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PubMed2005

Two novel mutations, L490R and V561X, of the transferrin receptor 2 gene in Japanese patients with hemochromatosis.

BACKGROUND AND OBJECTIVES: The low prevalence of the C282Y mutation of the HFE gene in Japan means that the genetic background of hemochromatosis in Japanese patients remains unclear. In a previous report, we showed that 3 patients from one family had an AVAQ 594-597 deletion of the transferrin receptor (TfR2) gene. This suggests that the TfR2 gene is involved in hemochromatosis in Japanese patients. DESIGN AND METHODS: Nine patients clinically diagnosed with hemochromatosis were included in the study. DNA was extracted from whole blood samples collected with informed consent. The HFE and TfR2 genes were analyzed by sequencing the coding region and splicing sites. RESULTS: There were no mutations in the HFE gene. In the TfR2 gene, 2 novel mutations, 1469T->G (L490R) and 1665delC (V561X), were found in 2 patients. A known variation, 714C-> (I238M), was also found in the patient with L490R. The patient homozygous for both L490R and I238M presented with a mild manifestation of hemochromatosis at the age of 41 years. His liver was cirrhotic with parenchymal iron deposits and the result of a glucose tolerance test was compatible with diabetes mellitus. The patient homozygous for V561X had severe iron overload with the triad of cirrhosis, diabetes mellitus and skin pigmentation at the age of 58 years. INTERPRETATION AND CONCLUSIONS: Taken together with the previous report, 5 of our 12 patients with hemochromatosis manifesting in middle age had mutations in the TfR2 gene. Thus, TfR2 plays a role in the pathogenesis of hemochromatosis in Japan.

Adult↗
PubMed1990

Overview of hemochromatosis.

Hemochromatosis is an autosomal recessive genetic disorder that occurs with high prevalence in populations of European origin. The gene that is abnormal in hemochromatosis is found on the short arm of chromosome 6 in close proximity (approximately 1 centimorgan) to HLA-A, but the product coded for by that gene is unknown. The pathogenetic mechanism in hemochromatosis is that of continued, excessive absorption of dietary iron with loss of normal control mechanisms, leading to a gradual but vast expansion of storage iron as ferritin and especially as hemosiderin. Through mechanisms that probably include peroxidation of lipid membranes, the excess iron injures hepatocytes, islet B cells, gonadotropes in the anterior pituitary, myocardium, synovial cells, and chondrocytes, and probably other cells and tissues as well. Most patients with hemochromatosis remain undiagnosed throughout life. Removal of the excess iron by phlebotomy will prevent all of the complications of hemochromatosis when begun early and will significantly improve survival in virtually all patients. It is important, therefore, that the diagnosis of hemochromatosis be considered much more frequently in clinical medicine in order that this effective therapy be utilized.

Female↗
PubMed1989

HLA determinants in an Australian population of hemochromatosis patients and their families.

The frequencies of different HLA-A and -B alleles in 77 Australian patients with hemochromatosis have been compared with frequencies of HLA alleles not associated with hemochromatosis in 63 of their heterozygous relatives and with published population frequencies. As for all other populations reported, an association of HLA-A3 and HLA-B7 with the disease was found. A weak association with HLA-B12 was also detected. No other significant positive or negative associations with HLA alleles were detected. In addition, HLA-A2 and -B12 were in significant linkage disequilibrium in patients but not in controls, which may indicate a new mutation or recent recombination between HLA-A and hemochromatosis either in our patient group or in the founding population. HLA-A1 and -B8 and HLA-A29 and -B12 were in linkage disequilibrium in controls but not in patients, suggesting that this population is not segregating a hemochromatosis allele on either of these haplotypes. Genetic linkage analysis using the program LIPED showed strong linkage in 23/24 families, most of which had additional HLA alleles (other than A3 and B7) associated with hemochromatosis. This provides evidence for a single hemochromatosis locus, possibly with more than one allele.

Alleles↗
PubMed1989

Ferritin release by mononuclear cells in hereditary hemochromatosis.

