[A potential etiology of elevated ferritin: hyperferritinemia-cataract syndrome].
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Cataract↗
Biomedical subjects
C Beaumont
Publications and source records attributed to C Beaumont.
Iron metabolism, free radicals, and oxidative injury.
Iron has the capacity to accept and donate electrons readily. This capability makes it physiologically essential, as a useful component of cytochromes and oxygen-binding molecules. However, iron is also biochemically dangerous; it can damage tissues by catalyzing the conversion of hydrogen peroxide to free-radical ions that attack cellular membranes, protein and DNA. This threat is reduced in the healthy state where, because of the fine iron metabolism regulation, there is never appreciable concentration of 'free iron'. Under pathological conditions, iron metabolism and superoxide metabolism are clearly interactive. Each can exacerbate the toxicity of the other. Iron overload may amplify the damaging effects of superoxide overproduction in a very broad spectrum of inflammatory, both acute and chronic, conditions. Furthermore, chronic oxidative stress may modulate iron uptake and storage, leading to a self-sustained and ever-increasing spiral of cytotoxic and mutagenic events. The iron chelator deferroxamine is able to chelate 'free iron' even inside the cell. Its regular clinical use is to promote the excretion of an iron overload, when phlebotomy is harmful, and the dosage varies between 2-10 g/d. In conditions where deferroxamine is used to prevent the iron-driven oxygen toxicity, i.e., acute or chronic inflammatory diseases with oxidative stress, the dosage can be extremely reduced and the addition of antioxidants could be useful.
Antioxidants↗
Denaturing gradient gel electrophoresis screening for mutations in the hereditary hyperferritinaemia cataract syndrome.
Hereditary hyperferritinaemia cataract syndrome (HHCS) is characterized by hyperferritinaemia without iron overload. It is essential to differentiate true iron accumulation from HHCS as these patients rapidly develop iron-deficient anaemia when subjected to phlebotomies. The diagnosis of HHCS relies on the identification of point mutations or deletions present in the iron-responsive element of the first exon of the L-ferritin gene. However, many samples referred for diagnosis of putative HHCS are normal. To avoid unnecessary DNA sequencing, we have developed a diagnosis strategy based on the screening of the target DNA region by denaturing gradient gel electrophoresis. This method enabled the accurate identification of 11 different previously known mutations. This strategy will be of interest for family studies or for the screening of large series of patients.
5' Untranslated Regions↗
Estimation of the genetic parameters of meat characteristics and of their genetic correlations with growth and body composition in an experimental broiler line.
Genetic parameters of breast meat characteristics [pH 15 min postmortem (pH15min), ultimate pH (pHu), CIELAB color parameters (L*, lightness; a*, redness; b*, yellowness) and drip loss (DL)] as well as their genetic correlations with BW and body composition [breast yield (BRY) and abdominal fat percentage (AFP)] were estimated in an experimental meat-type chicken line. Heritability of the pH of meat was high for pHu (0.35 +/- 0.03) and even more so for pH15min (0.49 +/- 0.01). Color parameters appeared to be the most heritable traits, with heritability values ranging from 0.50 to 0.57. Drip loss heritability was estimated at 0.39 +/- 0.04. The rate and the extent of pH decline seemed to be controlled by different genes, as shown by the extremely low estimated genetic correlation (0.02 +/- 0.04) between pH15min and pHu. The ultimate pH of the meat was genetically very strongly related to its lightness (-0.91 +/- 0.02) and water-holding capacity (-0.83 +/- 0.04). These results suggest that selection for pHu could be exploited to prevent increased incidence of pale and exudative meat. The pH15min was poorly correlated with the other meat characteristics, with estimated correlations of 0.13, -0.23, 0.05, and -0.29 for L*, a*, b*, and DL, respectively. These results may be explained by the fact that, in our experimental conditions, pH15min remained high (between 6.01 and 6.75). Body weight and BRY exhibited poor genetic correlations (ranging from -0.06 to 0.13) with the pH of the meat at 15 min and 24 h postmortem. Both of the former traits were moderately negatively correlated with a* and b* values. A significant negative genetic correlation was observed between abdominal fatness and pHu. These results do not support the idea that selection for growth and breast development has a detrimental effect on breast meat quality even if, in the long term, the color intensity could be decreased.
