Haemochromatosis and HLA–H

Jazwinska, Elizabeth C.; Cullen, Lara M.; Busfield, Frances; Pyper, W.R.; Webb, Sonja I.; Powell, Lawrie W.; Morris, C. Phillip; Walsh, Tamara

doi:10.1038/ng1196-249

Cited by 414 publications

(240 citation statements)

References 12 publications

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“…This is a new MHC class I-like gene, where homozygosity for a single base pair mutation (C282Y), resulting in a cystein to tyrosine substitution at position 282, was found in 83% of HH patients. This finding was promptly confirmed by other groups who described the presence of the C282Y mutation in varying, but always very high, numbers of hemochro-matosis patients in several parts of the world (Barton et al 1997;Beutler et al 1996;Borot et al 1997;Carella et al 1997;Jazwinska et al 1996;Jouanolle et al 1996). A second mutation was also found in the HFE gene (H63D) resulting in a histidine to aspartic acid substitution at position 63.…”

Section: Introductionsupporting

confidence: 59%

Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis

Porto

Alves²,

Rodrigues³

et al. 1998

Immunogenetics

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Section: Introductionsupporting

confidence: 59%

Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis

Porto

Alves²,

Rodrigues³

et al. 1998

Immunogenetics

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“…10 This gene encodes an HLA class I-like protein and is mutated in greater than 85% of the patients with HHC of northern European descent. [10][11][12] Genetic testing was not possible in the current cohort. Therefore, this study did not analyze outcome based on HFE genotype.…”

Section: Discussionmentioning

confidence: 93%

Long-term follow-up after liver transplantation in patients with hepatic iron overload

et al. 1999

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Patients with hepatic iron overload who undergo orthotopic liver transplantation (OLT) have a worse 1-year survival than those who undergo transplantation for other indications; the long-term outcome in this population is unknown. The purpose of this study is to report long-term follow-up after OLT in a cohort of patients with hepatic iron overload. Five liver transplant centers in the United States reported follow-up data on 37 patients receiving a first liver transplant who had severe hepatic iron overload in their native livers. KaplanMeier 5-year survival among these patients was compared with survival data from all age-matched liver transplantations reported to the United Network for Organ Sharing (UNOS) over the same time period (1987 to 1993). The 5-year survival rate after OLT was 40% in the hepatic iron overload group compared with an overall survival rate of 62% for all patient groups from the UNOS registry (P ‫؍‬ .0009). Although sepsis was the cause of 53% of all deaths occurring within the first year after OLT, cardiac complications accounted for 50% of the late mortality in patients with hepatic iron overload. In conclusion, longterm survival after OLT is significantly decreased in patients with hepatic iron overload. Infectious and cardiac complications are the most common causes of death in these patients. Further studies are needed to define the relationship between hepatic iron overload and mortality and to examine the effect of iron depletion on outcome after OLT in this patient population.

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“…It has been suggested that other genetic and environmental factors might contribute to the modulation of iron metabolism. [33][34][35][36] In the more severe cases of iron overload, abnormally low numbers of lymphocytes, especially CD8 + T cells, remain a valuable indicator for disease prognosis. 37,38 This, in conjunction with the finding that the class I-like HFE molecule is encoded in the MHC, strongly suggest that an interplay between iron metabolism and immune function must exist.…”

Section: Discussionmentioning

confidence: 99%

The major histocompatibility complex-encoded class I-like HFE abrogates endocytosis of transferrin receptor by inducing receptor phosphorylation

Salter–Cid¹,

Brunmark²,

Peterson³

et al. 2000

Genes Immun

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The major histocompatibility complex-encoded gene, Hfe, has been implicated to play a pivotal role in hereditary hemochromatosis, a common autosomal recessive disorder of iron metabolism. The recent finding that a physical interaction between HFE and transferrin receptor establishes a functional link between HFE and transferrin receptormediated iron metabolism in the pathophysiology of hereditary hemochromatosis. To elucidate the underlying mechanisms by which HFE interacts with and affects transferrin receptor function, we have systematically investigated the consequences of the HFE-transferrin receptor interaction in cellular iron homeostasis. Herein we show that in HFEexpressing cells, the amount of intracellular transferrin is decreased by ෂ28%, despite a ෂ40% increase in surfaceexpressed transferrin receptor. Kinetic analysis of receptor-bound transferrin endocytosis reveals that HFE expression not only reduces transferrin binding but also abrogates transferrin receptor endocytosis. As a result, HFE expression leads to an accumulation of non-functional transferrin receptors at the cell surface, and a decrease in iron uptak. Moreover, HFE expression induces hyper-serine phosphorylation of the transferrin receptor. Taken together, these results suggest that HFE negatively modulates cellular iron uptake by impairing transferrin receptor endocytosis via HFE-induced receptor phosphorylation. Genes and Immunity (2000) 1, 409-417.

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Haemochromatosis and HLA–H

Cited by 414 publications

References 12 publications

Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis

Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29, and non-classical forms of hemochromatosis

Long-term follow-up after liver transplantation in patients with hepatic iron overload

The major histocompatibility complex-encoded class I-like HFE abrogates endocytosis of transferrin receptor by inducing receptor phosphorylation

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