New mutations inactivating transferrin receptor 2 in hemochromatosis type 3

Blood. 2001 May 1;97(9):2555-60. doi: 10.1182/blood.v97.9.2555.


Hereditary hemochromatosis usually results from C282Y homozygosity in the HFE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) has been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated by a homozygous nonsense mutation (Y250X). Here the identification of 2 new TFR2 mutations is reported. In a large inbred family from Campania, a frameshift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E60X) is identified. In a single patient with nonfamilial hemochromatosis, a T-->A transversion (T515A), which causes a Methionine-->Lysine substitution at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts-the alpha-transcript, which may encode a transmembrane protein, and the beta-transcript, a shorter, possibly intracellular variant. Based on their positions, the effects of the identified mutations on the 2 TFR2 forms are expected to differ. Y250X inactivates both transcripts, whereas E60X inactivates only the alpha-form. M172K has a complex effect: it causes a missense in the alpha-form, but it may also prevent the beta-form production because it affects its putative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homozygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Female
  • Hemochromatosis / etiology*
  • Hemochromatosis / genetics*
  • Hemochromatosis / metabolism
  • Humans
  • Iron / metabolism
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Receptors, Transferrin / genetics*
  • Receptors, Transferrin / metabolism
  • Transferrin / metabolism


  • Receptors, Transferrin
  • Transferrin
  • Iron