Animals↗
Genetic analysis of a selection experiment on the growth curve of chickens.
A selection experiment on the shape of the growth curve was performed on meat-type chickens through combined selection on juvenile and adult BW. Line X-+ was selected for low BW at 8 wk (BW8) and high BW at 36 wk (BW36). Line X+- was selected for high BW8 and low BW36. Line X++ was selected for high BW8 and BW36, and X-- was selected for low BW8 and BW36. Line X00 was maintained as an unselected control. Data on the first 14 generations (i.e., 38,693 birds) were used. The growth curve was modeled using a Gompertz function on 7,143 birds that were weighed regularly. Selection for higher BW8 increased BW from 4 to 16 wk, initial specific growth rate, and maturation rate and decreased age at inflection. Selection for higher BW36 resulted in increased BW36, asymptotic BW, and estimated BW at hatching. Body weights were more modified in Lines X++ and X--, but the growth curve parameters changed more in Lines X-+ and X-- than in Lines X++ and X+-.
Aging↗
[Hereditary hyperferritinemia syndrome and cataract].
UNLABELLED: Hereditary hyperferritinemia cataract is a recently described autosomal dominant syndrome, characterized by bilateral cataracts and elevated level of serum ferritin. PATIENTS: Three members of a family were investigated for cataract and hyperferritinemia. A 30-year-old woman had elevated serum ferritin levels and bilateral cataracts. She was treated for hemochromatosis, but serum iron and transferrin saturation were normal. Her two sons, nine and five years old, also had a high ferritin level and bilateral cataracts. RESULTS: The ferritin level was 1200 micrograms/L in the woman's serum, and respectively, 974 and 965 micrograms/L in the two boys' serum. The mother had a visual acuity of 8/10 in the right eye and 5/10 in the left eye. The cataract comprised fine crystalline cortical opacities, extending axially. The two sons had 7 to 8/10 in both eyes. No other ophthalmic abnormality was noted. These patients were heterozygous for a 16 bp deletion on the L-ferritin gene. DISCUSSION: Ferritin is an iron storage ubiquitous protein present in every cell. In hyperferritinemia cataract syndrome, serum iron and transferrin saturation are normal, and the elevated serum ferritin level is the consequence of an autosomal dominant disorder. The cataract is made up of the accumulation of small opacities disposed radially and more numerous on the outside edges, with relatively good visual acuity. The size of the cataract seems to be correlated to the serum ferritin level. In hemochromatosis, hyperferritinemia is related to increased iron stores and is not associated with cataracts.
Adult↗
Strengthening NZNO in a new industrial environment.
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Humans↗
Early embryonic lethality of H ferritin gene deletion in mice.
Ferritin molecules play an important role in the control of intracellular iron distribution and in the constitution of long term iron stores. In vitro studies on recombinant ferritin subunits have shown that the ferroxidase activity associated with the H subunit is necessary for iron uptake by the ferritin molecule, whereas the L subunit facilitates iron core formation inside the protein shell. However, plant and bacterial ferritins have only a single type of subunit which probably fulfills both functions. To assess the biological significance of the ferroxidase activity associated with the H subunit, we disrupted the H ferritin gene (Fth) in mice by homologous recombination. Fth(+/-) mice are healthy, fertile, and do not differ significantly from their control littermates. However, Fth(-/-) embryos die between 3.5 and 9.5 days of development, suggesting that there is no functional redundancy between the two ferritin subunits and that, in the absence of H subunits, L ferritin homopolymers are not able to maintain iron in a bioavailable and nontoxic form. The pattern of expression of the wild type Fth gene in 9.5-day embryos is suggestive of an important function of the H ferritin gene in the heart.
Animals↗
Crystallization and preliminary X-ray diffraction data of mouse L-chain apoferritin crystals.
Crystals of recombinant mouse L-chain apoferritin were obtained by the hanging-drop technique using ammonium sulfate as precipitant. Two crystal forms were observed in the same drop. The crystals belong to either the P2 monoclinic or to the P42(1)2 tetragonal space group. The monoclinic crystals diffracted to beyond 2.4 A resolution but were systematically twinned, while the tetragonal crystals diffracted to beyond 2.9 A. These crystallization conditions in the absence of metal salts should facilitate the study of the interaction between L-chain ferritins and heavy metals, particularly the iron core.