An anomaly of the iron-loading disorder hereditary hemochromatosis is that bone marrow iron stores remain low until later stages of the disease. The possibility that this may be related to a disorder of reticuloendothelial ferritin metabolism was examined by studying ferritin release from mononuclear cells. Ferritin release was measured in peripheral blood mononuclear cells from four patients with hemochromatosis who had not received treatment, from six patients with hemochromatosis who had received treatment, and from 10 age- and gender-matched controls by using a modified hemolytic plaque assay. Ferritin release from the hemochromatotic cells was enhanced when compared with that of controls, and added iron stimulated ferritin release to a comparable degree in both groups. Enhanced ferritin release above matched control values was found both in cells from patients with hemochromatosis with partial phlebotomy who had high serum ferritin values and in cells from patients with hemochromatosis with full phlebotomy who had normal serum ferritin values. The increased ferritin release observed in these studies may signify abnormal reticuloendothelial iron metabolism in hemochromatosis.

Aged↗
PubMed1994

Outcome of liver transplantation in patients with hemochromatosis.

Recent preliminary reports suggest a poor outcome of orthotopic liver transplantation for patients with hemochromatosis. We analyzed an institutional experience with orthotopic liver transplantation for hemochromatosis, focusing on factors contributing to increased morbidity and mortality. Between March 1988 and October 1992, nine of 249 adults (3.6%) undergoing orthotopic liver transplantation had hemochromatosis. Mean age was 53 yr (range, 42 to 62 yr), and eight of nine patients were men. The diagnosis of hemochromatosis was based on transferrin saturation > 62% and hepatic iron index > 2.0. Only two patients were known to have hemochromatosis before liver transplantation. All nine patients underwent standard cardiac evaluation before transplantation, and no patient had detectable pre-existing cardiac disease. One patient had a major operative cardiac complication as a result of pulmonary embolism and made a full recovery. Postoperatively, congestive heart failure developed in three patients and four patients had arrhythmias. One patient is undergoing phlebotomy for post-transplant cardiac complications from hemochromatosis. Two patients had primary hepatic tumors in the explant liver. There were four deaths caused by multiorgan failure with congestive heart failure (1), infection (2), and/or malignancy (2). Five patients are alive 3 to 25 mo post-transplant. The actuarial survival of the nine patients was 53% at 25 mo vs. 89% for 18 age- and sex-matched control transplant recipients (p = 0.1) and 81% for all other adult liver transplant recipients (p < 0.01). In five of seven patients, post-transplant liver biopsies revealed hepatic iron accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1994

Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population. In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. Overall, the establishment of a likely "hemochromatosis critical region" centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect.

Alleles↗
PubMed1997

Hereditary hemochromatosis: presentation and diagnosis in the 1990s.

OBJECTIVES: In the past, patients with hereditary hemochromatosis have been identified predominantly from symptomatic presentation or from family studies. In the 1990s, iron studies on routine screening chemistry panels have become more commonplace. The purpose of this paper is to describe the clinical, laboratory, and presenting features of a series of patients with hereditary hemochromatosis, diagnosed from 1990 to 1995. METHODS: Clinical information, serum and liver iron studies, liver histology, and phlebotomy requirements were evaluated in 40 patients with newly diagnosed hereditary hemochromatosis prospectively referred to a tertiary university-based hepatology clinic. RESULTS: Eighty-three percent of patients came to medical attention as a result of screening blood work: 73% were asymptomatic and 78% had normal physical examinations. Only three patients had cirrhosis from hemochromatosis alone, only two were diabetic, and only two had increased skin pigmentation. These findings are in contrast to previous reports of hemochromatosis probands in which patients with symptoms and more advanced disease were identified. The hepatic iron concentration, hepatic iron index, and age at diagnosis were similar for men and women. CONCLUSIONS: With the use of screening iron studies on routine serum chemistry panels, patients with hemochromatosis can be identified and subsequently treated before they have symptoms or organ damage.

Adult↗
PubMed1998

[Diagnosis of hereditary hemochromatosis with molecular analysis of DNA in patients with anti-HCV positive liver cirrhosis. Clinical case].

