencing of other genes (namely, HAMP, HJV/HFE2, SLC40A1, TFR2) was possibly performed in a last step using the same method. Results: We identified three rare HFE mutant alleles, two of which are undescribed, in the four studied patients. One patient bore a 13 nucleotide-deletion in exon 6 (c.[1022_1034del13], p.His341_Ala345>LeufsX119), which is predicted to lead to an abnormal, elongated protein. The two brothers had a substitution of the last nucleotide of exon 2 (c.[340G>A], p.Glu114Lys) that may modify the splicing of the 2d intron. The third patient, who bore an insertion of a A in exon 4 (c.[794dupA],p.[trp267LeufsX80]), has already been reported (1). Discussion: A vast majority of C282Y carriers will not develop iron overload and can be reassured. However, a careful step by step strategy at the clinical and genetic levels may allow to correctly identify those patients deserving further investigation. First, clinical examination and the assessment of iron parameters (SF and TS) allow identifying C282Y heterozygotes with an abnormal iron status. Once extrinsic factors such as heavy alcohol intake, virus or a dysmetabolic syndrome have been excluded, MRI is very useful to authenticate a high liver iron content. Second, HFE genotype must first exclude the presence of the H63D mutation. Compound heterozygozity for C282Y and H63D, a very widespread condition in our area, is usually associated with mild iron overload. Third, HFE sequencing can be undertaken and may identify new HFE variants as described here. The two novel mutations, a frameshift modifying the composition and the length of the C terminal end of the HFE protein and a substitution located at the last base of an exon, are likely to lead to an impaired function of HFE in association with the C282Y mutant. However, it is noteworthy that three of the four patients were diagnosed relatively late, after the 4th decade, as it is the case for C282Y homozygotes. Three further unrelated patients are currently under investigation in our laboratory for a similar clinical presentation. Finally, it can be noted that in those patients who will not have a HFE gene mutant identified, analysis of other genes implicated in iron overload must be performed to search for digenism or multigenism. None of our investigated patients had an additional gene abnormality.

Interaction Between Genotypes for HFE and TFR2 Genes Mutations and Iron Status in Brazilian Blood Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5382-5382
Author(s):  
Rodolfo D Cancado ◽  
Paulo CJL Santos ◽  
Samuel Rostelato ◽  
Cristiane T Terada ◽  
Iris Gonzales ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Serum Iron ◽  
Blood Donors ◽  
Binding Capacity ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
The Body ◽  
Hfe Gene ◽  
Automation System

Abstract Hereditary hemochromatosis (HH) is a disorder characterized by increased intestinal iron absorption, which leads to a progressive accumulation of iron in the body. This iron overload has been associated with mutations in HFE gene (C282Y, H63D and S65C) and other genes. The objectives of this study were to assess the frequencies of functional mutations in HFE and TFR2 genes and to investigate their relationship with the iron status in a sample of blood donors. Blood donors (n=542) were recruited at the Hemocenter of the Santa Casa Hospital, Sao Paulo, Brazil. The genotypes for HFE (C282Y, H63D and S65C) TFR2 (Y250X and Q690P) gene mutations were evaluated by PCR-RFLP. The concentrations of serum iron and total iron-binding capacity (TIBC) were measured by automation system Advia®(Bayer Diagnostics) and serum ferritin by Axsym System®(Abbott Laboratories). The frequencies of HFE 282Y, HFE 63D and HFE 65C alleles were 2.1, 13.6 and 0.6%, respectively. The frequency C282Y allele (2.1%) in Brazilian blood donors is lower than that observed in blood donors from Northern Europe (5.1 to 8.2%, P<0.05). The TFR2 250X and TFR2 690P alleles were not found in these subjects. The iron status was similar between HFE genotypes in women. However, men carrying HFE 282CY genotype had higher serum ferritin and lower TIBC concentrations when compared to the HFE 282CC genotype carriers. HFE 282CY genotype was also associated with higher transferrin saturation in men who donated blood at the first time. Moreover, male donors with HFE 63DD plus 63HD genotypes had higher serum iron and transferrin saturation when compared to those with HFE 63HH genotype. A relationship between HFE CY/HH/SS haplotype and lower TIBC concentrations was also found in men. The HFE 282Y and HFE 65C alleles were rare while the HFE 63D was frequent in blood donors. The mutations in TFR2 gene were not found in this study. The HFE 282Y and HFE 63D alleles were associated with alterations on iron status only in male blood donors.

