Genetics of haemochromatosis

doi:10.1016/S0140-6736(02)11607-2

The Lancet

Volume 360, Issue 9346, 23 November 2002, Pages 1673-1681

https://doi.org/10.1016/S0140-6736(02)11607-2 Get rights and content

Summary

After identification of the hereditary haemochromatosis gene HFE, and receipt of confirmation that most patients with the condition were homozygous for a single, founder mutation (C282Y), most assumed that C282Y would be a prevalent, highly penetrant mutation in a gene that plays a key part in the regulation of iron absorption and of whole-body iron homoeostasis. With carrier rates of between 10% and 15%, and a homozygote frequency of about one-in-150 in people of northern European descent, C282Y is certainly prevalent. However, it is not highly penetrant. The pronounced variation in phenotype in individuals with the same gene mutation has prompted the search for modifier genes at other loci, and for environmental factors that might affect expression of the condition. Progress in our understanding of how HFE regulates the absorption of dietary iron has been slow, but much can be learnt from the study of the rare instances of haemochromatosis that involve mutations in newly-identified iron-metabolism genes, such as TFR2—a transferrin receptor isoform—and ferroportin1/IREGl/MTP1—an intestinal iron transporter. The availability of definitive information on penetrance and the identity of genetic modifiers will aid the debate on whether population screening for haemochromatosis should be undertaken or whether alternative strategies should be implemented to improve early detection.

Section snippets

Clinical features

In haemochromatosis, iron accumulates first in the transferrin pool, manifested by a rise in serum transferrin saturation, and subsequently in tissue stores—especially the hepatic parenchyma—which is accompanied by a progressive increase in concentrations of serum ferritin.²⁵ The clinical features of the disease arise as a result of the progressive accumulation of iron in the parenchymal cells of the liver, pancreas, heart, and anterior pituitary. In the absence of treatment to reduce iron

Genetic background

The original observation of Simon and colleagues³² of linkage between a haemochromatosis locus and the major histocompatibility complex (MHC), and the presence of an ancestral haplotype¹¹ were of fundamental importance in the search for the haemochromatosis gene. Feder and co-workers' finally identified HFE in 1996, using a positional cloning strategy to isolate a 250 kb subregion on chromosome 6p that was conserved on chromosomes carrying the ancestral haplotype. After all the genes in this

Penetrance of mutations

The variability in clinical symptoms and signs in haemochromatosis, and the absence of a consensus on what phenotypic features should be used in studies to investigate penetrance, has lead to highly polarised views. The initial erroneous impression, that the homozygous C282Y genotype was highly penetrant, was based on results of genotyping in cross-sectional case series. However, patients in these studies were diagnosed in the pregenotyping era on the basis of iron overload and features of

HFE and its role in iron metabolism

The haemochromatosis gene encodes HFE, a 343 aminoacid protein1 that is homologous to MHC class I molecules, a family of transmembrane glycoproteins that function in the immune system by presenting peptide antigen to T cells. The protein is organised in three extracellular domains—α1, α2, and α3—a membrane spanning domain, and a short cytoplasmic tail; the α1 and α2 domain helices form the peptide-binding groove and interact with the T-cell receptor, and the highly conserved immunoglobulin-like

Iron absorption

Absorption of dietary iron takes place in the duodenum, where specific carrier molecules are expressed by the villus enterocyte (figure). Briefly, duodenal crypt cells are thought to receive signals about iron requirements in the body, in part through the binding of transferrin to the HFE/β2 microglubulin/TFR1 complex. Other less well defined signals are also thought to be involved.⁹⁷ Iron release from the endosome leads to variable degrees of cytosolic iron in the crypt cell, which in turn

Screening in haemochromatosis

Screening for iron overload with biochemical methods and with genotyping in patients who present with chronic liver disease or with symptoms and signs that could be caused by iron overload is good medical practice. Patients with type 2 diabetes mellitus, atypical cardiac failure, early onset impotence, and early or atypical arthritis have also been identified as target populations.²⁴ Additionally, the practice of screening the families of patients with iron overload is now well established,

Search strategy

PubMed was used to search for published material on haemochromatosis and related topics of iron metablosim, and on proteins of iron transport and storage. Emphasis was placed on papers published since 2000 and those that stressed the importance of the search for genes that modify the phenotype.

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Cited by (126)

