DiagnosisClinical DiagnosisTFR2-related hereditary hemochromatosis (TFR2-HHC) should be suspected in any individual with findings of iron overload (including hepatomegaly, hepatic cirrhosis, diabetes mellitus, cardiomyopathy, hypogonadism, arthritis - especially if involving the metacarpophalangeal joints, and progressive increase in skin pigmentation) in whom HFE-associated hereditary hemochromatosis has been excluded. More typically, individuals present with either of the following:Early clinical findings of hereditary hemochromatosis (including vague nonspecific symptoms, e.g., abdominal pain, fatigue, arthralgia, decreased libido) More frequently, biochemical evidence of iron overload in routinely used panels that include serum transferrin-iron saturation and serum concentrations of iron and ferritinNote: No specific diagnostic guidelines are available for TFR2-related hemochromatosis; however, guidelines/recommendations of scientific societies or experts for HFE-associated hereditary hemochromatosis are available (see following and references cited).TestingDiagnosis of TFR2-HHC is suspected in individuals with the following:Transferrin saturation higher than 45%. Normal range is between 20% and 35% saturation in both sexes.Serum ferritin concentration usually higher than 200 µg/L in females and higher than 300 µg/L in males. Normal ranges:Children and adolescents: 15-150 µg/LAdult males: 20-300 µg/LAdult females: 20-200 µg/LNote: The same biochemical iron parameters are used in diagnosis of HFE-associated hereditary hemochromatosis [Pietrangelo 2010].Liver biopsy. Findings on liver biopsy have been reported in a few individuals with TFR2-HHC [Girelli et al 2002, Pietrangelo et al 2005, Hsiao et al 2007, Pelucchi et al 2009]. Liver biopsy is used to assess:Histology; fibrosis or cirrhosisLiver iron concentration (LIC)Distribution of iron storage. Increased iron deposition in the hepatocytes and a decreasing gradient of iron stores are observed from portal to centrolobular areas [Girelli et al 2002, Pelucchi et al 2009], as in HFE-associated hereditary hemochromatosis).Imaging. Noninvasive techniques including MRI [Gandon et al 2004, St Pierre et al 2005] and SQUID developed to quantitate liver iron concentration have been applied to HFE-associated hereditary hemochromatosis [Carneiro et al 2004] but rarely to TFR2-HHC [Piperno et al 2004, Biasiotto et al 2008, Pelucchi et al 2009].Molecular Genetic TestingGene. TFR2 is the only gene in which mutations are known to cause TFR2-HHC.Clinical testingTargeted mutation analysis. A panel of four mutations (see Table 1) identifies mutations in fewer than 50% of individuals known to have TFR2-HHC.Sequence analysis. The mutation detection frequency by sequence analysis is higher than 98% [Biasiotto et al 2003].Table 1. Summary of Molecular Genetic Testing Used in TFR2-Related Hereditary HemochromatosisView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityTFR2Targeted mutation analysisc.88_89insC, c.313C>T, c.515T>A, c.750C>G, c.1861_1872del122Clinical Sequence analysisSequence variants 3>98%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Data are from the Italian population [Author, personal observation].3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Testing StrategyConfirmation of the diagnosis in a proband. In an individual with a clinical diagnosis of hemochromatosis and/or increased iron at liver biopsy (or MRI) and/or a family history of hemochromatosis AND no identifiable HFE mutations, molecular genetic testing for TFR2 mutations is appropriate. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TFR2.}

Natural HistoryTFR2-related hereditary hemochromatosis (TFR2-HHC) is characterized by deregulated, increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs [Camaschella et al 2000, Camaschella & Poggiali 2009].The age of onset in TFR2-HHC is earlier than in HFE-associated hereditary hemochromatosis. One child age 3.5 years had transferrin saturation and serum ferritin concentration that were increased for age [Piperno et al 2004]. Some individuals present with signs of iron overload in the second decade [Girelli et al 2002, Hattori et al 2003, Le Gac et al 2004, Piperno et al 2004, Biasiotto et al 2008, Gérolami et al 2008]. Others present as adults with abnormal serum iron studies or fatigue and arthralgia and/or signs of organ involvement (liver cirrhosis, diabetes, arthropathy) [Roetto et al 2001, Girelli et al 2002, Hattori et al 2003, Koyama et al 2005, Pelucchi et al 2009]. Severe joint involvement has been reported [Ricerca et al 2009].Disease progression is slower than in juvenile hereditary hemochromatosis, even in untreated individuals [De Gobbi et al 2002]. Even untreated, TFR2-HHC may not be progressive [Roetto et al 2001, Girelli et al 2002].When TFR2-HHC is progressive, complications can include cirrhosis, hypogonadotropic hypogonadism, and arthritis. Cardiomyopathy and diabetes mellitus are rare [Riva et al 2004] and hepatocellular carcinoma has not been observed in the limited number of affected individuals reported to date. Most individuals reported to date have been of Italian or Japanese ancestry. Individuals of Japanese ancestry were older at diagnosis than those of Italian ancestry and had hepatic iron loading; a few middle-aged Japanese males had cirrhosis [Hattori et al 2003, Koyama et al 2005].

