# 604250

HEMOCHROMATOSIS, TYPE 3; HFE3


Alternative titles; symbols

HEMOCHROMATOSIS DUE TO DEFECT IN TRANSFERRIN RECEPTOR 2


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
7q22.1 Hemochromatosis, type 3 604250 AR 3 TFR2 604720
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
CARDIOVASCULAR
Heart
- Cardiomyopathy
ABDOMEN
Liver
- Cirrhosis
- Hepatic fibrosis
GENITOURINARY
External Genitalia (Male)
- Hypogonadism
Internal Genitalia (Male)
- Impotence
- Decreased libido
Internal Genitalia (Female)
- Amenorrhea
SKELETAL
- Arthritis
SKIN, NAILS, & HAIR
Skin
- Hyperpigmentation
NEUROLOGIC
Behavioral Psychiatric Manifestations
- Fatigue
ENDOCRINE FEATURES
- Diabetes
HEMATOLOGY
- Neutropenia
- Anemia
- Lymphopenia
- Thrombocytopenic purpura
LABORATORY ABNORMALITIES
- Increased transferrin saturation
- Increased serum ferritin
- Increased serum iron
- Increased liver transaminases
MOLECULAR BASIS
- Caused by mutation in the transferrin receptor 2 gene (TFR2, 604720.0001)

TEXT

A number sign (#) is used with this entry because of evidence that hemochromatosis type 3 (HFE3) is caused by homozygous or compound heterozygous mutation in the transferrin receptor-2 gene (TFR2; 604720) on chromosome 7q22.

For general background information and a discussion of genetic heterogeneity of hereditary hemochromatosis, see 235200.


Clinical Features

Camaschella et al. (1999) described 2 iron-loaded sibs from a consanguineous Italian family. Both had a severe phenotype. The first sib presented with amenorrhea at age 31; liver biopsy and treatment were performed at age 36. In the second sib, decreased libido and impotence at age 21 were the first manifestations of the disease. He had latent diabetes. Cirrhosis was present in both. Serum ferritin was approximately 3,000 microg/liter in both.


Mapping

Using linkage analysis in a large consanguineous Sicilian family, Camaschella et al. (2000) demonstrated that the HFE3 locus was at chromosome 7q22, with a maximum lod score of 4.09 at theta = 0.0 for markers D7S477 and D7S647.


Molecular Genetics

Camaschella et al. (2000) identified a tyr-to-ter substitution at codon 250 of the TFR2 gene (604720.0001) in 2 Sicilian families segregating HFE3, one consanguineous.

Mattman et al. (2002) studied a group of hemochromatosis patients without a C282Y mutation in the HFE gene (613609.0001) and identified several sequence variants, including a homozygous missense mutation in the transferrin receptor-2 gene (604720.0005).

Griffiths and Cox (2000) reviewed the molecular pathophysiology of iron metabolism.


REFERENCES

  1. Camaschella, C., Fargion, S., Sampietro, M., Roetto, A., Bosio, S., Garozzo, G., Arosio, C., Piperno, A. Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology 29: 1563-1564, 1999. [PubMed: 10216143, related citations] [Full Text]

  2. 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]

  3. Griffiths, W., Cox, T. Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. Hum. Molec. Genet. 9: 2377-2382, 2000. [PubMed: 11005792, related citations] [Full Text]

  4. 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]


Victor A. McKusick - updated : 2/6/2003
George E. Tiller - updated : 12/4/2000
Ada Hamosh - updated : 4/27/2000
Creation Date:
Victor A. McKusick : 10/20/1999
carol : 10/24/2018
carol : 02/15/2017
carol : 11/03/2010
carol : 10/21/2010
alopez : 3/25/2010
mgross : 4/20/2005
ckniffin : 4/5/2004
tkritzer : 3/6/2003
carol : 2/13/2003
carol : 2/6/2003
terry : 2/6/2003
carol : 9/20/2002
carol : 8/6/2001
terry : 12/4/2000
carol : 7/6/2000
alopez : 4/28/2000
terry : 4/27/2000
alopez : 11/15/1999
carol : 10/20/1999

# 604250

HEMOCHROMATOSIS, TYPE 3; HFE3


Alternative titles; symbols

HEMOCHROMATOSIS DUE TO DEFECT IN TRANSFERRIN RECEPTOR 2


SNOMEDCT: 719974003;   ORPHA: 225123;   DO: 0111030;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
7q22.1 Hemochromatosis, type 3 604250 Autosomal recessive 3 TFR2 604720

TEXT

A number sign (#) is used with this entry because of evidence that hemochromatosis type 3 (HFE3) is caused by homozygous or compound heterozygous mutation in the transferrin receptor-2 gene (TFR2; 604720) on chromosome 7q22.

For general background information and a discussion of genetic heterogeneity of hereditary hemochromatosis, see 235200.


Clinical Features

Camaschella et al. (1999) described 2 iron-loaded sibs from a consanguineous Italian family. Both had a severe phenotype. The first sib presented with amenorrhea at age 31; liver biopsy and treatment were performed at age 36. In the second sib, decreased libido and impotence at age 21 were the first manifestations of the disease. He had latent diabetes. Cirrhosis was present in both. Serum ferritin was approximately 3,000 microg/liter in both.


Mapping

Using linkage analysis in a large consanguineous Sicilian family, Camaschella et al. (2000) demonstrated that the HFE3 locus was at chromosome 7q22, with a maximum lod score of 4.09 at theta = 0.0 for markers D7S477 and D7S647.


Molecular Genetics

Camaschella et al. (2000) identified a tyr-to-ter substitution at codon 250 of the TFR2 gene (604720.0001) in 2 Sicilian families segregating HFE3, one consanguineous.

Mattman et al. (2002) studied a group of hemochromatosis patients without a C282Y mutation in the HFE gene (613609.0001) and identified several sequence variants, including a homozygous missense mutation in the transferrin receptor-2 gene (604720.0005).

Griffiths and Cox (2000) reviewed the molecular pathophysiology of iron metabolism.


REFERENCES

  1. Camaschella, C., Fargion, S., Sampietro, M., Roetto, A., Bosio, S., Garozzo, G., Arosio, C., Piperno, A. Inherited HFE-unrelated hemochromatosis in Italian families. Hepatology 29: 1563-1564, 1999. [PubMed: 10216143] [Full Text: https://doi.org/10.1002/hep.510290509]

  2. 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]

  3. Griffiths, W., Cox, T. Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. Hum. Molec. Genet. 9: 2377-2382, 2000. [PubMed: 11005792] [Full Text: https://doi.org/10.1093/hmg/9.16.2377]

  4. 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]


Contributors:
Victor A. McKusick - updated : 2/6/2003
George E. Tiller - updated : 12/4/2000
Ada Hamosh - updated : 4/27/2000

Creation Date:
Victor A. McKusick : 10/20/1999

Edit History:
carol : 10/24/2018
carol : 02/15/2017
carol : 11/03/2010
carol : 10/21/2010
alopez : 3/25/2010
mgross : 4/20/2005
ckniffin : 4/5/2004
tkritzer : 3/6/2003
carol : 2/13/2003
carol : 2/6/2003
terry : 2/6/2003
carol : 9/20/2002
carol : 8/6/2001
terry : 12/4/2000
carol : 7/6/2000
alopez : 4/28/2000
terry : 4/27/2000
alopez : 11/15/1999
carol : 10/20/1999