Natural history of juvenile haemochromatosis

Gobbi, Marco De; Roetto, Antonella; Piperno, Alberto; Mariani, Raffaella; Alberti, Federica; Papanikolaou, George; Politou, Marianna; Lockitch, Gillian; Girelli, Domenico; Fargion, Silvia; Cox, T.M.; Gasparini, Paolo; Cazzola, Mario; Camaschella, Clara

doi:10.1046/j.1365-2141.2002.03509.x

Cited by 157 publications

(142 citation statements)

References 42 publications

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“…Homozygous or compound heterozygous mutations of HFE2 cause juvenile hemochromatosis (JH), a particularly severe form of HH (15,16). The central role of HFE2 in body iron homeostasis is supported by the most recent findings in mice with disruptions of both HFE2 alleles (Hjv Ϫ/Ϫ ), showing a marked increase of iron deposition in liver, pancreas, and heart (17,18).…”

mentioning

confidence: 56%

Evidence That Inhibition of Hemojuvelin Shedding in Response to Iron Is Mediated through Neogenin

Zhang

Anderson

Meyers

et al. 2007

Journal of Biological Chemistry

111

168

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Hemojuvelin (HJV), encoded by the gene HFE2, is a critical upstream regulator of hepcidin expression. Hepcidin, the central iron regulatory hormone, is secreted from hepatocytes, whereas HFE2 is highly expressed in skeletal muscle and liver. Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogenin and bone morphogenetic proteins (BMP2 and BMP4), and can be released from the cell membrane (shedding). In this study, we investigated the physiological significance and the underlying mechanism of HJV shedding. In acutely iron-deficient rats with markedly suppressed hepatic hepcidin expression, we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or protein levels in gastrocnemius muscle. Studies in both C2C12 (a mouse myoblast cell line) and HepG2 (a human hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liver could be the source of serum HJV. In agreement with the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by holo-transferrin in a concentrationdependent manner. Our present study showing that knockdown of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK293 cells markedly enhances this process, suggests that membrane HJV shedding is mediated by neogenin. The finding that neither BMP4 nor its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP signaling pathway in this process.

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mentioning

confidence: 56%

Evidence That Inhibition of Hemojuvelin Shedding in Response to Iron Is Mediated through Neogenin

Zhang

Anderson

Meyers

et al. 2007

Journal of Biological Chemistry

111

168

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“…Clinical manifestations are marked by an increased incidence of hypogonadism and cardiomyopathy. 21,22 Haemochromatosis type 3 refers to another autosomal recessive condition, which is due to mutations in the TFR2 gene and which could be classified as intermediate between the classical adult-type and the two juvenile types. 23 Finally, haemochromatosis type 4 is related to an adult autosomal dominant iron overload syndrome caused by mutations in the ferroportin 1 gene.…”

Section: Classification Of Haemochromatosismentioning

confidence: 99%

“…In the absence of treatment, juvenile haemochromatosis patients may succumb to heart failure before the age of 30 years. 21,22 Molecular basis Juvenile haemochromatosis is genetically heterogeneous, as it can be associated with mutations in two genes. The main locus was mapped to 1q21 by Roetto et al 66 in 1999.…”

Section: Molecular Genetics Of Haemochromatosis G Le Gac and C Férecmentioning

confidence: 99%

The molecular genetics of haemochromatosis

Gac

Férec

2005

Eur J Hum Genet

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The molecular basis of haemochromatosis has proved more complex than expected. After the 1996 identification of the main causative gene HFE and confirmation that most patients were homozygous for the founder C282Y mutation, it became clear that some families were linked to rarer conditions, first named 'non-HFE haemochromatosis'. The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes. Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. In turn, recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body's iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations.

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“…However, the fact that the patients with hemojuvelin mutations have no measurable urinary hepcidin levels makes it likely that the two proteins affect the same pathways [74]. Only homozygous states are associated with iron overload, while heterozygous subjects with either hepcidin or hemojuvelin mutations are symptomless and have normal iron parameters [71,75]. Hereditary hemochromatosis type 3 is an autosomal recessive disease caused by private mutations in the transferrin receptor 2 gene (TfR2) [19,76].…”

Section: Type 1 Hereditary Hemochromatosis (Omim 235200)mentioning

confidence: 99%

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

Franchini

2006

Am. J. Hematol.

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Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated timely. The elucidation of the molecular pathways of iron transport through cells and its control has led to the understanding of various genetic iron‐loading conditions. Four types of inherited iron overload have been recognized: type 1, the most common form with an autosomal recessive inheritance, is associated with mutations in the HFE gene on chromosome 6; type 2 (juvenile hemochromatosis) is an autosomal recessive disorder with causative mutations identified in the HJV gene (subtype A) on chromosome 1 and the HAMP gene (subtype B) on chromosome 19; type 3 has also an autosomal recessive inheritance with mutations in the TfR2 gene on chromosome 3; type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene on chromosome 2. In this review, the genetics, pathophysiology, diagnosis, clinical features, and management of these different types of hereditary hemochromatosis are briefly discussed. Am. J. Hematol. 81:202–209, 2006. © 2006 Wiley‐Liss, Inc.

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Natural history of juvenile haemochromatosis

Cited by 157 publications

References 42 publications

Evidence That Inhibition of Hemojuvelin Shedding in Response to Iron Is Mediated through Neogenin

Evidence That Inhibition of Hemojuvelin Shedding in Response to Iron Is Mediated through Neogenin

The molecular genetics of haemochromatosis

Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment

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