A case of hereditary hemochromatosis in a patient affected by anti-HCV positive liver cirrhosis is described. The difficulties for an exact diagnosis are underlined. Really, it can be particularly difficult to make a differential diagnosis between hereditary hemochromatosis and secondary hemochromatosis, if liver cirrhosis has already been found. Practically, at this stage of disease, the histological and clinical aspects of these two forms become completely interchangeable. Moreover, diagnostic difficulties increase when, at the same time, the patient presents more causes of potential liver damage. In this case report, the DNA-analysis, obtained by polymerase chain reaction amplification and enzymatic digestion, allows to make the diagnosis of hereditary hemochromatosis, because it showed the presence of two genetic mutations, considered responsible for the disease. Both the hereditary hemochromatosis and the HCV infection, had greatly contributed to the development of liver cirrhosis. In the future, DNA-analysis by amplification with polymerase chain reaction, can assume relevant importance for the screening of affected patients' first grade parents too. It could permit an early diagnosis of hereditary hemochromatosis and then to start a timelier and more efficacious therapy, to prevent an irreversible histological damage.

DNA↗
PubMed1999

Inherited HFE-unrelated hemochromatosis in Italian families.

Hemochromatosis (HH) is usually caused by the homozygous state for C282Y mutation in the HFE gene. A minority of iron loaded patients have no mutations in this gene. An infrequent subset shows an early-onset aggressive disorder, denoted juvenile hemochromatosis (JH), which has no linkage to 6p. In this report we describe six patients from three unrelated Italian families, four men and two women, aged 21 to 44 with the typical hemochromatosis phenotype, who are homozygous for the wild type allele at the HFE gene. In two families the disorder is unlinked to 6p; in one family some features of the juvenile form are seen, but linkage to 6p is not excluded. Our results point to genetic forms of hemochromatosis not associated with HFE and raise the problem of whether non-HFE hemochromatosis in Italy is related to the "juvenile" form. They also emphasize the importance of phenotypic as well as genetic diagnosis of HH.

Adult↗
PubMed1997

Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases.

This report assesses the degree of iron overload in a cohort of patients in relationship to the presence or absence of the recently described 845 G-->A (C282Y) and 187 C-->G (H63D) mutations in the HFE (HLA-H) gene. Sixty-one patients with hereditary hemochromatosis diagnosed either with liver biopsy or on clinical grounds were included in this analysis. Forty-one patients were homozygous for C282Y, the genotype considered to be characteristic of hereditary hemochromatosis. At the time of this analysis, 37 of these 41 patients had achieved a state of iron depletion and mobilizable iron was calculated: 19 had less than 4 grams. Twenty-five of these 41 patients had liver biopsies; 4 of these patients had a hepatic iron index less than 1.9. Of the 4 patients with a normal hepatic iron index, 3 had a quantitative hepatic iron of greater than 50 micromol/g dry weight, and one had an inadequate biopsy sample. These findings support our suspicion that individuals may have hereditary hemochromatosis and homozygous C282Y despite relatively low body iron stores. Five patients were compound heterozygotes for C282Y and H63D. Four of these patients underwent liver biopsy; two had a hepatic iron index greater than 1.9. a third patient had a hepatic iron index of 1.3 but a quantitative hepatic iron of 90.6 micromol/g dry weight. All patients were phlebotomized to a state of iron depletion and only one of these patients had a mobilizable iron greater than 4 grams. Three patients were homozygous for H63D; these patients had either a hepatic iron index >1.9 or greater than 4 grams of mobilizable iron. Patients with homozygous H63D and significant iron overload are not well described. Seven patients were heterozygous for either C282Y or H63D; 4 had significant iron overload but three did not. Five patients had no HFE mutations; one of these patients unequivocally has iron overload with a hepatic iron index of 4.4 We conclude that: (1) Identification of HFE mutations will be clinically useful in identifying patients with hereditary hemochromatosis, (2) Patient genotyping will help confirm a diagnosis of hereditary hemochromatosis in some patients with relatively low body iron stores, (3) Significant iron loading can occur in the absence of homozygous C282Y, adding to the evidence that genes other than HFE may be involved in iron loading, and (4) Homozygous H63D can be associated with significant iron overload.

Adult↗
PubMed1999

A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria.

