Alternative titles; symbols
SNOMEDCT: 1303911001, 719975002; ORPHA: 647834, 648562; DO: 0111028;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q32.2 | Hemochromatosis, type 4 | 606069 | Autosomal dominant | 3 | SLC40A1 | 604653 |
A number sign (#) is used with this entry because hemochromatosis type 4 (HFE4) is caused by heterozygous mutation in the SLC40A1 gene (604653), which encodes ferroportin, on chromosome 2q32.
Hemochromatosis type 4 (HFE4) is a dominantly inherited iron overload disorder with heterogeneous phenotypic manifestations that can be classified into 2 groups. One group is characterized by an early rise in ferritin (see 134790) levels with low to normal transferrin (190000) saturation and iron accumulation predominantly in macrophages. The other group is similar to classical hemochromatosis, with high transferrin saturation and prominent parenchymal iron loading (summary by De Domenico et al., 2005).
For general background information and a discussion of genetic heterogeneity of hereditary hemochromatosis, see 235200.
Pietrangelo et al. (1999) described an Italian family with an autosomal dominant form of hemochromatosis not associated with mutations in the HFE gene (613609) and not linked to 6p. Fifteen members of this pedigree suffered from iron overload resulting in hepatic fibrosis, diabetes, impotence, and arrhythmias. In addition to autosomal dominant inheritance, features distinguishing this entity from classic hemochromatosis included early iron accumulation in reticuloendothelial cells and a marked increase in serum ferritin prior to elevation of the transferrin saturation. Several patients showed a reduced tolerance to phlebotomy and became anemic on therapy despite persistently elevated serum ferritin values. In general, anemia early in life was a feature.
Njajou et al. (2001) studied a large Dutch family segregating an autosomal dominant form of hemochromatosis. Individuals were considered affected if they had serum ferritin levels exceeding 450 ng/ml and/or transferrin saturation exceeding 50%. A final diagnosis of hemochromatosis was made using results obtained by liver biopsy and/or magnetic resonance imaging. Clinical symptoms of affected individuals were similar to those of other patients with hemochromatosis and included joint pains, osteoarthritis, fatigue, cardiomyopathies, and endocrine disorders. The age of onset of the disorder was up to 60 years in males and about 10 years later in females.
Njajou et al. (2001) carried out a genomewide scan for linkage in the Dutch family with autosomal dominant hemochromatosis. The maximum lod score (3.01 at theta of 0.0) was found with marker D2S389 on chromosome 2. In the critical region, the SLC40A1 gene was identified as the most likely candidate.
In the Italian family with autosomal dominant hemochromatosis reported by Pietrangelo et al. (1999), Montosi et al. (2001) mapped the disorder to 2q32.
The pattern of transmission of HFE4 in the family studied by Njajou et al. (2001) was consistent with autosomal dominant inheritance.
Njajou et al. (2001) detected a missense mutation in the SLC40A1 gene (604653.0001) in a large Dutch family with autosomal dominant hemochromatosis.
Montosi et al. (2001) identified a missense mutation (604653.0002) in the SLC40A1 gene in the Italian family with autosomal dominant hemochromatosis reported by Pietrangelo et al. (1999).
De Domenico et al. (2005) demonstrated that ferroportin is multimeric and that mutant ferroportin can be defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. The authors concluded that mutant ferroportin can act as a dominant negative, thus providing a molecular basis for the dominant inheritance of the disease as well as the different patient phenotypes.
Cremonesi et al. (2005) studied 2 Italian families and 1 of Chinese descent with elevated serum ferritin levels and identified heterozygosity for 3 different mutations in the SLC40A1 gene, respectively. The authors noted the variability in phenotypes between the families and suggested that the mutation (604653.0007) in the first Italian family, in which the proband had a liver biopsy showing heavy iron deposition in both hepatocytes and Kupffer cells, likely caused decreased responsiveness to hepcidin, whereas the mutations (604653.0008 and 604653.0009) in the latter 2 families likely caused defective localization of the protein to the cell surface.
Cremonesi, L., Forni, G. L., Soriani, N., Lamagna, M., Fermo, I., Daraio, F., Galli, A., Pietra, D., Malcovati, L., Ferrari, M., Camaschella, C., Cazzola, M. Genetic and clinical heterogeneity of ferroportin disease. Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit. J. Haemat. 132: 806 only, 2006. [PubMed: 16351644] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05815.x]
De Domenico, I., Ward, D. M., Nemeth, E., Vaughn, M. B., Musci, G., Ganz, T., Kaplan, J. The molecular basis of ferroportin-linked hemochromatosis. Proc. Nat. Acad. Sci. 102: 8955-8960, 2005. [PubMed: 15956209] [Full Text: https://doi.org/10.1073/pnas.0503804102]
Montosi, G., Donovan, A., Totaro, A., Garuti, C., Pignatti, E., Cassanelli, S., Trenor, C. C., Gasparini, P., Andrews, N. C., Pietrangelo, A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108: 619-623, 2001. [PubMed: 11518736] [Full Text: https://doi.org/10.1172/JCI13468]
Njajou, O. T., Vaessen, N., Joosse, M., Berghuis, B., van Dongen, J. W. F., Breuning, M. H., Snijders, P. J. L. M., Rutten, W. P. F., Sandkuijl, L. A., Oostra, B. A., van Duijn, C. M., Heutink, P. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature Genet. 28: 213-214, 2001. [PubMed: 11431687] [Full Text: https://doi.org/10.1038/90038]
Pietrangelo, A., Montosi, G., Totaro, A., Garuti, C., Conte, D., Cassanelli, S., Fraquelli, M., Sardini, C., Vasta, F., Gasparini, P. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. New Eng. J. Med. 341: 725-732, 1999. [PubMed: 10471458] [Full Text: https://doi.org/10.1056/NEJM199909023411003]