Hemochromatosis, Type 3

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.