Hemochromatosis due to mutations in transferrin receptor 2.

Antonella Roetto, Filomena Daraio, Federica Alberti, Paolo Porporato, Angelita Calì, Marco De Gobbi, Clara Camaschella

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

A rare recessive disorder which leads to iron overload and severe clinical complications similar to those reported in HFE-related hemochromatosis has been delineated and sometimes called hemochromatosis type 3. The gene responsible is Transferrin Receptor 2 (TFR2), which maps to chromosome 7q22. The TFR2 gene presents a significative homology to transferrin receptor (TFRC) gene, encodes for a transmembrane protein with a large extracellular domain, is able to bind transferrin, even if with lower affinity than TFRC. The TFR2 function is still unclear. The transcript does not contain IRE elements and is not modified by the cellular iron status. At variance with TFRC, interactions between TFR2 and HFE do not occur, at least in their soluble forms. TFR2 is spliced in two alternative forms, alfa and beta. The alfa form is strongly expressed in the liver. The beta form, codified from a start site in exon 4 of the alpha, has a low and ubiquitous expression. Using anti-TFR2 monoclonal antibodies we have confirmed expression of the protein in the liver but also in duodenal epithelial cells, and studied the protein functional behaviour in cell lines, in response to iron addition, iron deprivation and olo-transferrin exposure. Our results suggest a regulatory role of TFR2 in iron metabolism. Five TFR2 homozygous mutations have been documented in HFE3 patients: a nonsense mutation (Y250X); a C insertion that causes a frameshift and a premature stop codon (E60X); a missense mutation (M172K); a 12 basepair deletion in exon 16, that causes 4 aminoacid loss (AVAQ 594-597del) in the extracellular domain of TFR2; a missense mutation in exon 17 (Q690P). The mutation analysis supports the hypothesis that all are private mutations. 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. Although the rarity of TFR2 mutations limits their usefulness in diagnostic/screening programs, their study can contribute to a better understanding of the protein function.

Original languageEnglish
Pages (from-to)465-470
Number of pages6
JournalBlood cells, molecules & diseases
Volume29
Issue number3
Publication statusPublished - Nov 2002

Fingerprint

Transferrin Receptors
Hemochromatosis
Mutation
Iron
Exons
Iron Overload
Nonsense Codon
Missense Mutation
Transferrin
Proteins
Genes
Liver

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Hematology

Cite this

Roetto, A., Daraio, F., Alberti, F., Porporato, P., Calì, A., De Gobbi, M., & Camaschella, C. (2002). Hemochromatosis due to mutations in transferrin receptor 2. Blood cells, molecules & diseases, 29(3), 465-470.

Hemochromatosis due to mutations in transferrin receptor 2. / Roetto, Antonella; Daraio, Filomena; Alberti, Federica; Porporato, Paolo; Calì, Angelita; De Gobbi, Marco; Camaschella, Clara.

In: Blood cells, molecules & diseases, Vol. 29, No. 3, 11.2002, p. 465-470.

Research output: Contribution to journalArticle

Roetto, A, Daraio, F, Alberti, F, Porporato, P, Calì, A, De Gobbi, M & Camaschella, C 2002, 'Hemochromatosis due to mutations in transferrin receptor 2.', Blood cells, molecules & diseases, vol. 29, no. 3, pp. 465-470.
Roetto A, Daraio F, Alberti F, Porporato P, Calì A, De Gobbi M et al. Hemochromatosis due to mutations in transferrin receptor 2. Blood cells, molecules & diseases. 2002 Nov;29(3):465-470.
Roetto, Antonella ; Daraio, Filomena ; Alberti, Federica ; Porporato, Paolo ; Calì, Angelita ; De Gobbi, Marco ; Camaschella, Clara. / Hemochromatosis due to mutations in transferrin receptor 2. In: Blood cells, molecules & diseases. 2002 ; Vol. 29, No. 3. pp. 465-470.
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