scholarly journals HFE Gene Mutation Status Predicts Response to Gemtuzumab Ozogamicin in AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1307-1307 ◽  
Author(s):  
Etienne Paubelle ◽  
Alice Marceau ◽  
Florence Zylbersztejn ◽  
Mickael Dussiot ◽  
Ivan Cruz Moura ◽  
...  
Keyword(s):  
Total Dose ◽  
Conflicts Of Interest ◽  
Hereditary Hemochromatosis ◽  
Gemtuzumab Ozogamicin ◽  
Hfe Gene ◽  
Study Cohort ◽  
Dependent Manner ◽  
Wild Type ◽  
Significant Difference ◽  
Hfe Mutations

Abstract BACKROUND: The protein defective in type 1 hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins, associates with beta2-microglobulin and is implicated in membranous protein recycling. Gemtuzumab ozogamicin (GO), a monoclonal antibody directed against CD33 linked to a cytotoxic agent, has been used with controversial effects in acute myeloid leukemia (AML). Internalization of GO is required for its anti-leukemic effect. Therefore, we hypothesized that H63D or C282Y HFE gene mutations may impair GO activity by preventing its internalization. METHODS: Wild type, C282Y and H63D HFE leukemic cells and primary cell were used to assess effects of GO alone or in combination with cytarabine on cell proliferation and apoptosis. Flow cytometry, confocal and AMNIS stream analysis were used to evaluate GO internalization. HFE mutations were analyzed by PCR analysis on DNA from patients included in clinical studies. Post-hoc subgroup analysis was performed to assess in vivo the role of HFE status on GO efficacy and toxicity among the 280 patients of the ALFA-0701 study as a study cohort (patients aged 50-70 years; GO 3mg/m² on days 1, 4, and 7 of chemotherapy and on day 1 of the first and second induction ; total dose 15 mg/m² ) and then on the GOELAMS-LAM 2006 IR study (patients aged 18-60 years; GO 6 mg/m² on day 4 of chemotherapy during the induction and the first consolidation; total dose 12 mg/m²) and UK NCRI AML17 study (patients aged 18-81 years; GO 3 vs 6 mg/m² on day 1 of chemotherapy but not during consolidation) as validating cohorts. RESULTS: GO induced cell death by apoptosis in AML cell lines and primary cells in a dose-dependent manner and synergistically in combination with cytarabine. However, the IC5O of GO was significantly higher in HFE mutated cells (125 vs 10 ng/mL p<0.001). To further understand this phenomenon, the CD33 internalization was analyzed upon GO or anti-CD33 antibody exposure. In line with the cytotoxic effect, CD33 was significantly less internalized in HFE mutant cells (17.4% vs 65.1% after 1 hour, p<0.01). HFE mutations were screened in 242 of the 280 ALFA-0701 patients with DNA available. There were 155 non-mutated patients (64%), 68 (28%) heterozygous for H63D, 11 (5%) heterozygous for C282Y, and 8 (3%) homozygous for H63D, which is consistent with the prevalence of the various mutations in the French population. Median age was 62 years (50-71) and the M/F ratio was 0.5, equally distributed among the different groups. No significant difference was observed with respect to the diagnosis of various hematological parameters, including white blood cell count, blasts number, cytogenetic subgroups, molecular mutation incidences (FLT3, NPM1, CEBPA, IDH, DNMT3A). In the ALFA-0701 study cohort, HFE wild-type (WT) patients had a higher overall survival (OS) when treated in the GO arm (median, not reached vs 19.5 months, p=0.0193). In contrast, OS was similar among patients with heterozygotes HFE mutations treated in the GO and the control arm (median, 19.9 vs 21.9, p=0.9675). In confirmatory cohorts, GO treatment led to a trend to increased OS in the GOELAMS-LAM 2006 IR cohort only in HFE WT patients (4-year OS with GO 62% vs 48%, p=0.08) but not in mutated patients (4-year OS with GO 73% vs 64%, p=0.45). Furthermore, in this cohort in the FLT3 WT patients subgroup, GO further improve OS in WT patients (4-year OS with GO 72% vs 50%, p=0.017), but not in patients with heterozygous HFE mutation (4-year OS with GO 80% vs 65%, p=0.23) In the UK NCRI AML17 cohort, which used GO only during induction, 245 patients were randomized between GO at 3mg/m2 and 6mg/m2 and evaluated for HFE status. Overall there was no effect of GO dose on outcomes, and no evidence of either any heterogeneity by HFE, nor any subgroup, which showed a differential effect of GO dose. CONCLUSIONS: Future studies should focus on optimising the fractionated schedule for GO at the 3mg/m2. Fractionated high doses (3x3mg/m2) during induction and single dose during consolidation seems to be the best schedule. Most importantly, the effect of GO treatment differed between HFE WT and heterozygote mutated AML patients. GO only increased OS among HFE WT patients. This is likely related to impaired internalization of the CD33 target. Our data suggest that HFE status should be used as a companion test to predict outcome of AML treated with GO. Disclosures No relevant conflicts of interest to declare.