Genotype-Phenotype CorrelationsThe limited number of individuals reported and the private nature of the mutations do not permit genotype-phenotype correlations.Presence of the p.His63Asp allele of HFE (NP_000401.1; NM_000410.3) has been described in individuals with TFR2-HHC [Camaschella et al 2000, Piperno et al 2004]; however, the contribution of the p.His63Asp allele to the TFR2-related iron overload is unclear.Inheritance of compound heterozygosity for the HFE mutations p.Cys282Tyr (NP_000401.1; NM_000410.3:c. 845G>A) and p.His63Asp and homozygosity for the TFR2 mutation p.Gln317X produced a phenotype of juvenile hemochromatosis in a single family [Pietrangelo et al 2005].

Differential DiagnosisTFR2-related hereditary hemochromatosis (TFR2-HHC, sometimes called type 3 HHC) needs to be distinguished from other primary iron overload disorders as well as from secondary iron overload disorders. No specific studies have evaluated the percentage of TFR2 mutations detected in individuals with non-HFE-associated hereditary hemochromatosis. Primary Iron Overload DisordersPrimary overload disorders are characterized by increased absorption of iron from a normal diet.HFE-related hereditary hemochromatosis (hemochromatosis type 1) is the most common form. HFE-associated hereditary hemochromatosis is characterized by excessive storage of iron, particularly in the liver, skin, pancreas, heart, joints, and pituitary, resulting in hypogonadotropic hypogonadism. Without therapy, males may develop symptoms between ages 40 and 60 years and females after menopause. Hepatic fibrosis or cirrhosis may occur in untreated individuals after age 40 years. A large fraction of homozygotes (98% in some series) [Asberg et al 2001, Beutler et al 2002] for mutations in this gene do not develop clinical symptoms (i.e., penetrance is low). Inheritance is autosomal recessive.Juvenile hereditary hemochromatosis (sometimes called type 2 HHC) has an earlier age of onset and more severe clinical manifestations than HFE-related hereditary hemochromatosis. Two causative genes (hence, two clinically indistinguishable "subtypes") have been identified: type 2A, caused by mutations in HJV encoding hemojuvelin; and type 2B, caused by mutations in HAMP. Onset of severe iron overload typically occurs in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has not been reported. The main cause of death is cardiac-related disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced. Inheritance is autosomal recessive [Roetto et al 1999, Camaschella et al 2000, De Gobbi et al 2002].Ferroportin-related hereditary hemochromatosis (hemochromatosis type 4) is caused by mutations in SLC40A1, or solute carrier family 40 (iron-regulated transporter) member 1, which encodes ferroportin. Onset is late. Unlike all other varieties of hemochromatosis, iron storage in most cases affects reticuloendothelial rather than parenchymal cells [Montosi et al 2001, Njajou et al 2001]. Inheritance is autosomal dominant.Recently, two types of ferroportin disease have been recognized. The more common “ferroportin disease type A” is caused by mutations that reduce the iron export from macrophages resulting in macrophage iron accumulation and low-normal transferrin saturation [Schimanski et al 2005]. The less common “ferroportin disease type B” is caused by hepcidin-resistant mutations that permit continued export of iron from macrophages resulting in disease that resembles HFE-associated hereditary hemochromatosis with high transferrin saturation and iron in hepatocytes [Drakesmith et al 2005, Wallace & Subramaniam 2007]. Some persons have an intermediate phenotype with a mixed pattern of liver iron accumulation. Aceruloplasminemia is characterized by iron accumulation in the brain and the visceral organs, manifest as retinal degeneration, diabetes mellitus, and neurologic disease (movement disorders and ataxia) in individuals older than age 25 years. Early treatment with iron chelators can diminish iron accumulation and ameliorate symptoms. Aceruloplasminemia is caused by