* 604720

TRANSFERRIN RECEPTOR 2; TFR2


HGNC Approved Gene Symbol: TFR2

Cytogenetic location: 7q22.1     Genomic coordinates (GRCh38): 7:100,620,420-100,641,552 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q22.1 Hemochromatosis, type 3 604250 AR 3

TEXT

Cloning and Expression

While attempting to isolate genes encoding new transcriptional factors from a TF-1 (erythroid leukemia) cell cDNA library, Kawabata et al. (1999) cloned an 831-bp human cDNA fragment that had significant amino acid homology to the middle portion of the classic transferrin receptor protein (TFRC; 190010). Using 5-prime/3-prime RACE, they cloned a full-length, 2.9-kb cDNA, which they designated TFR2. They identified 2 transcripts: a 2.9-kb transcript, called alpha, and an approximately 2.5-kb transcript, called beta, which was cloned from an HL60 (myeloid leukemia) cell cDNA library. The alpha form predicts an 801-amino acid type II membrane protein that shares 45% identity and 66% similarity in its extracellular domain with TFRC. The beta form, which may be an alternative product of splicing or promoter usage, lacks the amino-terminal portion of TFR2-alpha, including the putative transmembrane domain. Northern blot analysis showed that the alpha form is predominantly expressed in the liver and also in the K562 erythromegakaryocytic cell line; no expression of the beta form was found. By RT-PCR analysis, TFR2-alpha was expressed in the liver, spleen, lung, muscle, prostate, and peripheral blood mononuclear cells, whereas expression of TFR-beta was found in all tissues tested. Expression of human TFR2 conferred binding of holotransferrin and uptake of transferrin-bound iron to a Chinese hamster ovary cell line lacking endogenous TFRC. Kawabata et al. (1999) concluded that TFR2-alpha may be a second transferrin receptor that can mediate cellular iron transport.


Gene Function

The majority of hepatic iron uptake under normal circumstances is transferrin-mediated. However, expression of TFRC in hepatocytes, as in other nonreticuloendothelial cell types, is downregulated in response to increased intracellular iron. As a consequence, TFRC expression in liver is undetectable in hereditary hemochromatosis (235200) patients with hepatic iron loading. Nonetheless, hepatic iron loading in hemochromatosis patients is progressive. Fleming et al. (2000) provided support for a mechanism that involves the uptake of transferrin-bound iron by TFR2. By screening a murine EST database for Tfrc sequences, they identified a cDNA encoding a protein homologous to murine Tfrc. They characterized the murine TFR2 ortholog and compared expression of murine Tfrc and Tfr2 in normal mice, mice with iron deficiency, and mice with iron overload. Unlike Tfrc, the Tfr2 transcript was highly expressed in hepatocytes, was not regulated by tissue iron status, and was not downregulated in a murine model of hereditary hemochromatosis. From these observations, Fleming et al. (2000) proposed that TFR2 continues to mediate uptake of transferrin-bound iron by the liver after TFRC is downregulated by iron overload, and thus may explain increased susceptibility of the liver to iron loading in hereditary hemochromatosis.


Gene Structure

Kawabata et al. (1999) determined the genomic structure of the TFR2 gene. The alpha transcript contains 18 exons. The beta transcript lacks exons 1 through 3 and has an additional 142 bases at the 5-prime end of exon 4.


Mapping

By radiation hybrid analysis, Kawabata et al. (1999) mapped the TFR2 gene to chromosome 7q22.


Molecular Genetics

Camaschella et al. (2000) identified a premature termination mutation at codon 250 in the TFR2 gene in homozygosity in a Sicilian family segregating hemochromatosis type 3 (HFE3; 604250). The Y250X mutation (604720.0001) identified by Camaschella et al. (2000) is located in a region shared by both the alpha and beta transcripts of TFR2. A phenotype of iron overload associated with the absence of the functional gene suggested TFR2 is more likely involved in iron regulation rather than iron uptake. Although TFR2 is highly expressed in an erythroid cell line, none of the HFE3 patients that they studied showed erythrocyte abnormalities. Rather, the patients tolerated long-term phlebotomies without developing anemia. Thus, Camaschella et al. (2000) concluded that TFR2, in contrast to TFRC, is not essential during erythroid maturation.