Animals↗
Inactivation of iron responsive element-binding capacity and aconitase function of iron regulatory protein-1 of skin cells by ultraviolet A.
The ultraviolet-A (UVA) component of sunlight produces in cutaneous cells a highly toxic oxidative stress mediated by redox cycling reactions of Fe ions. A tight regulation of cell iron uptake and storage by iron regulatory proteins (IRP) of keratinocytes and fibroblasts avoids these damaging reactions. We report here that about 40 J/cm2 of UVA are required to inactivate half of the binding capacity of apo-IRP-1 to iron responsive elements (IRE) of RNA whereas 15 J/cm2 already inhibit half of the holo-IRP-1 aconitase activity. No increase in the holo-IRP-1 activity is observed during the apo-IRP-1 photoinactivation suggesting that UVA does not trigger a shift between these two forms. As opposed to holo-IRP-1, which contains a 4Fe-4S cluster, apo-IRP-1 has no UVA chromophore. Thus it should be inactivated indirectly by reactive oxygen species generated by the UVA-induced endogenous photo-oxidative stress. The apo-IRP-1 photoinactivation is weakly prevented by the lipophilic oxyradical scavenger vitamin E but not by the hydrophilic azide anion, a singlet oxygen quencher or by diethyldithiocarbamate, a superoxide dismutase inhibitor. However, full protection against photoinactivation of the apo form is observed after incubation with N-acetylcysteine but the latter only partially protects the aconitase function of the holo-IRP-1 from photoinactivation. The marked difference in the kinetics of photoinactivation of the apo and holo forms, the light dose-independent effect of the sulfhydril group reagent, 2-mercaptoethanol and the partial protection brought by the ferric ion complexing agent desferrioxamine suggest that the photochemistry of the 4Fe-4S cluster of the holo form plays little, if any, role in the photoinactivation of the apo-IRP-1/IRE interaction. It is concluded that the apo/holo equilibrium is irreversibly destroyed by UVA irradiation.
Aconitate Hydratase↗
Genetic analysis of growth curve parameters for male and female chickens resulting from selection on shape of growth curve.
The objectives of this research were to evaluate gender differences and selection on body weight as they affect growth curves of chickens. Marginal posterior densities of growth curve parameters were studied by Gibbs sampling on 10,671 male and female chickens originating from five lines. Line X-+ was selected on low body weight at 8 wk (BW8) and high body weight at 36 wk (BW36), line X+- on high BW8 and low BW36, X++ on high BW8 and BW36, X-- on low BW8, and BW36, and X00 was an unselected control line. Growth was modeled by a Gompertz function. Heritabilities and genetic correlations among parameters of the Gompertz curve were estimated. Marginal posterior densities were drawn for parameters of the growth curve and for sexual dimorphism at ages ranging from hatching to 1 yr. Lines selected for a higher BW8 had higher initial specific growth rates (L), higher maturation rates (K), and lower ages at inflection (T(I)). Lines selected for a higher BW36 had higher asymptotic body weights (A). Estimates of A, L, and T(I) were higher in males and K was higher in females. Difference between sexes for A was greater in the line selected for a lower BW8 and a higher BW36. Dimorphism for L and K was the lowest in lines X++ and X--, respectively. The greatest difference in T(I) was observed in the line selected for lower BW8 and BW36. Sexual dimorphism of body weight was lower at most ages in the lightest line. Before 15 wk, sexual dimorphism in X++ line was lower than in the line selected for higher BW8 and lower BW36. The increase in sexual dimorphism with body weight could be reduced by selecting animals on body weight at two ages instead of one, as is usually done in commercial lines.
Animals↗
[Intracellular iron metabolism].
Iron is essential to life but it is poorly soluble in biological fluids and toxic in excess. Organisms have developed multiple proteins to insure iron transport and storage, and some of these have only been discovered recently. Among them, members of the Nramp family are transmembrane proteins which transport several divalent cations, including Fe2+. These proteins participate in intestinal iron absorption, erythopoiesis and microbial defence. Frataxin, which is deficient in Friedreich's ataxia, regulates iron flux through mitochondria. The intracellular labile iron pool, an intermediate form of iron between different subcellular compartments, regulates ferritin synthesis and stability of mRNA coding for proteins of iron transport. Subunit composition of ferritin plays an important role in the control of the size of this labile iron pool.