the complete lack of ceruloplasmin ferroxidase activity resulting from mutations in CP, which encodes ceruloplasmin. Inheritance is autosomal recessive.African iron overload was originally described in Africans who drink a traditional beer brewed in non-galvanized steel drums. The disease does not develop in all beer drinkers, suggesting the existence of a genetic susceptibility. A missense change (NP_055400.1:p.Gln248His; NM_014585.5:c.744G>T) in SLC40A1 encoding ferroportin has been reported in Africans and African Americans with iron overload by independent groups [Beutler et al 2003, Gordeuk et al 2003], but the functional effect of this mutation in vitro is controversial [Drakesmith et al 2005, McNamara et al 2005, Barton et al 2007]. In the large HEIRS study the association of increased serum ferritin concentration and the polymorphism was found only in males [Rivers et al 2007].In neonatal hemochromatosis iron overload occurs in the fetus, likely secondary to different causes. At birth, liver failure dominates the clinical picture. The disease is extremely severe, often fatal, unless liver transplantation is performed. Inheritance is unknown. Recently, an immunologic pathogenesis has been proposed for recurrent cases because treatment of at-risk pregnancies with high-dose IV IGg resulted in significant improvement of the outcome [Whitington & Hibbard 2004].Secondary Iron Overload DisordersSecondary iron overload disorders include iron excess resulting from different conditions. The most severe disorders result from transfusions for chronic anemia such as beta-thalassemia or sickle cell disease. Secondary iron overload may result from ingested iron in foods, cookware, and medicines, as well as parenteral iron from iron injections.This group also includes a range of liver diseases associated with parenchymal liver disease (e.g., alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasia, porphyria cutanea tarda) and inflammatory disorders such as rheumatoid arthritis (which are questionable because inflammatory disorders are not true iron-loading disorders).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with TFR2-related hereditary hemochromatosis (TFR2-HHC), the following are recommended (based on recommendations for HFE-associated hereditary hemochromatosis):Liver biopsy for evaluation of abnormal liver function tests and establishing prognosis when serum ferritin concentration is greater than 1000 ng/mL and/or when hepatomegaly is present [Guyader et al 1998]Serum concentration of gonadotropins (FSH and LH) to assess pituitary function. Depending on the results, a GnRH stimulation test may be necessary.Serum concentration of testosterone to assess testicular function; serum concentration of estradiol to assess ovarian functionRadiographs of the affected joint(s) to assess persistent arthralgia or arthropathyCardiac evaluation (ECG and echocardiography) for all symptomatic individuals and those with severe iron overload (ferritin >1000 ng/mL)Screening for diabetes mellitus by fasting serum glucose concentration and oral glucose tolerance test (OGTT)Treatment of ManifestationsThe following recommendations are based on guidelines proposed for HFE-associated hereditary hemochromatosis in Europe [European Association for the Study of the Liver 2010; see ] and an expert review [Adams & Barton 2010]. However, it should be emphasized that since TFR2-HHC is rare and may progress differently from HFE-associated hemochromatosis, individual treatment is important.Individuals with increased serum ferritin concentration should be treated by the same protocol as for HFE-associated hereditary hemochromatosis.Therapeutic phlebotomy. Periodic phlebotomy (i.e., removal of a unit of blood) is a simple, inexpensive, safe, and effective way to remove excess iron. Each unit of blood (400-500 mL) with a hematocrit of 40% contains approximately 160-200 mg of iron.The usual therapy is weekly phlebotomy; however, twice weekly phlebotomy may be useful initially to accelerate iron depletion. On average, men require