Haptoglobin modifies the hemochromatosis phenotype in mice

Abstract

Classic hereditary hemochromatosis (HH)is a common genetic disorder of iron metabolism caused by a mutation in the HFE gene. Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH. Several candidate modifier genes have been proposed in mice and humans, including haptoglobin. Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. It delivers free plasma hemoglobin to the reticuloendothelial system, thus reducing loss of hemoglobin through the glomeruli and allowing hemeiron recycling. IntroductionClassic hereditary hemochromatosis (HH) is a common genetic disorder of iron metabolism characterized by a gradual but progressive expansion of the plasma iron compartment. Affected patients develop toxic iron overload and tissue damage including liver cirrhosis, hepatocarcinoma, and heart disease. Most patients with HH are homozygous for a missense mutation (C282Y) that disrupts the conformation of HFE, an atypical major histocompatibility class I molecule. 1 Similar to human patients, mice lacking the Hfe protein or producing a mutated protein analogous to the human C282Y protein develop increased hepatic iron levels and elevated transferrin saturation. 2,3 Whereas C282Y is among the most prevalent human mutations, the clinical penetrance of the disease is low, suggesting that the HFE C282Y mutation is a necessary but not sufficient cause of clinical HH. 4 Variable penetrance may be due to epigenetic, environmental, and genetic factors. 5 Also, in mice there is a marked difference in hepatic iron loading between C57BL/6 and DBA/2 Hfe Ϫ/Ϫ strains, indicating that other genes modify the murine HH phenotype. 6,7 Several candidate modifier genes have been proposed in mice and humans, 8-10 including haptoglobin (Hp). Hp is the plasma protein with the highest binding affinity for hemoglobin (K d Ϸ 1 pM). 11 It binds free hemoglobin and delivers it to the reticuloendothelial system by CD163 receptor-mediated endocytosis. 12 Thus, Hp is believed to reduce loss of hemoglobin through the glomeruli and to allow heme-iron recycling.Hp is synthesized as a single polypeptide, which is cleaved into ␣-and ␤-chains. The mammalian isoform Hp1-1 is a homodimer of 2 Hp molecules linked by a single disulfide bond through their respective ␣-chains. In humans, a variant with a longer ␣-chain is also present. Individuals homozygous for the longer allele show a multimeric Hp phenotype designated Hp2-2. Hp2-1 refers to the molecular phenotype (both Hp dimers and multimers) seen in humans heterozygous for the 2 variant alleles. Complexes of hemoglobin and multimeric Hp (the 2-2 phenotype) exhibit higher functional affinity for CD163 than do complexes of hemoglobin and dimeric Hp (the 1-1 phenotype).In healthy men, the Hp2-2 type is associated with higher serum iron and ferritin levels than the Hp2-1 and Hp1-1 types. Moreover, in healthy men carrying the Hp2-2 type, a fraction of Hphemo...

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

“…Hemopexin seems to be required for this process because hemopexin-null mice show minimal heme loading in hepatocytes after heme overload (66). The observation that hemopexin-null mice, as well as haptoglobin-null mice, have normal hepatic non-heme iron levels suggests that heme iron uptake pathways are not significant contributors to hepatic iron stores under normal circumstances (82,83).…”

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

“…5,6 Association studies between genetic markers and disease phenotype have given conflicting results. [7][8][9][10][11][12][13][14] More recently, candidate gene studies revealed significant associations between single nucleotide polymorphisms (SNPs) in genes involved in iron metabolism and indices of iron overload in p.C282Y homozygotes. Milet et al focused on two biologically relevant gene categories: genes involved in non-HFE-hereditary hemochromatosis (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression (BMP2, BMP4, HJV, SMAD1, 4 and 5, and IL6).…”

Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders

“…The penetrance of hemochromatosis is a controversial issue 18,19 ; it is influenced by sex, age, environmental factors, and modifier genes. Studies of the identification of modifiers are promising in animal models, 20,21 but the identification of human modifiers remains complex.…”