Rôle du gène FTL dans les hyperferritinémies inexpliquées

RENNES1-BU Santé (352382103) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Iron disorders of genetic origin: a changing world.

International audienceIron disorders of genetic origin are mainly composed of iron overload diseases, the most frequent being HFE-related hemochromatosis. Hepcidin deficiency underlies iron overload in HFE-hemochromatosis as well as in several other genetic iron excess disorders, such as hemojuvelin or hepcidin-related hemochromatosis and transferrin receptor 2-related hemochromatosis. Deficiency of ferroportin, the only known cellular protein iron exporter, produces iron overload in the typical form of ferroportin disease. By contrast, genetically enhanced hepcidin production, as observed in matriptase-2 deficiency, generates iron-refractory iron deficiency anemia. Diagnosis of these iron storage disorders is usually established noninvasively through combined biochemical, imaging and genetic approaches. Moreover, improved knowledge of the molecular mechanisms accounting for the variations of iron stores opens the way of novel therapeutic approaches aiming to restore normal iron homeostasis. In this review, we will summarize recent findings about these various genetic entities that have been identified owing to an exemplary interplay between clinicians and basic scientists

A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis

Bone morphogenetic protein (BMP) signaling activates transcription of the master iron regulator hepcidin in the liver. This study shows that a heterozygous mutation in the BMP-responsive element of the hepcidin gene promoter is associated with massive iron overload in a patient homozygous for the common HFE mutation, suggesting a new molecular mechanism of iron overload

Non-HFE hemochromatosis: Pathophysiological and diagnostic aspects.

International audienceRare genetic iron overload diseases are an evolving field due to major advances in genetics and molecular biology. Genetic iron overload has long been confined to the classical type 1 hemochromatosis related to the HFE C282Y mutation. Breakthroughs in the understanding of iron metabolism biology and molecular mechanisms led to the discovery of new genes and subsequently, new types of hemochromatosis. To date, four types of hemochromatosis have been identified: HFE-related or type1 hemochromatosis, the most frequent form in Caucasians, and four rare types, named type 2 (A and B) hemochromatosis (juvenile hemochromatosis due to hemojuvelin and hepcidin mutation), type 3 hemochromatosis (related to transferrin receptor 2 mutation), and type 4 (A and B) hemochromatosis (ferroportin disease). The diagnosis relies on the comprehension of the involved physiological defect that can now be explored by biological and imaging tools, which allow non-invasive assessment of iron metabolism. A multidisciplinary approach is essential to support the physicians in the diagnosis and management of those rare diseases

Molecular diagnosis of genetic iron-overload disorders.

International audienceGenetic iron overload has long been confined to the picture of classical hemochromatosis related to the HFE C282Y mutation (type 1 hemochromatosis). C282Y homozygosity affects approximately three people out of 1000 of the Caucasian population, representing one of the most frequent genetic predispositions. It has, however, rapidly become clear that the HFE C282Y mutation is not the sole culprit in genetic iron overload. Several novel mutations in HFE and other genes have been discovered and related to various entities, which are now known as types 2, 3 and 4 hemochromatosis. These diseases are far less frequent than the classical type 1 hemochromatosis but, by contrast, are not limited to the Caucasian population. Molecular diagnosis obviously plays a key role in the diagnostic strategy. In the future, it will undoubtedly enable not only identification of new diagnostic markers, but also provide potential molecular targets for pathophysiologically based innovative therapeutic approaches

Hereditary hypotransferrinemia can lead to elevated transferrin saturation and, when associated to HFE or HAMP mutations, to iron overload

International audienceAs our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome

The Monoclonal Anti-Transferrin Antibody Syndrome: A Way for a Better Understanding of Iron Metabolism

International audienceMeeting Abstract: 3

Monoclonal anti-transferrin antibody: A paradigm for better understanding of iron metabolism.

International audienceA 82 years old patient was admitted for persisting abnormalities of iron metabolismparameters in the context IgG kappa monoclonal gammopathy, discovered 12 years before,and classified as MGUS (monoclonal gammopathy of undetermined significance). Serum ironand transferrin concentration were constantly extremely high (96.9 μmol/L and 5.0 g/L,respectively), transferrin saturation was elevated (77.5% ; N<45%) and serum ferritinmoderately increased (608μg/L ; N<300 μg/L). Hemochromatosis was ruled out(1) : no tissueiron overload was present and genetic studies searching for mutations in HFE and non HFEgenes, were negative (p.Cys282Tyr mutation, HJV (HFE2), HAMP, TFR2, BMP6, SLC40A1 andFTL)