Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy.
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BACKGROUND: Two common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease. OBJECTIVE: To investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy. DESIGN AND SETTING: Case-control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre. METHODS: 207 unrelated white patients with dilated cardiomyopathy, followed up for 259 patient years, and 200 controls were tested for HFE C282Y and H63D mutations by polymerase chain reaction and restriction digestion. RESULTS: 31/207 patients (15%) v 24/200 controls (12%) carried C282Y (adjusted odds ratio (OR) 1.2 (95% confidence interval 0.7 to 2.2)), 74/207 (36%) v 53/200 (27%) carried H63D (OR 1.6 (1.1 to 2.5)), and 10/207 (4.8%) v 4/200 (2%) were compound heterozygotes (OR 2.6 (0.8 to 8.5)). Four patients and six controls were H63D homozygous and one was C282Y homozygous. There was a progressive increase in mean serum iron ([Fe]) and transferrin saturations from patients with no mutation ([Fe] = 16.3 micromol/l, transferrin saturation = 23.7%) through H63D heterozygotes (17.5 micromol/l, 25.8%), C282Y heterozygotes (17.1 micromol/l, 26.6%), H63D homozygotes (20.0 micromol/l, 33.5%), compound heterozygotes (26.8 micromol/l, 41.7%), and C282Y homozygotes (34 micromol/l, 71%). At follow up (median 90 months) the rate of death or cardiac transplantation was 52/207 (25%). C282Y heterozygotes had less ventricular dilatation (mean (SD): 59.9 (1.7) mm v 64.9 (0.9) mm, p < 0.05), better fractional shortening (24 (1. 7)% v 18.8 (1.4)%, p < 0.01), and a trend towards improved survival without transplantation. [Fe] and transferrin saturation did not correlate with disease severity and were not associated with reduced survival. CONCLUSIONS: The frequency of the H63D mutation is significantly increased in patients with idiopathic dilated cardiomyopathy. As H63D has a relatively minor effect on iron status, the mechanism of this association may be unrelated to iron metabolism. (+info)
Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases.
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Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene. (+info)
Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.
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Porphyria cutanea tarda is a skin disease caused by photosensitization by porphyrins whose accumulation is caused by deficiency of hepatic uroporphyrin- ogen decarboxylase activity. Mutations in the uroporphyrinogen decarboxylase gene are present in the low-penetrant, autosomal dominant familial form but not in the commoner sporadic form of porphyria cutanea tarda. We have investigated the relationship between age of onset of skin lesions and mutations (C282Y, H63D) in the hemochromatosis gene in familial (19 patients) and sporadic porphyria cutanea tarda (65 patients). Familial porphyria cutanea tarda was identified by mutational analysis of the uroporphyrinogen decarboxylase gene. Five previously described and eight novel mutations (A80S, R144P, L216Q, E218K, L282R, G303S, 402-403delGT, IVS2 + 2 delTAA) were identified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda, the effect being more marked in familial porphyria cutanea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation has much less effect on the development of the disease. (+info)
Hereditary hemochromatosis in a patient with congenital dyserythropoietic anemia.
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Herein is described the case of a young woman presenting with iron overload and macrocytosis. The initial diagnosis was hereditary hemochromatosis. Severe anemia developed after a few phlebotomies, and she was also found to have congenital dyserythropoietic anemia that, though not completely typical, resembled type II. Only genetic testing allowed the definition of the coexistence of the 2 diseases, both responsible for the iron overload. This report points out the need to consider congenital dyserythropoietic anemia in patients with hemochromatosis and unexplained macrocytosis and, conversely, to check for the presence of hereditary hemochromatosis in patients with congenital dyserythropoietic anemia and severe iron overload. To the authors' knowledge, this is the first report of homozygosity for the C282Y mutation of the HFE gene in a patient affected by congenital dyserythropoietic anemia. (+info)
Hepatic iron overload in aceruloplasminaemia.
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We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux. (+info)
Interactions of the ectodomain of HFE with the transferrin receptor are critical for iron homeostasis in cells.
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Expression of wild type HFE reduces the ferritin levels of cells in culture. In this report we demonstrate that the predominant hereditary hemochromatosis mutation, C282Y(2) HFE, does not reduce ferritin expression. However, the second mutation, H63D HFE, reduces ferritin expression to a level indistinguishable from cells expressing wild type HFE. Further, two HFE cytoplasmic domain mutations engineered to disrupt potential signal transduction, S335M and Y342C, were functionally indistinguishable from wild type HFE in this assay, as was soluble HFE. These results implicate a role for the interaction of HFE with the transferrin receptor in lowering cellular ferritin levels. (+info)
Disease-related conditions in relatives of patients with hemochromatosis.
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BACKGROUND: Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. Although screening has been proposed, the proportion of homozygotes with conditions related to hemochromatosis is uncertain. METHODS: We studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis. We identified probands who presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. We identified homozygous relatives, mainly siblings, on the basis of HLA identity with the proband and by HFE genotyping. Disease-related conditions were cirrhosis, hepatic fibrosis, elevated amino-transferase values, and hemochromatotic arthropathy. RESULTS: We identified 214 homozygous relatives of 291 homozygous probands. Of the 113 men in this group (mean age, 41 years), 96 (85 percent) had iron overload, and 43 (38 percent) had at least one disease-related condition. Of the 52 men over 40 years of age, 27 (52 percent) had at least one disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68 percent) had iron overload, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years of age, 7 (16 percent) had at least one disease-related condition. If the proband had a disease-related condition, relatives who were men were more likely to have morbidity than if the proband had no disease-related condition. CONCLUSIONS: A substantial number of homozygous relatives of patients with hemochromatosis--more commonly men than women--have conditions related to hemochromatosis that have yet to be detected clinically. (+info)
Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles.
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Screening for hereditary hemochromatosis (HHC) by means of transferrin saturation (TS) levels has been advocated and will identify many patients who are asymptomatic. The purposes of this study were (1) to determine HFE genotypes among asymptomatic HHC patients and correlate this profile with the degree of iron overload and (2) to evaluate the relationship between mobilized iron (mob Fe), age, serum ferritin (SF), and quantitative hepatic iron (QHI) in this population. One hundred twenty-three asymptomatic HHC patients were evaluated; all had quantitative phlebotomy to determine mob Fe and genotyping for C282Y and H63D mutations. Liver biopsies with QHI determinations were performed on 72 of the 123 patients. Of the entire group, 60% were homozygous for C282Y, and 13% were compound heterozygotes (C282Y/H63D). Among asymptomatic patients, the prevalence of homozygous C282Y is lower compared with previous studies that include clinically affected patients. Of those patients with more than 4 g mob Fe, 77% were homozygous C282Y. Asymptomatic patients with lower iron burdens frequently had genotypes other than homozygous C282Y. There was no correlation between age and mob Fe in these patients; however, there was a correlation between mob Fe and both SF (r = 0.68) and QHI (r = 0.75). In conclusion, asymptomatic patients with moderate iron overload had a different genotypic profile than was seen in advanced iron overload. The significance of identifying patients with modest degrees of iron loading, who may not be homozygous for C282Y, must be addressed if routine TS screening is to be implemented. (Blood. 2000;96:3707-3711) (+info)