Carrier Proteins↗
The haptoglobin 2-2 phenotype affects serum markers of iron status in healthy males.
BACKGROUND: Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. METHODS: Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled ((125)I) hemoglobin-haptoglobin complexes. RESULTS: In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of (125)I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. CONCLUSIONS: The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.
Adolescent↗
H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties.
The labile iron pool (LIP) of animal cells has been implicated in cell iron regulation and as a key component of the oxidative-stress response. A major mechanism commonly implied in the downregulation of LIP has been the induced expression of ferritin (FT), particularly the heavy subunits (H-FT) that display ferroxidase activity. The effects of H-FT on LIP and other physiological parameters were studied in murine erythroleukemia (MEL) cells stably transfected with H-FT subunits. Clones expressing different levels of H-FT displayed similar concentrations of total cell iron (0.3 +/- 0.1 mmol/L) and of reduced/total glutathione. However, with increasing H-FT levels the cells expressed lower levels of LIP and reactive oxygen species (ROS) and ensuing cell death after iron loads and oxidative challenges. These results provide direct experimental support for the alleged roles of H-FT as a regulator of labile cell iron and as a possible attenuator of the oxidative cell response. H-FT overexpression was of no apparent consequence to the cellular proliferative capacity. However, concomitant with the acquisition of iron and redox regulatory capacities, the H-FT-transfectant cells commensurately acquired multidrug resistance (MDR) properties. These properties were identified as increased expression of MDR1 mRNA (by reverse transcription polymerase chain reaction [RT-PCR]), P-glycoprotein (Western immunoblotting), drug transport activity (verapamil-sensitive drug efflux), and drug cytotoxicity associated with increased MDR1 or PgP. Although enhanced MDR expression per se evoked no significant changes in either LIP levels or ROS production, it might be essential for the survival of H-FT transfectants, possibly by expediting the export of cell-generated metabolites.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Genetic parameters of growth curve parameters in male and female chickens.
1. Individual growth curves of 7143 chickens selected for the form of the growth curve were fitted using the Laird form of the Gompertz function, BW4=BW0xe(L/K)(1-e-Kt) where BWt is the body weight at age t, BW0 the estimated hatching weight, L the initial specific growth rate and K the maturation rate. 2. Line and sex effects were significant for each parameter of the growth curve. In males, L, BW0, age and body weight at inflection (T(I)and BWI) were higher whereas K was lower than in females. Lines selected for high adult body weight had higher BW0 and BW(I) whereas lines selected for high juvenile body weight had larger estimates of L and lower estimates of T(I). 3. Data from 38,474 animals were included in order to estimate the genetic parameters of growth curve parameters in males and females, considering them as sex-limited traits. Genetic parameters were estimated with REML (REstricted Maximum Likelihood) and an animal model. Maternal genetic effects were also included. 4. Heritabilities of the growth curve parameters were moderate to high and ranged between 0.31 and 0.54, L, BW0 in both sexes and BW(I) in males exhibited significant maternal heritability. Heritabilities differed between males and females for BWI and T(I). Genetic correlations between sexes differed significantly from one for all parameters. L, K and T(I) were highly correlated but correlations involving BW0 and BW(I) were low to moderate. 5. Sexual dimorphism of body weight at 8 and 36 weeks and of L, K and T(I) was moderately heritable. Selection on growth curve parameters could modify the difference between sexes in precocity and thus in body weight at a given age.
Animals↗
The identification of ferritin in the nucleus of K562 cells, and investigation of a possible role in the transcriptional regulation of adult beta-globin gene expression.