Feder et al. (1996) found that about 15% of hereditary hemochromatosis patients of northern European descent do not carry the C282Y mutation of the HFE gene (613609.0001). Mattman et al. (2002) studied a group of non-C282Y hemochromatosis patients and identified several sequence variants, including a homozygous missense mutation in exon 17 of the TFR2 gene, which resulted in a gln690-to-pro amino acid change (604720.0005).

Hofmann et al. (2002) performed mutation analysis of the TFR2 gene in patients with atypical hemochromatosis. They also questioned whether differences in penetrance of the HFE C282Y mutation (613609.0001) were associated with mutations in the TFR2 gene. They studied sib pairs homozygous for cys282-to-tyr with a discordant phenotype. The most common discordance between homozygous sibs was in serum transferrin concentration. Many of these patients, however, also exhibited significant differences in liver fibrosis and liver enzyme levels. They also studied individuals who were not homozygous for C282Y with evidence of iron excess, and other atypical groups. In a pair of brothers homozygous for the C282Y mutation, they found an arg455-to-gln mutation in TFR2 (604720.0004) only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. Unlike TFR1 expression, TFR2 expression is not downregulated in the liver of iron-loaded mice (Fleming et al., 2000). The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare.

Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.


Animal Model

To characterize the role of TFR2 in iron homeostasis, Fleming et al. (2002) generated a premature stop codon (Y245X), which was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. Codon 245 is the mouse ortholog of codon 250, which is involved in the C250Y mutation (604720.0001) of TFR2 in human hemochromatosis, and is located in a region that is conserved between the mouse and human genomes. Fleming et al. (2002) observed that by 4 weeks of age, mice homozygous for the Y245X mutation developed periportal hepatic iron loading, splenic iron sparing, and elevated serum transferrin saturations. Thus, the mutant mice seemed to provide a faithful model for the abnormalities in iron homeostasis observed in patients with loss of TFR2. Heterozygous mice did not differ in any measured parameter from wildtype mice.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 HEMOCHROMATOSIS, TYPE 3

TFR2, TYR250TER
  
RCV000005711

In 2 families from Sicily who met diagnostic criteria for hemochromatosis (HFE3; 604250) but were not linked to the HFE locus (235200), one of which was consanguineous, Camaschella et al. (2000) identified a C-to-G transversion in exon 6 at position 750 of the TFR2 cDNA sequence, resulting in a tyrosine (TAC)-to-stop (TAG) substitution at residue 250 (Y250X). This substitution created a MaeI site. All affected members of the consanguineous family were homozygous for Y250X, whereas obligate carriers were heterozygous. One patient in the nonconsanguineous family was homozygous for this mutation. Camaschella et al. (2000) did not find the Y250X mutation in 100 normal chromosomes or in 12 hemochromatosis patients who did not have mutations in HFE.


.0002 HEMOCHROMATOSIS, TYPE 3

TFR2, 1-BP INS, 84C
  
RCV000005712...

In all affected members of a large inbred family in Campania in southern Italy segregating hemochromatosis (HFE3; 604250), Roetto et al. (2001) found a 1-bp insertion of a cytosine residue in homozygous state in exon 2 in a polyC tract (84-88 insC). The mutation resulted in a frameshift followed by a premature stop codon, a glu60-to-ter (E60X) substitution. Because of consanguinity, a pseudodominant pedigree pattern was observed in an affected father and his 3 affected children in one branch of the family. Heterozygosity was not associated with iron overload, even in individuals also heterozygous for H63D (613609.0002) at the HFE locus or for the beta-thalassemia trait.


.0003 HEMOCHROMATOSIS, TYPE 3

TFR2, MET172LYS
  
RCV000005713

In a family in which the proband had severe hemochromatosis (HFE3; 604250), Roetto et al. (2001) found homozygosity for a T-to-A transversion (515T-A) in exon 4 of TFR2 cDNA, resulting in a met172-to-lys (M172K) substitution of the protein. The proband had cirrhosis, hypogonadism, and cardiac disease. He had inherited beta-thalassemia in heterozygous state from his mother.


.0004 HEMOCHROMATOSIS, TYPE 1, MODIFIER OF

TFR2, ARG455GLN
  
RCV000005714...

Hofmann et al. (2002) studied 2 brothers who were homozygous for the common hemochromatosis-causing mutation of the HFE gene, cys282 to tyr (613609.0001). Direct nucleotide sequencing found a G-to-A transversion at nucleotide 1391, resulting in an arg455-to-gln (R455Q) amino acid change in the TFR2 gene. The R455Q mutation was present in only 1 of the brothers homozygous for C282Y; that brother had evidence of liver fibrosis, whereas the other brother did not.


.0005 HEMOCHROMATOSIS, TYPE 3

TFR2, GLN690PRO
  
RCV000005715

In a Portuguese man with severe hemochromatosis (HFE3; 604250) and in 2 family members, Mattman et al. (2002) found a gln690-to-pro (Q690P) mutation in the TFR2 gene. The patient presented at 29 years of age with fatigue, hypogonadotropic hypogonadism, hyperpigmentation, mild elevation of liver transaminases, and idiopathic thrombocytopenic purpura. He had markedly elevated serum iron indices and had had more than 12 g of iron removed via phlebotomy in the previous 4 years. Additional hematologic abnormalities included mild normocytic anemia and lymphopenia. He was heterozygous for the H63D mutation in the HFE gene (613609.0002). Mattman et al. (2002) stated that this patient was the only one of 89 non-C282Y hereditary chromatosis patients of predominately mixed European descent in whom mutation of the TFR2 gene had been found.


REFERENCES

  1. Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nature Genet. 25: 14-15, 2000. [PubMed: 10802645, related citations] [Full Text]

  2. Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13: 399-408, 1996. [PubMed: 8696333, related citations] [Full Text]

  3. Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc. Nat. Acad. Sci. 99: 10653-10658, 2002. [PubMed: 12134060, images, related citations] [Full Text]

  4. Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc. Nat. Acad. Sci. 97: 2214-2219, 2000. [PubMed: 10681454, images, related citations] [Full Text]

  5. Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P. Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter) Blood 100: 1099-1100, 2002. [PubMed: 12150153, related citations] [Full Text]

  6. Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family. J. Biol. Chem. 274: 20826-20832, 1999. [PubMed: 10409623, related citations] [Full Text]

  7. Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 100: 1075-1077, 2002. [PubMed: 12130528, related citations] [Full Text]

  8. Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97: 2555-2560, 2001. [PubMed: 11313241, related citations] [Full Text]

  9. Wallace, D. F., Subramaniam, V. N. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet. Med. 18: 618-626, 2016. [PubMed: 26633544, related citations] [Full Text]


Ada Hamosh - updated : 10/23/2018
Victor A. McKusick - updated : 3/6/2003
Victor A. McKusick - updated : 3/4/2003
Victor A. McKusick - updated : 9/27/2002
Victor A. McKusick - updated : 7/17/2001
Ada Hamosh - updated : 4/27/2000
Wilson H. Y. Lo - updated : 4/4/2000
Creation Date:
Victor A. McKusick : 3/23/2000
carol : 10/24/2018
alopez : 10/23/2018
alopez : 03/01/2018
carol : 10/21/2010
carol : 3/17/2006
terry : 9/8/2003
cwells : 3/6/2003
terry : 3/4/2003
cwells : 10/1/2002
carol : 9/27/2002
mcapotos : 8/7/2001
mcapotos : 7/26/2001
terry : 7/17/2001
alopez : 7/9/2001
carol : 7/6/2000
alopez : 4/28/2000
terry : 4/27/2000
carol : 4/6/2000
carol : 4/4/2000
mgross : 3/24/2000
mgross : 3/23/2000

* 604720

TRANSFERRIN RECEPTOR 2; TFR2


HGNC Approved Gene Symbol: TFR2

SNOMEDCT: 719974003;  


Cytogenetic location: 7q22.1     Genomic coordinates (GRCh38): 7:100,620,420-100,641,552 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q22.1 Hemochromatosis, type 3 604250 Autosomal recessive 3

TEXT

Cloning and Expression

While attempting to isolate genes encoding new transcriptional factors from a TF-1 (erythroid leukemia) cell cDNA library, Kawabata et al. (1999) cloned an 831-bp human cDNA fragment that had significant amino acid homology to the middle portion of the classic transferrin receptor protein (TFRC; 190010). Using 5-prime/3-prime RACE, they cloned a full-length, 2.9-kb cDNA, which they designated TFR2. They identified 2 transcripts: a 2.9-kb transcript, called alpha, and an approximately 2.5-kb transcript, called beta, which was cloned from an HL60 (myeloid leukemia) cell cDNA library. The alpha form predicts an 801-amino acid type II membrane protein that shares 45% identity and 66% similarity in its extracellular domain with TFRC. The beta form, which may be an alternative product of splicing or promoter usage, lacks the amino-terminal portion of TFR2-alpha, including the putative transmembrane domain. Northern blot analysis showed that the alpha form is predominantly expressed in the liver and also in the K562 erythromegakaryocytic cell line; no expression of the beta form was found. By RT-PCR analysis, TFR2-alpha was expressed in the liver, spleen, lung, muscle, prostate, and peripheral blood mononuclear cells, whereas expression of TFR-beta was found in all tissues tested. Expression of human TFR2 conferred binding of holotransferrin and uptake of transferrin-bound iron to a Chinese hamster ovary cell line lacking endogenous TFRC. Kawabata et al. (1999) concluded that TFR2-alpha may be a second transferrin receptor that can mediate cellular iron transport.


Gene Function

The majority of hepatic iron uptake under normal circumstances is transferrin-mediated. However, expression of TFRC in hepatocytes, as in other nonreticuloendothelial cell types, is downregulated in response to increased intracellular iron. As a consequence, TFRC expression in liver is undetectable in hereditary hemochromatosis (235200) patients with hepatic iron loading. Nonetheless, hepatic iron loading in hemochromatosis patients is progressive. Fleming et al. (2000) provided support for a mechanism that involves the uptake of transferrin-bound iron by TFR2. By screening a murine EST database for Tfrc sequences, they identified a cDNA encoding a protein homologous to murine Tfrc. They characterized the murine TFR2 ortholog and compared expression of murine Tfrc and Tfr2 in normal mice, mice with iron deficiency, and mice with iron overload. Unlike Tfrc, the Tfr2 transcript was highly expressed in hepatocytes, was not regulated by tissue iron status, and was not downregulated in a murine model of hereditary hemochromatosis. From these observations, Fleming et al. (2000) proposed that TFR2 continues to mediate uptake of transferrin-bound iron by the liver after TFRC is downregulated by iron overload, and thus may explain increased susceptibility of the liver to iron loading in hereditary hemochromatosis.


Gene Structure

Kawabata et al. (1999) determined the genomic structure of the TFR2 gene. The alpha transcript contains 18 exons. The beta transcript lacks exons 1 through 3 and has an additional 142 bases at the 5-prime end of exon 4.


Mapping

By radiation hybrid analysis, Kawabata et al. (1999) mapped the TFR2 gene to chromosome 7q22.


Molecular Genetics

Camaschella et al. (2000) identified a premature termination mutation at codon 250 in the TFR2 gene in homozygosity in a Sicilian family segregating hemochromatosis type 3 (HFE3; 604250). The Y250X mutation (604720.0001) identified by Camaschella et al. (2000) is located in a region shared by both the alpha and beta transcripts of TFR2. A phenotype of iron overload associated with the absence of the functional gene suggested TFR2 is more likely involved in iron regulation rather than iron uptake. Although TFR2 is highly expressed in an erythroid cell line, none of the HFE3 patients that they studied showed erythrocyte abnormalities. Rather, the patients tolerated long-term phlebotomies without developing anemia. Thus, Camaschella et al. (2000) concluded that TFR2, in contrast to TFRC, is not essential during erythroid maturation.

Feder et al. (1996) found that about 15% of hereditary hemochromatosis patients of northern European descent do not carry the C282Y mutation of the HFE gene (613609.0001). Mattman et al. (2002) studied a group of non-C282Y hemochromatosis patients and identified several sequence variants, including a homozygous missense mutation in exon 17 of the TFR2 gene, which resulted in a gln690-to-pro amino acid change (604720.0005).

Hofmann et al. (2002) performed mutation analysis of the TFR2 gene in patients with atypical hemochromatosis. They also questioned whether differences in penetrance of the HFE C282Y mutation (613609.0001) were associated with mutations in the TFR2 gene. They studied sib pairs homozygous for cys282-to-tyr with a discordant phenotype. The most common discordance between homozygous sibs was in serum transferrin concentration. Many of these patients, however, also exhibited significant differences in liver fibrosis and liver enzyme levels. They also studied individuals who were not homozygous for C282Y with evidence of iron excess, and other atypical groups. In a pair of brothers homozygous for the C282Y mutation, they found an arg455-to-gln mutation in TFR2 (604720.0004) only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. Unlike TFR1 expression, TFR2 expression is not downregulated in the liver of iron-loaded mice (Fleming et al., 2000). The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare.

Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.


Animal Model

To characterize the role of TFR2 in iron homeostasis, Fleming et al. (2002) generated a premature stop codon (Y245X), which was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. Codon 245 is the mouse ortholog of codon 250, which is involved in the C250Y mutation (604720.0001) of TFR2 in human hemochromatosis, and is located in a region that is conserved between the mouse and human genomes. Fleming et al. (2002) observed that by 4 weeks of age, mice homozygous for the Y245X mutation developed periportal hepatic iron loading, splenic iron sparing, and elevated serum transferrin saturations. Thus, the mutant mice seemed to provide a faithful model for the abnormalities in iron homeostasis observed in patients with loss of TFR2. Heterozygous mice did not differ in any measured parameter from wildtype mice.


ALLELIC VARIANTS 5 Selected Examples):

.0001   HEMOCHROMATOSIS, TYPE 3

TFR2, TYR250TER
SNP: rs80338880, gnomAD: rs80338880, ClinVar: RCV000005711

In 2 families from Sicily who met diagnostic criteria for hemochromatosis (HFE3; 604250) but were not linked to the HFE locus (235200), one of which was consanguineous, Camaschella et al. (2000) identified a C-to-G transversion in exon 6 at position 750 of the TFR2 cDNA sequence, resulting in a tyrosine (TAC)-to-stop (TAG) substitution at residue 250 (Y250X). This substitution created a MaeI site. All affected members of the consanguineous family were homozygous for Y250X, whereas obligate carriers were heterozygous. One patient in the nonconsanguineous family was homozygous for this mutation. Camaschella et al. (2000) did not find the Y250X mutation in 100 normal chromosomes or in 12 hemochromatosis patients who did not have mutations in HFE.


.0002   HEMOCHROMATOSIS, TYPE 3

TFR2, 1-BP INS, 84C
SNP: rs80338877, gnomAD: rs80338877, ClinVar: RCV000005712, RCV001381389

In all affected members of a large inbred family in Campania in southern Italy segregating hemochromatosis (HFE3; 604250), Roetto et al. (2001) found a 1-bp insertion of a cytosine residue in homozygous state in exon 2 in a polyC tract (84-88 insC). The mutation resulted in a frameshift followed by a premature stop codon, a glu60-to-ter (E60X) substitution. Because of consanguinity, a pseudodominant pedigree pattern was observed in an affected father and his 3 affected children in one branch of the family. Heterozygosity was not associated with iron overload, even in individuals also heterozygous for H63D (613609.0002) at the HFE locus or for the beta-thalassemia trait.


.0003   HEMOCHROMATOSIS, TYPE 3

TFR2, MET172LYS
SNP: rs80338879, gnomAD: rs80338879, ClinVar: RCV000005713

In a family in which the proband had severe hemochromatosis (HFE3; 604250), Roetto et al. (2001) found homozygosity for a T-to-A transversion (515T-A) in exon 4 of TFR2 cDNA, resulting in a met172-to-lys (M172K) substitution of the protein. The proband had cirrhosis, hypogonadism, and cardiac disease. He had inherited beta-thalassemia in heterozygous state from his mother.


.0004   HEMOCHROMATOSIS, TYPE 1, MODIFIER OF

TFR2, ARG455GLN
SNP: rs41303501, gnomAD: rs41303501, ClinVar: RCV000005714, RCV000020537, RCV000168108, RCV001081144, RCV003914812

Hofmann et al. (2002) studied 2 brothers who were homozygous for the common hemochromatosis-causing mutation of the HFE gene, cys282 to tyr (613609.0001). Direct nucleotide sequencing found a G-to-A transversion at nucleotide 1391, resulting in an arg455-to-gln (R455Q) amino acid change in the TFR2 gene. The R455Q mutation was present in only 1 of the brothers homozygous for C282Y; that brother had evidence of liver fibrosis, whereas the other brother did not.


.0005   HEMOCHROMATOSIS, TYPE 3

TFR2, GLN690PRO
SNP: rs80338889, gnomAD: rs80338889, ClinVar: RCV000005715

In a Portuguese man with severe hemochromatosis (HFE3; 604250) and in 2 family members, Mattman et al. (2002) found a gln690-to-pro (Q690P) mutation in the TFR2 gene. The patient presented at 29 years of age with fatigue, hypogonadotropic hypogonadism, hyperpigmentation, mild elevation of liver transaminases, and idiopathic thrombocytopenic purpura. He had markedly elevated serum iron indices and had had more than 12 g of iron removed via phlebotomy in the previous 4 years. Additional hematologic abnormalities included mild normocytic anemia and lymphopenia. He was heterozygous for the H63D mutation in the HFE gene (613609.0002). Mattman et al. (2002) stated that this patient was the only one of 89 non-C282Y hereditary chromatosis patients of predominately mixed European descent in whom mutation of the TFR2 gene had been found.


REFERENCES

  1. Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nature Genet. 25: 14-15, 2000. [PubMed: 10802645] [Full Text: https://doi.org/10.1038/75534]

  2. Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13: 399-408, 1996. [PubMed: 8696333] [Full Text: https://doi.org/10.1038/ng0896-399]

  3. Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc. Nat. Acad. Sci. 99: 10653-10658, 2002. [PubMed: 12134060] [Full Text: https://doi.org/10.1073/pnas.162360699]

  4. Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc. Nat. Acad. Sci. 97: 2214-2219, 2000. [PubMed: 10681454] [Full Text: https://doi.org/10.1073/pnas.040548097]

  5. Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P. Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter) Blood 100: 1099-1100, 2002. [PubMed: 12150153] [Full Text: https://doi.org/10.1182/blood-2002-04-1077]

  6. Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family. J. Biol. Chem. 274: 20826-20832, 1999. [PubMed: 10409623] [Full Text: https://doi.org/10.1074/jbc.274.30.20826]

  7. Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 100: 1075-1077, 2002. [PubMed: 12130528] [Full Text: https://doi.org/10.1182/blood-2002-01-0133]

  8. Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97: 2555-2560, 2001. [PubMed: 11313241] [Full Text: https://doi.org/10.1182/blood.v97.9.2555]

  9. Wallace, D. F., Subramaniam, V. N. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet. Med. 18: 618-626, 2016. [PubMed: 26633544] [Full Text: https://doi.org/10.1038/gim.2015.140]


Contributors:
Ada Hamosh - updated : 10/23/2018
Victor A. McKusick - updated : 3/6/2003
Victor A. McKusick - updated : 3/4/2003
Victor A. McKusick - updated : 9/27/2002
Victor A. McKusick - updated : 7/17/2001
Ada Hamosh - updated : 4/27/2000
Wilson H. Y. Lo - updated : 4/4/2000

Creation Date:
Victor A. McKusick : 3/23/2000

Edit History:
carol : 10/24/2018
alopez : 10/23/2018
alopez : 03/01/2018
carol : 10/21/2010
carol : 3/17/2006
terry : 9/8/2003
cwells : 3/6/2003
terry : 3/4/2003
cwells : 10/1/2002
carol : 9/27/2002
mcapotos : 8/7/2001
mcapotos : 7/26/2001
terry : 7/17/2001
alopez : 7/9/2001
carol : 7/6/2000
alopez : 4/28/2000
terry : 4/27/2000
carol : 4/6/2000
carol : 4/4/2000
mgross : 3/24/2000
mgross : 3/23/2000