scholarly journals Multiplex Allele-Specific PCR for Simultaneous Detection of H63D and C282Y HFE Mutations in Hereditary Hemochromatosis

2018 ◽  
Vol 3 (1) ◽  
pp. 10-17
Author(s):  
Heleen H Arts ◽  
Barry Eng ◽  
John S Waye
Keyword(s):  
Hereditary Hemochromatosis ◽  
Simultaneous Detection ◽  
Turnaround Time ◽  
Molecular Diagnostic ◽  
Hfe Gene ◽  
Specific Pcr ◽  
Liver And Pancreas ◽  
Allele Specific ◽  
Hfe Mutations ◽  
Allele Specific Pcr

Abstract Background Hereditary hemochromatosis (HH) is characterized by excessive iron absorption in the intestine, which can lead to failure of vital organs such as the heart, liver, and pancreas. Among northern Europeans, HH is most often associated with the C282Y and H63D mutations of the HFE gene. We developed a test that allows screening for both mutations in a single reaction. Methods A multiplex allele-specific PCR was developed for simultaneous genotyping of the H63D and C282Y HFE mutations. PCR fragments were designed such that the resulting PCR product can be analyzed in a single polyacrylamide gel lane. Results Test results from our multiplex assay were concordant with genotypes of 55 Canadian patients with suspected hemochromatosis, which had previously been established by allele-specific PCRs that targeted H63D and C282Y in separate reactions. Conclusions Molecular diagnostic detection of H63D and C282Y mutations can be achieved by a variety of methods, but these are not necessarily time-efficient or economical. Multiplex allele-specific PCR is an excellent tool for molecular diagnostic screening for H63D and C282Y mutations in patients with suspected hemochromatosis. This method is inexpensive, accurate, and highly efficient in terms of labor, throughput, and turnaround time.

scholarly journals Complete Scanning of the Hereditary Hemochromatosis Gene (HFE) by Use of Denaturing HPLC

2001 ◽  
Vol 47 (9) ◽  
pp. 1633-1640 ◽  
Author(s):  
Gerald Le Gac ◽  
Catherine Mura ◽  
Claude Férec
Keyword(s):  
Hereditary Hemochromatosis ◽  
Hfe Gene ◽  
Test Accuracy ◽  
Melting Profile ◽  
Coding Region ◽  
Hemochromatosis Gene ◽  
Hfe Mutations ◽  
Methods Analytical ◽  
Positive Controls ◽  
Experimental Melting

Abstract Background: Between 4% and 35% of hereditary hemochromatosis (HC) probands are C282Y or H63D heterozygotes or lack both of these two common HFE mutations, and 15 novel HFE mutations have been described recently. We evaluated denaturing HPLC (DHPLC) for screening of the whole HFE coding region and further defined whether HC probands with an incomplete HFE genotype carry uncommon mutations. Methods: Analytical conditions for each coding exon were determined by a combination of computer melting profile predictions and experimental melting curves. To test accuracy for scanning the complete HFE coding region and optimize DHPLC running conditions, each melting domain was investigated with at least one mutation or one polymorphism as reference. We tested 100 DNA samples harboring the C282Y, H63D, or S65C mutations and 17 artificially created positive controls that carried either 1 of the 14 other known HFE mutations or 3 selected polymorphisms. Results: Investigations on each of the coding exons 1, 2, 4, 5, and 6 could be performed at one analysis temperature. Coding exon 3 displayed a more complex melting profile and required two analysis temperatures. DHPLC detected all known HFE mutations as well as the three selected polymorphisms. Conclusions: DHPLC can be used to scan the HFE gene in HC probands in whom at least one chromosome lacks an assigned mutation.