C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population
2017, HOMO- Journal of Comparative Human Biology
The Basques live at the Western extremity of the Pyrenees. According to linguistic and genetic data they could be considered as one of the most ancient European populations. Numerous studies have evidenced particular patterns in the frequency of several genetic polymorphisms in this relatively unmixed human group. We discuss herein the puzzling distribution of the two major hemochromatosis HFE mutations associated with hereditary hemochromatosis. Thus, one can observe a low frequency of C282Y and, in contrast, one of the highest European frequencies of H63D. Genetic drift (enhanced by the long history and the small size of this population), long persistence of Paleolithic iron-rich diet, lower exposure to major infectious threats and limited mixing with both Celts and Vikings (who demonstrate the highest prevalence of C282Y) could be the underlying factors explaining these particular genetic features. Historical and environmental data represent key elements for understanding the role of the different evolutionary forces which shape the genetic profile of human populations.
Study of the effect of HFE gene mutations on iron overload in Egyptian thalassemia patients
2015, Egyptian Journal of Medical Human Genetics
HFE gene mutations have been shown to be responsible for hereditary hemochromatosis. Their effect on iron load in β-thalassemia patients and carriers remains controversial.
We aimed to determine the prevalence of HFE gene mutations (C282Y and H63D) in β-thalassemia patients and carriers and to investigate its effect on their serum ferritin levels.
A total of 100 β-thalassemia subjects; 75 patients and 25 carriers were screened for HFE gene mutations by PCR-RFLP. Serum ferritin measured by ELISA was evaluated in relation to HFE mutations.
Twenty-eight β-thalassemia patients (37.3%) were heterozygotes for H63D mutation (H/D), 8 (10.7%) were D/D and 39 (52%) were negative (H/H). Among carriers, 4 (16%) were D/D and 21 (84%) were H/H homozygotes. C282Y mutant allele was not detected in any of the subjects. Serum ferritin levels were significantly higher in β-thalassemia patients heterozygotes or homozygotes for H63D mutation compared to those without mutation (p = 0.000). Carriers homozygotes for H63D mutation showed significantly higher serum ferritin levels compared to those without mutation (p < 0.001).
Homozygosity for H63D mutation tends to be associated with higher ferritin levels in beta-thalassemia patients and carriers suggesting its modulating effect on iron load in these cases.
Hemochromatosis HFE in children - Still underestimated
2012, Pediatria Polska
Hemochromatosis is a disease of iron overload. There are primary – inherited diseases leading to increased intestinal absorption and secondary caused by multi transfusions or iron pills and iron rich food intake. Hereditary hemochromatosis is a metabolic disorder caused by mutations of genes that control iron metabolism. Mutations in HFE gene localized on the short arm of chromosome 6 are responsible for autosomal recessive hemochromatosis type 1. The disease symptoms are observed in adult males. The aim of the study was to analyse iron metabolism in 41 children. In chosen cases HFE mutations were determined.
HFE mutations were documented in 15 cases.
Iron metabolism tests are indispensable in the diagnosis of its elevated status. In chosen cases molecular tests are essential.
Cells under siege: Viral glycoprotein interactions at the cell surface
2011, Journal of Structural Biology
Citation Excerpt :
A major portion of the TfR1 ectodomain has been crystallized and shown to consist of a protease-like domain, a helical domain and an apical domain (Fig. 4A) (Bennett et al., 2000; Lawrence et al., 1999). Structures of TfR1 in complex with Tf and HFE, a membrane glycoprotein associated with hereditary haemochromatosis (Bomford, 2002; Lebron et al., 1999), have been elucidated by cryo-electron microscopy (Cheng et al., 2004) and crystallography (Bennett et al., 2000), respectively. HFE can compete with Tf for binding and both complex structures revealed a 2:2 stoichiometry (Fig. 4B).
As obligate parasites, viruses are required to enter and replicate within their host, a process which employs many of their proteins to hijack natural cellular processes. High resolution X-ray crystallographic analysis has proven to be an ideal method to visualize the mechanisms by which such virus-host interactions occur and has revealed the innovative capacity of viruses to adapt efficiently to their hosts. In this review, we draw upon recently elucidated paramyxovirus-, arenavirus-, and poxvirus-host protein complex crystal structures to reveal both the capacity of viruses to appropriate one component of a physiological protein–protein binding event (often modifying it to out-compete the host-protein), and the ability to utilize novel binding sites on host cell surface receptors. The structures discussed shed light on a number of biological processes ranging from viral entry to virulence and host antagonism. Drawn together they reveal the common strategies which viruses have evolved to interact with their natural host. The structures also support molecular level rationales for how viruses can be transmitted to unrelated organisms and thus pose severe health risks.
Copper and iron in Alzheimer's disease: A systematic review and its dietary implications
2012, British Journal of Nutrition
HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank
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ReviewGenetics of haemochromatosis

Summary

Section snippets

Clinical features

Genetic background

Penetrance of mutations

HFE and its role in iron metabolism

Iron absorption

Screening in haemochromatosis

Search strategy

Am J Hun Genet

Blood

Blood

Blood

Blood

Mol Cell

J Biol Chem

J Hepatol

Gastroenterology

Gastroenterology

Cell

J Biol Chem

Gastroenterology

Hepatology

Clin Chim Acta

Am J Med

Hepatology

J Biol Chem

Blood Cells Mol Dis

J Hepatol

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Blood Cell Mol Dis

Blood Cell Mol Dis

Blood

J Hepatol

Gastroenterology

Lancet

J Hepatol

Gastroenterology

Gastroenterology

Blood Cells Mol Dis

Blood Cells Mol Dis

Blood Cells Mol Dis

Blood Cells Mol Dis

Blood Cells Mol Dis

Hepatology

J Hepatol

Blood

Immunity

Int J Biochem Cell Biol

Blood

J Biol Chem

FEES Lett

Biochim Biophys Acta

Hepatology

Blood

A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis

Nat Genet

The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22

Nat Genet

Review
Genetics of haemochromatosis