removal of twice as many units of blood as women.Weekly phlebotomy is carried out until the serum ferritin concentration is 100 ng/mL or lower. Serum ferritin concentration should be measured following each phlebotomy or every other phlebotomy [Adams & Barton 2010]:Once the serum ferritin concentration is approximately 50 ng/mL, monitoring serum ferritin concentration every three to four months is adequate.If the serum ferritin concentration is 50 ng/mL or higher despite a significant reduction in hematocrit, phlebotomies need to be spaced further apart.Note: Although experience is limited because of the small number of affected individuals identified worldwide, it should be noted that transferrin saturation remains high in TFR2-related hereditary hemochromatosis when serum ferritin concentration is low (<50 ng/mL), even after intensive phlebotomy [Girelli et al 2011; Camaschella & Roetto, unpublished observation].Maintenance therapy. The goal is to maintain serum ferritin concentration around 50 ng/mL and transferrin-iron saturation below 50%. Phlebotomy to prevent reaccumulation of iron is performed about every three to four months for men and once or twice a year for women.Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible. Iron chelators such as subcutaneous desferrioxamine are used as a first choice in case of concomitant anemia [Riva et al 2004] or cardiac dysfunction.Note: At present, oral iron chelators are not available to treat hemochromatosis. However, a phase I/II trial has been completed with daily administration of deferasirox in persons with newly diagnosed HFE-HHC with iron overload and without evidence of liver cirrhosis. The trial demonstrated that treatment is feasible, safe, and effective; side effects were mostly related to the GI tract [Phatak et al 2010].Treatment of clinical complicationsCirrhosis should be treated and followed up as in other conditions. Although cirrhosis is not reversible by phlebotomy, individuals with cirrhosis benefit from iron removal in that it reduces the risk of hepatocellular cancer.Hypogonadism is irreversible and requires lifelong hormone replacement therapy in males and females. Use of gonadotropins has successfully restored fertility and induced pregnancy in women who have been treated for other forms of hemochromatosis.Arthropathy requires nonsteroidal anti-inflammatory drugs (NSAIDs) and is barely influenced by phlebotomy. In some cases, joint replacement has been performed.Cardiac failure is treated with diuretics, ACE inhibitors, cardiac glycosides, and iron chelation by intravenous or subcutaneous deferioxamine.Diabetes mellitus may require lifelong insulin treatment. Iron removal may improve control of diabetes mellitus but cannot reestablish normal glucose metabolism.Prevention of Primary ManifestationsIn affected individuals with increased serum ferritin concentration, prevention of primary manifestations is accomplished by weekly phlebotomy to deplete iron stores (see Treatment of Manifestations).SurveillanceOnce the serum ferritin concentration is around 50 ng/mL, monitoring serum ferritin concentration every three to four months is adequate.Although hepatocellular carcinoma has not been reported in individuals with TFR2-associated hereditary hemochromatosis, surveillance for its development should be performed in persons with cirrhosis by monitoring liver ultrasound examinations and serum concentrations of alpha-fetoprotein, as in persons with cirrhosis with HFE-associated hereditary hemochromatosis.Agents/Circumstances to AvoidAvoid the following:Medicinal ironMineral supplementsExcess vitamin CUncooked seafood (because of the risk of infection from microorganisms thriving under conditions of excess iron)For those with hepatic involvement, alcohol intake should be restricted because it increases iron absorption and is toxic to the hepatocytes.Evaluation of Relatives at RiskIf the disease-causing mutations in the family are known, it is appropriate to offer molecular genetic testing to at-risk relatives to allow early diagnosis and treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementWomen with hemochromatosis do not need treatment during pregnancy because the fetal utilization of maternal iron effectively reduces the mother’s iron load during pregnancy.