C282Y Mutation and Hepatic Iron Status in Hepatitis C and Cryptogenic Cirrhosis

2000 ◽  
Vol 124 (11) ◽  
pp. 1632-1635
Author(s):  
Priti Lal ◽  
Helen Fernandes ◽  
Baburao Koneru ◽  
Ernest Albanese ◽  
Meera Hameed
Keyword(s):  
Hepatitis C ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
High Risk Patient ◽  
Iron Deposition ◽  
Hfe Gene ◽  
Hepatic Iron ◽  
C282y Mutation ◽  
Cryptogenic Cirrhosis

Abstract Background.—Increased iron deposition in liver is seen in both primary and secondary hemochromatosis. However, it is not uncommon to see significant iron deposition in a liver biopsy, explant, or autopsy specimen without any significant clinical risk factor. Because of the discovery of the candidate gene (HFE) for hereditary hemochromatosis, we may now be able to screen high-risk patient populations for the abnormal mutation (C282Y). Materials and Methods.—In this study we analyzed the livers of 50 transplant patients with a diagnosis of either hepatitis C cirrhosis or cryptogenic cirrhosis for the prevalence of the more common C282Y mutation of the HFE gene and correlated the findings to hepatic iron concentration. Results.—Of the 26 cases of hepatitis C cirrhosis, 3 were found to be heterozygous for the C282Y mutation. Of the 22 cases of cryptogenic cirrhosis, 1 was found to be heterozygous for the C282Y mutation. Stainable iron was increased in hepatitis C cirrhosis (76.9%) as compared to cryptogenic cirrhosis (50%) (P = .05). Of the 3 heterozygotes with hepatitis C cirrhosis, 2 showed hepatic iron concentrations of 3+ and 4+, and 1 showed 1+. Conclusions.—We conclude that patients with hepatitis C have an increased tendency to accumulate iron in the liver, and mutations in the HFE gene play a minor role in hepatic accumulation of iron in these patients.

Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1125-1129 ◽  
Author(s):  
Giuliana Montosi ◽  
Paola Paglia ◽  
Cinzia Garuti ◽  
Carlos A. Guzman ◽  
Judy M. Bastin ◽  
...  
Keyword(s):  
Single Gene ◽  
Hereditary Hemochromatosis ◽  
Phenotypic Expression ◽  
Hereditary Diseases ◽  
Transduction Efficiency ◽  
Hfe Gene ◽  
Wild Type ◽  
Iron Deficient ◽  
High Level

Hereditary hemochromatosis (HC) is one of the most common single-gene hereditary diseases. A phenotypic hallmark of HC is low iron in reticuloendothelial cells in spite of body iron overload. Most patients with HC have the same mutation, a change of cysteine at position 282 to tyrosine (C282Y) in the HFE protein. The role of HFE in iron metabolism and the basis for the phenotypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we studied monocytes–macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expressing HC and transfected them with wild-type HFE by using an attenuated Salmonella typhimurium strain as a gene carrier. The Salmonella system allowed us to deliver genes of interest specifically to monocytes–macrophages with high transduction efficiency. The accumulation of 55Fe delivered by55Fe-Tf was significantly lower in macrophages from patients with HC than from controls expressing wild-type HFE. Transfection of HC macrophages with the HFE gene resulted in a high level of expression of HFE protein at the cell surface. The accumulation of 55Fe delivered by 55Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the55Fe-ferritin pool within the HFE-transfected cells. These results suggest that the iron-deficient phenotype of HC macrophages is a direct effect of the HFE mutation, and they demonstrate a role for HFE in the accumulation of iron in these cells.

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