A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

Feder, John N.; Gnirke, Andreas; Thomas, Winston; Tsuchihashi, Zenta; Ruddy, David A.; Basava, Alivelu; Dormishian, F.; Domingo, Rodolfo; Ellis, Michael C.; Fullan, A.; Hinton, L.M.; Jones, Nora; Kimmel, Bruce E.; Kronmal, Gregory S.; Lauer, Peter; Lee, V.K.; Loeb, Deborah B.; Mapa, Felipa; McClelland, Erin E.; Meyer, Nicole C.; Mintier, Gabriel A.; Moeller, Niels; Moore, Theodore B.; Morikang, Ebenezer; Prass, Cynthia E.; Quintana, Leah; Starnes, Steven M.; Schatzman, Randall C.; Brunke, Karen J.; Drayna, Dennis; Risch, Neil; Bacon, Bruce R.; Wolff, Roger K.

doi:10.1038/ng0896-399

Cited by 3,444 publications

(2,730 citation statements)

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“…1 It is clear that the fundamental abnormality present in this condition is excessive absorption of iron in the duodenum. Two different theories regarding how the abnormal HFE protein coded by the HFE mutation results in excessive iron accumulation have been proposed ( Figure 1-steps 3); they are not mutually exclusive.…”

Section: Pathophysiology and Clinical Manifestations Of Hemochromatosismentioning

confidence: 99%

Iron overload syndromes and the liver

Batts

2007

Modern Pathology

134

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Section: Pathophysiology and Clinical Manifestations Of Hemochromatosismentioning

confidence: 99%

Iron overload syndromes and the liver

Batts

2007

Modern Pathology

134

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“…Most patients with haemochromatosis are homozygous for a single nucleotide substitution (C282Y) in the haemochromatosis gene (HFE) [3]. The wild-type HFE protein forms a heterodimer with β 2 -microglobulin.…”

Section: Introductionmentioning

confidence: 99%

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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Aims/hypothesis: The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects and methods: Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. Results: The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Conclusions/interpretation: Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

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“…6p22.2), has a much weaker effect on iron absorption, and does not prevent cell surface expression as in C282Y, but rather simply reduces HFE's efficacy in downregulating iron uptake (Feder et al, 1998). C282Y homozygosity is the predominant form associated with clinical symptoms in 80 to 92% of cases (Feder et al, 1996; Hanson et al, 2001; Aguilar‐Martinez et al, 2011). H63D is unlikely to produce hemochromatosis, even in homozygotes (Beutler, 2006; Adams, 2014; Kelley et al, 2014).…”

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The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

Heath

Axton

McCullough

et al. 2016

American J Phys Anthropol

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ObjectivesThe C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment.Materials and MethodsTo address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis.ResultsOur findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend.DiscussionThe results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic. Am J Phys Anthropol 160:86–101, 2016. © 2016 The Authors American Journal of Physical Anthropology Published by Wiley Periodicals, Inc.

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A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

Cited by 3,444 publications

References 58 publications

Iron overload syndromes and the liver

Iron overload syndromes and the liver

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

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