Figure 1 - uploaded by Guillermo Gervasini
Content may be subject to copyright.
Hereditary hemochromatosis type 3 families: families and mutations in TFR2 gene. (A) Pedigrees of three HH type 3 families. The probands are indicated with an arrow. Black symbols denote affected individuals, half-filled black symbols denote unaffected carriers. Individuals studied at the molecular level are indicated with the symbol #. (B) Partial amino acid sequence alignment of TFR2 protein in 23 species in the vicinity of p.Gly792Arg mutation. Uniprot accession numbers are reported for each sequence. Below the alignment a star (*) indicates 100% conservation of the amino acid, semicolons and dots indicate amino acids with similar but not identical properties. (C) Homology model of TFR2 dimerization interface. In blue, surface representation of a wild-type TFR2 monomer. In yellow, a cartoon representation of a TFR2 monomer with the p.Gly792Arg mutation colored in red. Note that G792R=Gly792Arg, Q306*=Gln306* and Q672*=Gln672*.
Source publication
Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The...
Contexts in source publication
Context 1
... II.1 (Fig. 1A) is a Spanish woman that in Sep- tember 1985 at 31 years of age presented with a history of 2 years of duration of hot flashes, asthenia and amen- orrhea. Clinical examination revealed loss of body hair, low body weight, and slight affectation of small joints in the hands. She was diagnosed of hypogonadotropic hyp- ogonadism (with ...
Context 2
... second patient is a 23-year-old Spanish woman who came to our attention in September 2007 for an elevation of serum ferritin (Fig. 1A). She also referred an alteration in hepatic enzymes at 15 years old of age. The liver In blue, surface representation of a wild-type TFR2 monomer. In yellow, a cartoon representation of a TFR2 monomer with the p.Gly792Arg mutation colored in red. Note that G792R=Gly792Arg, Q306*=Gln306* and Q672*=Gln672*. ...
Context 3
... third patient is a young boy of 14 years old, diag- nosed at 12 years old because of recurrent dizziness (Fig. 1A). The neurological and cardiologic examination showed no abnormalities; however, laboratory tests showed an increase in transferrin saturation and hyperf- erritinemia (see Table 1). There was no family history of iron disorders or consanguinity. The presence of C282Y and H63D variations in HFE gene were ruled out and complete sequencing ...
Context 4
... families 1 and 2 present a previously described (Lee and Barton 2006) but uncharacterized mis- sense mutation, p.Gly792Arg. The proband II.1 and her sister II.4 in family 1 present this mutation in homozy- gous state while the proband II in family 2 presents this mutation in compound heterozygous state with a novel splicing mutation (c.1606-8A>G) (Figs. 1A, 2). To the best of our knowledge, this is the first time that the p.Gly792Arg mutation is reported in a pedigree (family 1) in a homozygous ...
Context 5
... TFR2 nonsense mutations (Gln306* and Gln672*) in compound heterozygous state in proband II.2 of family 3, a pediatric case. These muta- tions are absent from public databases (ENSEMBL, NCBI, 1000 Genomes) and each one was inherited from a hetero- zygous and unaffected parent. The proband's siblings were also carrying only one single TFR2 mutation (Fig. 1A). In the proband, these two mutations will produce a truncated no-functional TFR2 protein lacking the transferrin receptor dimeric domain from both alleles (Fig. ...
Context 6
... dimeric domain (Fig. 2) and was predicted to be deleterious by SIFT( Kumar et al. 2009) and PolyPhen-2 ( Adzhubei et al. 2010) programs. To confirm and under- stand its disruptive nature we performed a progressive series of bioinformatics and computational analyses. Study of the multiple sequence alignment of the TFR2 family (23 sequences, Fig. 1B) showed that glycine at position 792 is absolutely conserved, pointing to its rele- vance to protein function/structure. Mutations breaking such extreme conservation patterns are generally associ- ated with severe functional loss (Ferrer-Costa et al. 2002), particularly when involving large deviations in physico- chemical properties, as ...
Context 7
... TFR2). The structure model shows that the G792 mutation is located at the end of an alpha-helix, near TFR2's C-terminus and within its dimerization domain. Further structural analysis shows that this loca- tion is half-buried (37.6% relative accessibility, measured with NACCESS ( Hubbard et al. 1991)) and at the inter- phase between TFR2 monomers (Fig. 1C). This result, in accordance with the previous bioinformatics analyses, sup- ports the idea that the impact of p.Gly792Arg mutation on TFR2 function is the result of a combined negative effect both on dimer structure and monomer ...
Similar publications
Objective: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) leading to oligodendrocyte destruction, demyelination, remyelination, astrocytic scar formation, and neurodegeneration, all being associated with inflammation. Iron may contribute to the pathogenesis and progression of MS due to its accumulation in the human...