BACKGROUND/AIMS: The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings. METHODS: In 217 patients, the phenotypic diagnosis of hemochromatosis was based on strict bioclinical and/or histological criteria, and their genotypic profile (C282Y and H63D mutations) was determined. RESULTS: 1) 209 of the 217 probands were C282Y +/+. In 33 cases, an HFE-identical sibling was identified. Two of them had neither a clinical nor a biochemical phenotypic profile of hemochromatosis in the absence of any external factor which might have attenuated this expression. 2) Eight patients (seven males) were not C282Y +/+. Their genotypic profiles were: (C282Y +/-): six cases (four were H63D +/- and two H63D -/-); (C282Y -/-): two cases (one was H63D +/+, one H63D +/-). Phenotypic expression consisted of six cases of mild liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload (one with alcoholic cirrhosis). Three HFE-identical siblings were identified, none of them presenting with iron excess. CONCLUSIONS: In our population: 1) The classical phenotypic criteria fitted, in 96.3% of cases, with a homogeneous genotypic entity defined by homozygosity for the C282Y mutation. Incomplete penetrance of the homozygous status was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might present with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.

Adult↗
PubMed2002

A homozygous HFE gene splice site mutation (IVS5+1 G/A) in a hereditary hemochromatosis patient of Vietnamese origin.

The vast majority of Caucasian patients presenting with hereditary hemochromatosis demonstrate a single homozygous missense mutation in the HFE gene (C282Y). The underlying genetic defects in hemochromatosis patients of non-Caucasian origin are largely unknown. A 48-year-old man of Vietnamese origin presented with insulin-dependent diabetes mellitus, tertiary adrenocortical insufficiency, and laboratory results highly indicative of hereditary hemochromatosis. Because the patient was negative for the known HFE gene mutations C282Y, H63D, and S65C HFE, the entire coding region and intron/exon boundaries of the HFE gene was investigated. Sequencing studies identified a homozygous G-to-A transition at position +1 of intron 5 (IVS5+1 G/A). This newly described mutation alters the invariant G at position +1 of the 5' splice site causing altered mRNA splicing and exon skipping with exon 4 being spliced to exon 6. Both heterozygously affected children (age 19 and 20 years) had moderately increased ferritin levels with normal serum iron concentration and transferrin saturation. The newly described mutation was not detected in a control group consisting of 220 Caucasian individuals as verified by allele-specific polymerase chain reaction. We describe for the first time a homozygous HFE splice site mutation (IVS5+1 G/A) in a non-Caucasian patient with hereditary hemochromatosis. Although the absence of this novel HFE gene mutation in Caucasian subjects suggests that the mutation is exclusive to this family, mutation screening in populations of different ethnic background is recommended to precisely define its contribution to hereditary hemochromatosis in non-Caucasian patients.

Asian People↗
PubMed2002

Juvenile hemochromatosis.

Juvenile hemochromatosis or type 2 hemochromatosis is a rare inherited recessive disease, which leads to severe iron overload earlier in life than HFE-related hemochromatosis. Increased transferrin saturation and serum ferritin as well as parenchymal iron deposition and liver fibrosis may be observed in childhood. Clinical symptoms of hypogonadism and cardiac disease develop before the age of 30. The disease is usually progressive and if untreated may become fatal because of heart failure. The type 2 hemochromatosis locus maps to chromosome 1q21, but the gene has not yet been isolated. The severity and the early expression of juvenile hemochromatosis suggest that the gene product has a crucial role in the regulation of iron homeostasis.

Adolescent↗
PubMed1999

A population-based study of the clinical expression of the hemochromatosis gene.

BACKGROUND AND METHODS: Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. RESULTS: Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. CONCLUSIONS: In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

Adult↗
PubMedDate not supplied

Diagnosis of hemochromatosis in family members of probands: a comparison of phenotyping and HFE genotyping.

PURPOSE: We wanted to compare phenotyping and HFE genotyping for diagnosis of hemochromatosis in 150 family members of 61 probands. METHODS: Phenotypes were defined by persistent transferrin saturation elevation, iron overload, or both; genotypes were defined by HFE mutation analysis. RESULTS: Twenty-five family members were C282Y homozygotes; 23 of these (92%) had a hemochromatosis phenotype. Twenty-three family members had HFE genotype C282Y/H63D; eight of these (35%) had a hemochromatosis phenotype. Six of 102 (6%) family members who inherited other HFE genotypes had a hemochromatosis phenotype. CONCLUSION: Phenotyping and genotyping are complementary in diagnosing hemochromatosis among family members of probands.