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. TFR2-Related Hereditary Hemochromatosis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTFR27q22​.1Transferrin receptor protein 2TFR2 @ LOVDTFR2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for TFR2-Related Hereditary Hemochromatosis (View All in OMIM) View in own window 604250HEMOCHROMATOSIS, TYPE 3; HFE3 604720TRANSFERRIN RECEPTOR 2; TFR2Molecular Genetic PathogenesisTFR2-encoded protein is highly expressed in the hepatocytes and its function is likely related to the hepcidin pathway that regulates iron homeostasis.The hepatic peptide hepcidin (encoded by HAMP) is a circulating hormone that regulates the absorption of dietary iron from the duodenum. Hepcidin expression is inappropriately decreased in hereditary hemochromatosis and is abnormally increased in the anemia of chronic diseases. Other hepatic proteins essential for normal iron homeostasis, including HFE, transferrin receptor protein 2 (TfR2), and hemojuvelin, function at least in part by modulating the expression of hepcidin [Hentze et al 2010].Individuals with homozygous TFR2 mutations have increased intestinal iron absorption that causes iron overload. Low/absent levels of urinary hepcidin have been reported in TFR2-related hereditary hemochromatosis [Nemeth et al 2005], suggesting that TFR2 is a modulator of hepcidin. A time course of serum hepcidin after a single dose of oral iron in two individuals homozygous for a TFR2 mutation revealed absence of hepcidin response [Girelli et al 2011]. A similar finding of down-regulation (or lack of up-regulation following iron loading) of mRNA of hepcidin in liver has been documented in mice with inactive Tfr2 [Kawabata et al 2005, Wallace et al 2005].Normal allelic variants. TFR2 is 2471 bp long and consists of 18 exons. There are two main alternatively spliced variants (see Figure 1):FigureFigure 1. Schematic representation of the localization of TFR2 mutations. Causal mutations are illustrated in bold above the gene; exonic normal variants are marked below the gene (see Table 2). The two alternatively spliced TFR2 transcripts are also (more...)Alpha, corresponding to transcription of all exons. Alpha-TFR2 is prevalently and highly expressed in hepatocytes. Two alpha-TFR2 cDNAs of 2.9 and 2.3 kb are recognized. The first (Genbank accession AF053356) lacks 81 nucleotides in exon 8 and is 18 nucleotides longer in exon 18 [Glockner et al 1998] when compared to the second (Genbank accession AF067864) [Kawabata et al 1999].Beta, which has an in-frame transcription start site in exon 4 [Kawabata et al 1999]. Beta-TFR2 cDNA (NM_001206855.1) lacks exons 1-3 and has 142 additional bases at its 5' end. Beta TFR2 is expressed ubiquitously at very low levels. Based on animal models, it has been proposed that the beta form (NP_001193784.1) has a role in regulating iron export in the spleen [Roetto et al 2010] (see Normal gene product).Several exonic normal DNA variants have been described (see Figure 1); they are either silent or missense mutations present also in control individuals [Lee et al 2001, Biasiotto et al 2008]. Two nucleotide normal variants have been identified in the non-coding region of TFR2 [Meregalli et al 2000, Biasiotto et al 2008]. A TFR2 intronic SNP (rs7385804) was associated with physiologic serum iron modification in genome-wide association studies [Pichler et al 2011].Pathologic allelic variants. Seventeen causal mutations have been reported; most are rare or private [Roetto et al 2002, Lee & Barton 2006, Hsiao et al 2007, Biasiotto et al 2008, Gérolami et al 2008, Pelucchi et al 2009] (see Table 2):The most frequent mutation is p.Tyr250X, identified in four different Italian families [Camaschella et al 2000, Piperno et al 2004] who live in the same geographical area and thus may be