New mutations inactivating transferrin receptor 2 in hemochromatosis type 3

Antonella Roetto, Angela Totaro, Alberto Piperno, Antonio Piga, Filomena Longo, Giovanni Garozzo, Angelita Calì, Marco De Gobbi, Paolo Gasparini, Clara Camaschella

Research output: Contribution to journalArticle

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 α-transcript, which may encode a transmembrane protein, and the β-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 α-form. M172K has a complex effect: it causes a missense in the α-form, but it may also prevent the β-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.

Original languageEnglish
Pages (from-to)2555-2560
Number of pages6
JournalBlood
Volume97
Issue number9
DOIs
Publication statusPublished - May 1 2001

Fingerprint

Transferrin Receptors
Hemochromatosis
Mutation
Genes
Nonsense Codon
Frameshift Mutation
Iron Overload
Initiator Codon
Homozygote
Chromosomes
Exons
Proteins
Substitution reactions
Iron
Type 2 Hemochromatosis
Type 3 Hemochromatosis
Phenotype

ASJC Scopus subject areas

  • Hematology

Cite this

Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., ... Camaschella, C. (2001). New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood, 97(9), 2555-2560. https://doi.org/10.1182/blood.V97.9.2555

New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. / Roetto, Antonella; Totaro, Angela; Piperno, Alberto; Piga, Antonio; Longo, Filomena; Garozzo, Giovanni; Calì, Angelita; De Gobbi, Marco; Gasparini, Paolo; Camaschella, Clara.

In: Blood, Vol. 97, No. 9, 01.05.2001, p. 2555-2560.

Research output: Contribution to journalArticle

Roetto, A, Totaro, A, Piperno, A, Piga, A, Longo, F, Garozzo, G, Calì, A, De Gobbi, M, Gasparini, P & Camaschella, C 2001, 'New mutations inactivating transferrin receptor 2 in hemochromatosis type 3', Blood, vol. 97, no. 9, pp. 2555-2560. https://doi.org/10.1182/blood.V97.9.2555
Roetto A, Totaro A, Piperno A, Piga A, Longo F, Garozzo G et al. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood. 2001 May 1;97(9):2555-2560. https://doi.org/10.1182/blood.V97.9.2555
Roetto, Antonella ; Totaro, Angela ; Piperno, Alberto ; Piga, Antonio ; Longo, Filomena ; Garozzo, Giovanni ; Calì, Angelita ; De Gobbi, Marco ; Gasparini, Paolo ; Camaschella, Clara. / New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. In: Blood. 2001 ; Vol. 97, No. 9. pp. 2555-2560.
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