Adult↗
PubMed2004

Expression of the HFE hemochromatosis gene in a community-based population of elderly women.

BACKGROUND AND AIM: Recent studies suggest that the clinical penetrance of associated hereditary hemochromatosis, defined as either the C282Y homozygote or compound heterozygote HFE genotype status, is much lower than previously thought. METHODS: We investigated the clinical penetrance and phenotypic expression of HFE-associated hereditary hemochromatosis in a community-based population of 1352 elderly female subjects with a mean age of 75 years. Serum transferrin saturation and ferritin levels were determined on all subjects bearing a C282Y mutation and a subset of wild-type C282Y subjects. RESULTS: The prevalences of the C282Y homozygous and compound heterozygous HFE genotypes were 0.15% (2/1352) and 2.0% (27/1352), respectively. The observed prevalence of 0.15% for C282Y homozygotes borders on significance (P = 0.054) for deviation from the Hardy-Weinberg population equilibrium calculations, which predict a prevalence of 0.49%, whereas the observed and predicted compound heterozygote prevalences were not significantly different. Clinical symptoms of hemochromatosis were absent in both the C282Y homozygote subjects. Of the compound heterozygous subjects, 2/27 (7%) had elevated serum transferrin saturation and ferritin values; however, clinical symptoms of hemochromatosis were absent in both. Considered as a whole, the compound heterozygous subjects had markedly elevated means for serum iron (19.4 vs 16.0 micromol/L, P = 0.0008), transferrin saturation (34.8% vs 25.2%, P < 0.0001) and ferritin (157 vs 92 microg/L, P = 0.002) compared with the wild-type subjects. CONCLUSION: The C282Y homozygous HFE hereditary hemochromatosis genotype was under-represented in this elderly cohort, whereas the compound heterozygous genotype was not. None of the homozygous or compound heterozygous subjects expressed the phenotype of iron overload disease.

Aged↗
PubMed2000

HFE-associated hereditary hemochromatosis.

Hereditary hemochromatosis is a common inherited disorder of the iron metabolism. Screening studies indicate that it has a prevalence of one in 200 to 400, depending on the population studied, and a carrier rate of about one in seven to one in 10. Feder et al identified the hereditary hemochromatosis gene (HFE) in 1996 and two candidate mutations; the C282Y mutation has been shown to be responsible for the majority of the hereditary hemochromatosis cases worldwide. The gene discovery has led to rapid advances in the field of iron metabolism. Although the basic defect is still not fully understood, much is known about the sequence of events leading to iron overload. Hereditary hemochromatosis is a major candidate for population screening and meets the screening criteria of the World Health Organization, and Wilson and Jungner. It is one of the most prevalent genetic diseases in white populations, and, importantly, early diagnosis and simple effective treatment allow normal life expectancy. The discovery of the HFE gene and the frequency of the single C282Y mutation as a cause of most cases of hereditary hemochromatosis allow the possibility of widespread genetic testing. However, the logistics, and the psychological and social consequence of this, coupled with incomplete expression of the genotype, necessitate further studies before population screening can be justified.

Genotype↗
PubMed2000

Genes that modify the hemochromatosis phenotype in mice.

Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mutation in HFE, which encodes an atypical HLA class I protein involved in regulation of intestinal iron absorption. To gain insight into the pathogenesis of hemochromatosis, we have bred Hfe knockout mice to strains carrying other mutations that impair normal iron metabolism. Compound mutant mice lacking both Hfe and its interacting protein, beta-2 microglobulin (B2m), deposit more tissue iron than mice lacking Hfe only, suggesting that another B2m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicating that hemochromatosis involves iron flux through DMT1. Similarly, compound mutants deficient in both Hfe and hephaestin (Heph) show less iron loading than do Hfe knockout mice, indicating that iron absorption in hemochromatosis involves the function of Heph as well. Finally, compound mutants lacking Hfe and the transferrin receptor accumulate more tissue iron than do mice lacking Hfe alone, consistent with the idea that interaction between these two proteins contributes to the control of normal iron absorption. In addition to providing insight into the pathogenesis of HH, our results suggest that each of these genes might be a candidate modifier of the human hemochromatosis phenotype.

Animals↗