distantly related.p.Arg30Profs*31 has been found in a single large Italian family [Roetto et al 2002].p.Met172Lys has been found in two unrelated Italian families [Roetto et al 2001, Majore et al 2006].A recurrent mutation is a deletion of 12 nucleotides in a 12-nucleotide repeat in exon 16, which results in a four-amino acid deletion p.Ala621_Gln624del (see Figure 1) [Girelli et al 2002, Hattori et al 2003].The private mutation p.Arg105X was characterized in two affected young siblings from France [Le Gac et al 2004].Two novel mutations (p.Leu490Arg and p.Ser556Alafs*6) were characterized in Japanese individuals [Koyama et al 2005].p.Gln317X was reported in association with HFE p.Cys282Tyr and p.His63Asp compound heterozygosity in two siblings with a juvenile phenotype and in association with wild-type HFE in a brother with a classic type of HHC [Pietrangelo et al 2005]. See Genotype-Phenotype Correlations for HFE mutation references.Two novel TFR2 mutations (p.Arg396X and p.Gly792Arg) associated to an already characterized polymorphic variant (p.Arg455Gln) [Hofmann et al 2002] have been found in a single Scottish individual.A new missense mutation has been characterized in a Taiwanese woman with the disease [Hsiao et al 2007].In an Italian mutation study, one subject compound heterozygous for two new mutations (p.Asn411del and p.Ala444Thr) together with two siblings homozygous for a new causal variant (c.2137-1G>A) have been recently identified [Biasiotto et al 2008].A combination of the known mutation (p.Arg396X) and a new variant (c. 1538-2 A>G) in compound heterozygosity has been identified in a young woman of Italian descent [Gérolami et al 2008].Screening of an iron-overloaded population identified a novel missense mutation (p.Phe280Leu) in compound heterozygosity with the HFE H63D variant [Mendes et al 2009]. Its causal effect is not demonstrated, but the mutation involves a highly conserved amino acid. A new splicing mutation that causes the skipping of TFR2 exon 4 has been identified at the homozygous state in a 47-year-old woman with iron overload [Pelucchi et al 2009].For more information, see Table A and Figure 1.Table 2. Selected TFR2 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change
(Alias ¹)Reference SequencesReferenceNormalc.97C>Ap.His33AsnNM_003227​.3
NP_003218​.2Biasiotto et al [2008]c.224C>Tp.Ala75ValBiasiotto et al [2003]c.473+49C>A
(IVS3+49)--Biasiotto et al [2008]c.1851C>T
(1878C>T) p.(=) ^{2(Ala617Ala)Meregalli et al [2000]c.714C>Gp.Ile238MetLee et al [2001]c.1364G>Ap.Arg455GlnHofmann et al [2002] c.1770C>Tp.(=)
(Asp590Asp)Lee et al [2001]c.1851C>Tp.(=)
(Ala617Ala)Lee et al [2001]c.2228C>Tp.Ala743ValLee et al [2001]Pathologicc.64G>A p.Val22IleBiasiotto et al [2003]c.88_89insC
(ins88C)p.Arg30Profs*31
(E60X)Roetto et al [2001]c.313C>Tp.Arg105X
(E60X)Le Gac et al [2004]c.515T>Ap.Met172LysRoetto et al [2001]c.2137-1G>A
(IVS17+5636)--Biasiotto et al [2008]c.750C>Gp.Tyr250XCamaschella et al [2000]c.949C>Tp.Gln317XPietrangelo et al [2005]c.1186C>Tp.Arg396XLee & Barton [2006]c.1231_1233delp.Asn411delBiasiotto et al [2008]c.1330G>A p.Ala444ThrBiasiotto et al [2008]c.1403G>Ap.Arg468His
(Arg481His)Hsiao et al [2007]c.1469T>Gp.Leu490ArgKoyama et al [2005]c.1665delCp.Ser556Alafs*6
(Val561X)Koyama et al [2005]c.1861_1872del12p.Ala621_Gln624del
(AVAQ621-624del)Girelli et al [2002]c.2069A>Cp.Gln690Proc.2374G>Ap.Gly792ArgLee & Barton [2006]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. The designation p.