We studied the subcellular distribution of ferritin in K562 cells by immunofluorescence techniques and have made a reappraisal of a direct binding interaction between ferritin and the proximal promoter region of the human beta-globin gene, as previously mentioned in the literature. Confocal microscopy indicates that ferritin, the iron-storage protein, is present in the nucleus of K562 cells, in addition to its expected cytoplasmic localisation. The stain distribution suggests that it is not directly associated with the nuclear matrix. Using a gel mobility shift assay, a protein that cross-reacts with monoclonal ferritin antibodies competitively binds to a double-stranded oligonucleotide spanning the region situated 150 base pairs upstream from the beta-globin transcription start site. Despite this antibody cross-reactivity, the protein is unlike cytosolic ferritin as it appears to be highly sensitive to both temperature and freeze-thaw cycles, and UV-crosslinking experiments indicate that the molecular mass of the protein factor lies between 90 and 100 kDa. In conclusion, while the intranuclear location of ferritin is described in the present study, ferritin is not in direct contact with the beta-globin promoter region.
Adult↗
Role of ferritin in the control of the labile iron pool in murine erythroleukemia cells.
In vitro studies have shown that ferritin iron incorporation is mediated by a ferroxidase activity associated with ferritin H subunits (H-Ft) and a nucleation center associated with ferritin L subunits (L-Ft). To assess the role played by the ferritin subunits in regulating intracellular iron distribution, we transfected mouse erythroleukemia cells with the H-Ft subunit gene mutated in the iron-responsive element. Stable transfectants displayed high H-Ft levels and reduced endogenous L-Ft levels, resulting in a marked change in the H:L subunit ratio from 1:1 in control cells to as high as 20:1 in some transfected clones. The effects of H-Ft overexpression on the labile iron pool were determined in intact cells by a novel method based on the fluorescent metallosensor calcein. H-Ft overexpression resulted in a significant reduction in the iron pool, from 1.3 microM in control cells to 0.56 microM in H-Ft transfectants, and in higher buffering capacity following iron loads. A fraction of the H-Ft-associated iron was labile, available to cell-permeant, but not cell-impermeant, chelators. The results of this study provide the first in vivo direct demonstration of the capacity of H-Ft to sequester cell iron and to regulate the levels of the labile iron pool.
Animals↗
Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome.
Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal and dominant disease caused by heterogeneous mutations in the iron responsive element (IRE) of the 5' untranslated flanking region of ferritin L-chain mRNA, which reduce the binding to the trans iron regulatory proteins and make L-chain synthesis constitutively upregulated. In the several families identified so far, the serum and tissue L-ferritin levels are fivefold to 20-fold higher than in nonaffected control subjects, iron metabolism is apparently normal, and the only relevant clinical symptom is early onset, bilateral cataract. Some pathogenetic aspects of HHCS remain obscure, with particular reference to the isoferritins produced by HHCS cells, as well as the mechanism of cataract formation. We analyzed lymphoblastoid cell lines obtained from two nonaffected control subjects and from HHCS patients carrying the substitution A40G (Paris-1), G41C (Verona-1), and the deletion of the residues 10-38 (Verona-2) in the IRE structure. Enzyme-linked immunosorbent assays specific for the H- and L-type ferritins showed that L-ferritin levels were up to 20-fold higher in HHCS than in control cells and were not affected by iron supplementation or chelation. Sequential immunoprecipitation experiments of metabolically-labeled cells with specific antibodies indicated that in HHCS cells about half of the L-chain was assembled in L-chain homopolymers, which did not incorporate iron, and the other half was assembled in isoferritins with a high proportion of L-chain. In control cells, all ferritin was assembled in functional heteropolymers with equivalent proportion of H- and L-chains. Cellular and ferritin iron uptake was slightly higher in HHCS than control cells. In addition, we analyzed the lens recovered from cataract surgery of a HHCS patient. We found it to contain about 10-fold more L-ferritin than control lens. The ferritin was fully soluble with a low iron content. It was purified and partially characterized. Our data indicate that: (1) in HHCS cells a large proportion of L-ferritin accumulates as nonfunctional L-chain 24 homopolymers; (2) the concomitant fivefold to 10-fold expansion of ferritin heteropolymers, with a shift to L-chain-rich isoferritins, does not have major effects on cellular iron metabolism; (3) L-chain accumulation occurs also in the lens, where it may induce cataract formation by altering the delicate equilibrium between other water-soluble proteins (ie, crystallins) and/or the antioxidant properties.
Antioxidants↗