Citations
... • Type 3 (mutations of transferrin receptor-2 gene): Autosomal recessive disorder that is seen both in whites and non-whites. Its onset is at 30-40 years [224]. • Type 4 (mutations of the ferroportin gene): Autosomal dominant disease that is seen both in whites and non-whites. ...
Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals.
... It starts between ages 30 and 40.Ferroportin gene mutations, or type 4, are an autosomal dominant disorder that affects both white people and non-white people. The age range for its onset is 10-80 [13][14][15]. ...
A condition known as hemochromatosis results in excessive iron deposition, which damages several organs. Hemochromatosis affects the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary among other organs. Famous diagnostician and teacher Dr. Armand Trosseau published the first medical description of a patient with hemochromatosis in a French pathology paper in 1865.Hemochromatosis is a well-defined illness that can be brought on by mutations in any gene that restricts iron entry into the blood. It is typified by normal iron-driven erythropoiesis and hazardous iron accumulation in parenchymal cells of essential organs. When Feder et al. found in 1996 that a mutation in HFE caused hereditary hemochromatosis, it was a significant discovery for the field of hemochromatosis research.Systemic iron excess of hereditary origin resulting from a hepcidin deficiency, including reduced hepcidin-ferroportin binding activity or production, is known as hemochromatosis. A correct diagnosis of this illness is frequently challenging due to the wide range, lack of specificity, and vagueness of its signs and symptoms. The early warning signs and symptoms include arthralgia, weakness, weight loss, and stomach pain.In this review study, we discuss the pathophysiology, epidemiology, symptoms, and aetiology of hemochromatosis.
... It starts between ages 30 and 40.Ferroportin gene mutations, or type 4, are an autosomal dominant disorder that affects both white people and non-white people. The age range for its onset is 10-80 [13][14][15]. ...
A condition known as hemochromatosis results in excessive iron deposition, which damages several organs. Hemochromatosis affects the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary among other organs. Famous diagnostician and teacher Dr. Armand Trosseau published the first medical description of a patient with hemochromatosis in a French pathology paper in 1865.Hemochromatosis is a well-defined illness that can be brought on by mutations in any gene that restricts iron entry into the blood. It is typified by normal iron-driven erythropoiesis and hazardous iron accumulation in parenchymal cells of essential organs. When Feder et al. found in 1996 that a mutation in HFE caused hereditary hemochromatosis, it was a significant discovery for the field of hemochromatosis research.Systemic iron excess of hereditary origin resulting from a hepcidin deficiency, including reduced hepcidin-ferroportin binding activity or production, is known as hemochromatosis. A correct diagnosis of this illness is frequently challenging due to the wide range, lack of specificity, and vagueness of its signs and symptoms. The early warning signs and symptoms include arthralgia, weakness, weight loss, and stomach pain.In this review study, we discuss the pathophysiology, epidemiology, symptoms, and aetiology of hemochromatosis.
... [35,45]. Different types of hemochromatosis are currently under discussion [34,35], now focusing on the most recent proposal (Table 2) [35,[46][47][48]. Autosomal-recessive disorder that is seen both in whites and non-whites. ...
... Joshi et al., 2015 [48] Type 4 Mutations in the ferroportin gene Autosomal-dominant disease seen both in whites and non-whites. Its onset is at 10-80 years. ...
Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.
... In both conditions, iron deprivation caused the opposite effect compared to iron loading [230]. Mutations within TfR2 have functional consequences and cause hereditary hemochromatosis (HH) type 3 [231]. The prevalence of pathogenic TfR2 genotypes depends on ethnicity [146,232]. ...
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.
... Mutations in hemojuvelin BMP co-receptor (HJV) and hepcidin antimicrobial peptide (HAMP) genes (type 2a and 2b HH, respectively) result in juvenile hemochromatosis, the most severe form of HH (Papanikolaou et al., 2004). Type 4 HH, also known as ferroportin (FPN) disease, is the only autosomal dominant form of hemochromatosis due to the mutations in the solute carrier family 40member 1(SLC40A1) gene (Joshi et al., 2015). Type 3 HH is a rare form of HH characterized by the genetic alterations in the transferrin receptor 2 (TFR2) gene, with an estimated allele prevalence between 0.0001 and 0.0004 among European populations (Wallace and Subramaniam, 2016). ...
... In recent years, increasing mutations in the TFR2 gene which are related to type 3 HH have been documented (Hernández et al., 2021;Joshi et al., 2015). As shown in Supplementary Table S1, a total of 33 pathogenic TFR2 mutations associated with HH have been described in the Human Gene Mutation Database (Stenson et al., 2020). ...