(=) means that no effect on protein level is expected.Normal gene product. TfR2 is a type II transmembrane glycoprotein characterized by short intracellular and transmembrane domains and a large extracellular domain. The TfR2 full-length transcript (the alpha form) originates an 801-amino acid transmembrane protein. Residues 1-80 correspond to the cytoplasmic domain, residues 81-104 correspond to the transmembrane, and amino acids 105-801 correspond to the extracellular domain. Cysteines 89-98 and 108-111 are involved in disulfide bonds, likely responsible for TFR2 homodimerization. A YQRV amino acid motif in the cytoplasmic domain, similar to the internalization signal (YTRF) of transferrin receptor (TFRC), could have the same function.TfR2 is highly expressed in hepatoma (HEPG2) and in erythroleukemia cell lines (K562) [Kawabata et al 1999]. It is expressed in the liver, especially in the hepatocytes, and at low levels in Kuppfer cells [Zhang et al 2004]. Recently it has been shown that TfR2 protein is expressed in erythroid cells in mice and humans and that TfR2 protein interacts with the erythropoietin receptor [Forejtnikovà et al 2010]. It remains to be determined if this erythroid expression has some relationship with hepcidin inhibition in erythroid expansion.Alpha-TfR2 binds and internalizes transferrin. However, binding occurs at low affinity (25- to 30-fold lower) [Kawabata et al 2000], as compared to that of the transferrin receptor (TFRC). Alpha-TfR2 protein shows significant amino acid homology with TFRC and the prostate-specific membrane antigen (PSMA), especially in the extracellular portion [Kawabata et al 1999]. Expression of TfR2 is in fact reported in several cancer cell lines and primary tumor cells [Calzolari et al 2009, Calzolari et al 2010] Beta-TfR2 lacks the cytoplasmic and transmembrane domains and could be an intracellular protein.TFR2 has no IRE elements in its 5' or 3' UTR and is not transcriptionally regulated by iron. TFR2 does not bind HFE in vitro because residues involved in HFE binding in TFRC are not conserved in TFR2 [West et al 2000]. TFR2 is also expressed by early erythroid progenitors but not by bone marrow precursors [Calzolari et al 2004, Forejtnikovà et al 2010].TFR2-encoded protein in HepG2 cell line is stabilized by diferric transferrin, which increases TFR2-encoded protein half-life [Johnson & Enns 2004, Robb & Wessling-Resnick 2004]. In addition, TFR2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies [Robb et al 2004]. Tfr2 stabilization by transferrin reduces Tfr2 lysosomal degradation and directs TFR2 toward the recycling endosome [Johnson et al 2007].The cytoplasmic domain is that involved in membrane stabilization after TF binding [Chen & Enns 2007]. In the present model, TfR2 stabilized on plasma membrane binds HFE to activate hepcidin [Gao et al 2009] but the molecular mechanism remain unclear.Animal models of the disease have been developed:A Tfr2-deficient mouse homozygous for Tfr2Y245X} [Fleming et al 2002], a mutation orthologous to the human p.Tyr250X [Camaschella et al 2000], the Tfr2-knockout mouse [Wallace et al 2005], and a conditional hepatic knock out [Wallace et al 2007]. All these mice show iron overload in liver and other organs with the spleen relatively free of iron as in the human disorder [Fleming et al 2002]. The Tfr2-null (knockout) shows significant iron overload and is unable to increase hepcidin in response to iron [Wallace et al 2005]. More recently other models have been developed: a murine line with selective inactivation of the Tfr2-beta isoform (KI mice), Tfr2 knock out animals within the identical genetic background, and a model with inactivation of both Tfr2-alpha and -beta isoforms in the liver and Tfr2-beta isoform in the other tissues (LCKO-KI) The latter animals develop earlier and more severe iron overload than KO, while KI animals have normal iron parameters and iron gene expression, but develop severe iron overload in the spleen [Roetto et al 2010]. Simultaneous inactivation of Tfr2 and Hfe in mice induces a more severe iron overload and a more marked hepcidin deficiency than inactivating the single genes [Wallace et al 2009]. This suggests some additive function for the two genes in hepcidin control [Wallace et al 2009].Abnormal gene product. The pathologic variants produce a truncated protein or an abnormally structured protein (e.g., p.Ala621_Gln624del, p.Leu490Arg, p.Gln690Pro). The mutation p.Met172Lys is of interest because it causes a missense in the alpha form but alters methionine, which is the putative initiation codon of beta TFR2 [Roetto et al 2001, Majore et al 2006].