New mutations inactivating transferrin receptor 2 in hemochromatosis type 3

Hereditary hemochromatosis usually results from C282Y homozygosity in the H FE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) ha s been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated b y a homozygous nonsense mutation (Y250X). Here the identification of 2 new TFR2 mutations is reported. In a large inbred family from Campania, a frame shift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E 60X) is identified. In a single patient with nonfamilial hemochromatosis, a T-->A transversion (T515A), which causes a Methionine-->Lysine substitutio n at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts-->the alpha -transcrip t, which may encode a transmembrane protein, and the beta -transcript, a sh orter, possibly intracellular variant. Based on their positions, the effect s of the identified mutations on the 2 TFR2forms are expected to differ. Y2 50X 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 pu tative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homo zygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identifi cation 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. (Blood, 2001;97:2555-2560) (C) 2001 by The American Society of Hematology.