Type 3 hereditary hemochromatosis (HH) is a rare form of HH characterized by genetic mutation in the TFR2 gene. Clinical features reported in patients with type 3 HH include abnormal liver function, liver fibrosis, cirrhosis, diabetes, hypogonadism, cardiomyopathy, and skin pigmentation. Since its original description in 2000, 33 pathogenic TFR2 mutations associated with HH have been described until now. Here, we first reported a Chinese pedigree of TFR2-related hemochromatosis with a novel compound heterozygous mutation c.1288G > A (p.G430R)/c.960T > A (p.Y320X). Interestingly, different phenotypes were reported although the proband and his sister shared the same gene mutation. This inconsistency between genotypes and phenotypes indicates multifactorial etiology contributing to the development of HH. Our report broadens the mutation spectrum of the TFR2 gene associated with HH.
... Up to date, a total of 45 families (66 affected patients) with non-HFE related HH d to pathogenic mutations in the TFR2 gene have been described in the literature (Table [24,25]. It has been shown that in a hepatic murine system (Hepa1-6 cells), the mur counterparts of four human TFR2 mutations (Met172Lys, AVAQ621_624del, Gln690 and Tyr250Ter) cause intracellular retention of the protein at the endoplasmic reticul [26]. ...
... Up to date, a total of 45 families (66 affected patients) with non-HFE related HH due to pathogenic mutations in the TFR2 gene have been described in the literature (Table A2) [24,25]. It has been shown that in a hepatic murine system (Hepa1-6 cells), the murine counterparts of four human TFR2 mutations (Met172Lys, AVAQ621_624del, Gln690Pro and Tyr250Ter) cause intracellular retention of the protein at the endoplasmic reticulum [26]. ...
Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of hemochromatosis, while non-HFE related hemochromatosis are rare cases. Here, we describe six new patients of non-HFE related HH from five different families. Two families (Family 1 and 2) have novel nonsense mutations in the HFE2 gene have novel nonsense mutations (p.Arg63Ter and Asp36ThrfsTer96). Three families have mutations in the TFR2 gene, one case has one previously unreported mutation (Family A—p.Asp680Tyr) and two cases have known pathogenic mutations (Family B and D—p.Trp781Ter and p.Gln672Ter respectively). Clinical, biochemical, and genetic data are discussed in all these cases. These rare cases of non-HFE related hereditary hemochromatosis highlight the importance of an earlier molecular diagnosis in a specialized center to prevent serious clinical complications.
... 66,67 TFR2-associated hereditary hemochromatosis is rare, with approximately 65 cases in 44 family lineages across a wide geographic area. 68 Although TFR2-HH was initially discovered in Italy, subsequent cases were found in Scotland, Spain, Japan and Taiwan. [68][69][70][71] However, TFR2associated HH is still most commonly found in Italy and Japan. ...
... 68 Although TFR2-HH was initially discovered in Italy, subsequent cases were found in Scotland, Spain, Japan and Taiwan. [68][69][70][71] However, TFR2associated HH is still most commonly found in Italy and Japan. ...
... 73 In a study of four unrelated Spanish patients with HH symptoms and no mutations in HFE, HJV, HAMP and SLC40A1, homozygous mutations in TFR2 were discovered, including a missense mutation p.G792R, and nonsense mutations p. Q306X and p.Q672X. 68 TFR2 sequencing as a single gene is available from Invitae 44 and Fulgent, 43 and whole exome sequencing is available from Blueprint Genetics, 42 Ivami 46 and Prevention Genetics. 45 Additionally, Baylor Genetics Laboratories has created a sequence-specific test designed to detect private mutations. ...
Hereditary hemochromatosis (HH) is an inherited iron overload disorder due to a deficiency of hepcidin, or a failure of hepcidin to degrade ferroportin. The most common form of HH, Type 1 HH, is most commonly due to a homozygous C282Y mutation in HFE and is relatively well understood in significance and action; however, other rare forms of HH (Types 2-4) exist and are more difficult to identify and diagnose in clinical practice. In this review, we describe the clinical characteristics of HH Type 2-4 and the mutation patterns that have been described in these conditions. We also review the different methods for genetic testing available in clinical practice and a pragmatic approach to the patient with suspected non-HFE HH.
... When iron stores become elevated in healthy individuals, the liver releases the iron regulator hepcidin to prevent iron overload [62,63]. Hepcidin reduces dietary iron uptake by blocking activity of the iron exporter ferroportin in enterocytes [62,64] and inherited disruptions to this pathway result in hemochromatosis (i.e., iron overload) [65][66][67][68][69]. We assessed liver hepcidin (Hamp) and duodenal ferroportin (Slc40a1) expression in rats at PD 15 to observe systemic iron homeostasis following daily postnatal iron supplementation, and to test for differences between FS and FC. ...
Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.
... or to ClinVar (http://www.ncbi.nlm.nih. gov/clinvar)[26,27]. ...
Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.
