title: New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.
abstract: 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.
authors: Dipartimento di Scienze Cliniche e Biologiche, Azienda Ospedaliera S. Luigi, Orbassano and Dipartimento di Pediatria, OIRM S. Anna, Turin, Italy.
authors: A
authors: A
authors: Roetto
authors: A
authors: A
authors: Totaro
authors: A
authors: A
authors: Piperno
authors: A
authors: A
authors: Piga
authors: F
authors: F
authors: Longo
authors: G
authors: G
authors: Garozzo
authors: A
authors: A
authors: Calì
authors: M
authors: M
authors: De Gobbi
authors: P
authors: P
authors: Gasparini
authors: C
authors: C
authors: Camaschella
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006432:Hemochromatosis / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron