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 language | English |
|---|---|
| Pages (from-to) | 2555-2560 |
| Number of pages | 6 |
| Journal | Blood |
| Volume | 97 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - May 1 2001 |
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ASJC Scopus subject areas
- Hematology
Cite this
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 journal › Article
}
TY - JOUR
T1 - New mutations inactivating transferrin receptor 2 in hemochromatosis type 3
AU - Roetto, Antonella
AU - Totaro, Angela
AU - Piperno, Alberto
AU - Piga, Antonio
AU - Longo, Filomena
AU - Garozzo, Giovanni
AU - Calì, Angelita
AU - De Gobbi, Marco
AU - Gasparini, Paolo
AU - Camaschella, Clara
PY - 2001/5/1
Y1 - 2001/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035353167&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035353167&partnerID=8YFLogxK
U2 - 10.1182/blood.V97.9.2555
DO - 10.1182/blood.V97.9.2555
M3 - Article
C2 - 11313241
AN - SCOPUS:0035353167
VL - 97
SP - 2555
EP - 2560
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -