Taking advantage of the collection of 178 DNA samples selected for increased transferrin saturation (>50% in males and >45% in females) from a previous large scale screening of Italian blood donors, we simultaneously assessed the presence of 14 hemochromatosis-associated molecular defects (11 of HFE and 3 of TFR2) by a reverse hybridization-based strip assay.
The first includes juvenile and TFR2-related hemochromatoses that, similar to HFE hemochromatosis, show recessive inheritance, increased transferrin saturation, iron storage in hepatocytes and responsiveness to phlebotomy.
The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes.
The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis.
The identification of HFE, the principal determinant of adult haemochromatosis (HFE1; OMIM 235200) and TfR2, recently implicated in a rarer form of the inherited disorder (HFE3; OMIM 604250), and the promise of candidate genes for juvenile haemochromatosis (HFE2; OMIM 602390) and neonatal haemochromatosis (OMIM 231100) provide the foundation for important studies into the control mechanism of iron balance in humans.
The implications of this observation for the understanding of the phenotypic features of haemochromatosis due to mutation of the TFR2 gene are discussed.
The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease.
The pathogenetic role of TFR2 in hemochromatosis has been recently further demonstrated through the targeted expression of the Y250X human mutation in mice, which develop sings of iron overload identical to the human disease.
The term hemochromatosis should refer to a unique clinicopathologic subset of iron-overload syndromes that currently includes the disorder related to the C282Y homozygote mutation of the hemochromatosis protein HFE (by far the most common form of hemochromatosis) and the rare disorders more recently attributed to the loss of transferrin receptor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportin mutations.
This report adds two more type 3 hereditary hemochromatosis cases which suggest that TFR2 mutations could be more frequently involved in non-HFE hemochromatosis than has been actually thought.
To date, four types of hemochromatosis have been identified: HFE-related or type1 hemochromatosis, the most frequent form in Caucasians, and four rare types, named type 2 (A and B) hemochromatosis (juvenile hemochromatosis due to hemojuvelin and hepcidin mutation), type 3 hemochromatosis (related to transferrin receptor 2 mutation), and type 4 (A and B) hemochromatosis (ferroportin disease).
To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population.
Using quantitative RT-PCR, the iron-dependent hepatic expression patterns of HAMP, HJV, and TFR2 were evaluated in human and murine HFE-related hemochromatosis.
We used a standard 96-well microplate with a single PCR condition in an adaptation of the SCAIP (single-condition amplification with internal primer) method to sequence the HFE (hemochromatosis), HAMP (hepcidin antimicrobial peptide), HFE2/HJV [hemochromatosis type 2 (juvenile)], SLC40A1 (ferroportin), and TFR2 (transferrin receptor 2) genes, and the 5' untranslated region of the FTL (ferritin, light polypeptide) gene.