Clara Camaschella

..The precise diagnosis of the genetic type of hemochromatosis is relevant for the follow-up, treatment, and for family counseling...

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..To discuss inherited iron disorders, their pathophysiology and clinical implications in the light of the recent advances in our knowledge of iron metabolism and its regulation...

..Spontaneous and engineered animal models of iron disorders have help to add further insights to the issue. A still incompletely understood aspect remains the regulation that erythropoiesis exerts on iron...

..In the future, these advances may be exploited for a more effective treatment of both genetic and acquired iron disorders...

..Understanding the molecular circuitry of iron control may lead to the identification of potential therapeutic targets for novel treatment strategies to be used in association with or as an alternative to phlebotomy...

..Local mitochondrial iron overload is present in all sideroblastic anaemias, whereas systemic iron overload occurs only in the forms because of primary or secondary deficiency of ALAS2...

..Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen the idea that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis...

..The proinflammatory status associated with chronic iron deficiency could explain the resistance to infection seen in this condition...

..The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV...

..Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia...

..The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver...

..We have previously shown that several hemojuvelin variants do not efficiently reach the plasma membrane, whereas a few N-terminal mutants localize to the plasma membrane...

..Our results underline the importance of LDLRA and CUB domains of matriptase-2...

..It is caused by mutations in the iron responsive element (IRE) of the ferritin light chain gene (FTL)...

..The results support a dual function for s- and m-HJV in iron deficiency and overload, respectively...

..Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South...

..GLRX5 function is highly conserved, but at variance with zebrafish, its defect in humans leads to anemia and iron overload...

..This condition should be considered not only in families with autosomal iron overload or hyperferritinaemia, but also in cases of unexplained hyperferritinaemia...

..The small liver peptide hepcidin is a major regulator of systemic iron homeostasis in mammals, adapting iron absorption to the body's demands. Two new studies now identify BMP6 as the key endogenous regulator of hepcidin...

..Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes...

..Here we propose that iron directly influences the Abeta production through the modulation of furin, a proconvertase involved in the regulation of the alpha-secretase-dependent processing of the amyloid protein precursor (APP)...

..This pilot study represents a first step toward developing a diagnostic microchip for large-scale analyses for epidemiological studies and screening of mutations associated with iron disorders...

..34 to 0.42 in the different isolates. Our study provides a dataset of hemoglobin levels for normal subjects of different geographical origin and indicate that hemoglobin levels are substantially influenced by heritable components...

..Studies of the hepcidin regulation by iron and inflammatory cytokines are revealing new pathways that might become targets of new therapeutic intervention in iron disorders...

..This finding indicates a fundamental role of hepcidin in inhibiting both iron absorption from duodenal cells and iron release from macrophages, and has opened up a new view of haemochromatosis as a disorder of hepcidin...

..The disease is prevalently due to C282Y and H63D mutations in the HFE gene, but additional molecular defects are present in a minority of patients...

..Our results clarify the natural history of the disease and are compatible with the hypothesis that the HFE2 gene has greater influence on iron absorption than other haemochromatosis-associated genes...

..The identification of all of the genes associated with haemochromatosis is critical for molecular-based diagnosis and central to our understanding of the regulation of iron homeostasis...

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..One was compound heterozygous (Asn411del/Ala444Thr) and the second was homozygous for a mutation affecting RNA splicing (IVS17+5636G>A). Another mutation (His33Asn) and a polymorphism were found in a group of 50 controls...

..Here we report data from a family carrying a new mutation of the transferrin receptor 2 gene...

..This study measured urinary hepcidin levels by SELDI-TOF-MS in a large group of HH patients at diagnosis and during treatment, including both C282Y homozygous and C282Y/H63D compound heterozygotes...

..The hepcidin response to oral iron is blunted in HFE-related hemochromatosis and not improved after iron depletion. The findings support the involvement of HFE in iron sensing and subsequent regulation of hepcidin...

..We identified a new mutation (C70R), which affects 1 of the 8 conserved cysteines that form the disulfide bonds and are critical for the stability of the polypeptide...

..02 was observed with marker D1S2344. A common ancestral haplotype, showing the presence of a founder effect, was identified. The analysis of recombinants allowed us to confirm the JH candidate region...

..Early iron overload may be assessed by biochemical parameters such as increased transferrin saturation and serum ferritin...

..Although the rarity of TFR2 mutations limits their usefulness in diagnostic/screening programs, their study can contribute to a better understanding of the protein function...

..Here we report the identification of two mutations (93delG and 166C-->T) in HAMP on 19q13 in two families with a new type of juvenile hemochromatosis...

..The severity and the early expression of juvenile hemochromatosis suggest that the gene product has a crucial role in the regulation of iron homeostasis...

..We propose that anemia, secondary to the impaired macrophage iron release, plays a major role in hepatic iron overload through increased absorption mediated by the erythroid regulator...

..Mutations either generate premature termination codons or were missense substitutions, affecting highly conserved residues, relevant to the protein structure and/or function...

..They both carried the Y250X mutation of the TFR2 gene in the homozygous state. We suggest that transferrin receptor-2 is important in maintaining iron balance in the first decades of life...

..Inflammatory cytokines did not play a major role in increasing hepcidin levels or in modifying iron homeostasis in this study...

..We propose that DMT1(C1246T) (R416C) represents a complete loss-of-function, and that a quantitative reduction in DMT1 expression is the cause of the microcytic anemia and iron overload in the patient...

..The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use...

..Furthermore, taken the differences in gene expression in dietary overload (increased Hfe but not Tfr2), distinct roles are suggested for Hfe and Tfr2 in Hepc activation...

..However, they are rare and explain only a minor portion of the variable penetrance of the disorder...

..The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron...