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CORRESPONDENCE Hemochromatosis type 4 is an atypical hemochromatosis
characterized by dominant inheritance, increased serum ferritin, normal transferrin saturation, and prevalent iron deposition in the
reticuloendothelial (RE) cells rather than in hepatocytes. Heterozygous
missense mutations of the iron export protein ferroportin 1 (FPN1)1-3 have been reported in 2 large
pedigrees.4-5 We have characterized a 3-base pair
deletion of FPN1 in 2 related Italians and in 1 unrelated British patient. The Italian proband (patient 1 in Table
1) was a 26-year-old female presenting
with mild anemia and normal erythrocyte indices. Serum iron and
transferrin saturation were slightly decreased, and serum ferritin
levels, increased. Hemolytic anemia and inflammatory chronic diseases
were excluded. Bone marrow aspirate showed normal erythroid
maturation. Liver biopsy did not reveal fibrosis. Perl staining was positive especially in Kupffer cells, with few hepatocyte granules. Quantitative liver iron concentration (LIC) was obtained by
magnetic susceptometry (SQUID).6-7 A low-intensity
venesection protocol reduced ferritin without causing anemia. The
proband's mother (patient 2) had breast cancer 3 years ago. She is in
complete remission, having undergone radical mastectomy and
chemotherapy and is being treated with tamoxifen. She has had
persistent hyperferritinemia over the last 3 years. Liver function
tests were normal. LIC was elevated. The British patient (patient 3)
was a 30-year-old asymptomatic male whose father had been diagnosed
with hemochromatosis. On presentation he had a raised ferritin but
normal transferrin saturation. He had a slight degree of hepatomegaly
and had normal liver function test results. On venesection
this patient's ferritin concentration returned to the normal range
without him becoming anemic. He has had 4.25 g iron removed.
All 3 patients are heterozygotes for the His63Asp mutation in HFE. Sequencing the whole FPN1 gene of the 2 Italian patients identified a heterozygous GTT deletion, corresponding to the loss of a valine in a 3 valine repeat at position 160-162 (Val162del) of the protein, likely due to a slipped strand mispairing. The same deletion in the British patient was first detected by denaturing high performance liquid chromatography (DHPLC) and then confirmed by sequence analysis. The finding of the same mutation in families of different ethnic origin (see accompanying articles by Devalia et al,8 page 695, and Wallace et al,9 page 692) suggests that Val162del results from multiple deletion events. Due to the mechanism of this deletion, it is likely to be the most common mutation both in hemochromatosis type 4 and possibly in non-Cys282Tyr hemochromatosis. The valine triplet where the deletion occurs is highly conserved in zebrafish, mice, and rats and is in close proximity to the Asn144His substitution,4 in the putative transmembrane domain involved in iron binding or transport. The latter finding supports the hypothesis of a "loss" rather than a "gain" of function as the pathogenic mechanism of iron accumulation in hemochromatosis type 4.10 FPN1 haploinsufficiency could represent a critical threshold for iron export of macrophages, but still be sufficient to allow iron export in enterocytes. Results on venesection indicate that, under forced conditions, iron can be mobilized from RE cells.
Antonella Roetto, Alison T. Merryweather-Clarke, Filomena Daraio, Karen Livesey, Jennifer J. Pointon, Giuliana Barbabietola, Antonio Piga, Peter H. Mackie, Kathryn J. H. Robson, and Clara Camaschella Supported by European Union contract QLRT-1999-02237. We thank Elanko Navaratnam for technical assistance. References 1. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin identifies a conserved vertebrate iron exporter. Nature. 2000;403:776-781[CrossRef][Medline] [Order article via Infotrieve]. 2. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;26:19906-19912. 3. McKie AYT, Marcian P, Rolfs A, et al. A novel duodenal iron-regulated, IREG-1, implicated in the basolateral transfer of iron to the circulation. Molecular Cell. 2000;5:299-309[CrossRef][Medline] [Order article via Infotrieve]. 4. Njajou OT, Vaessen, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature Genet. 2001;28:213-214[CrossRef][Medline] [Order article via Infotrieve]. 5. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619-623[CrossRef][Medline] [Order article via Infotrieve]. 6. Brittenham GM, Farrell DE, Harris JW, et al. Magnetic susceptibility measurement of human iron stores. New Engl J Med. 1982;307:1671-1675[Abstract]. 7. Brittenham GM. Non invasive methods for early detection of hereditary hemochromatosis. Ann New York Acad Sci. 1988;526:199-208[Medline] [Order article via Infotrieve].
8.
Devalia V, Carter K, Walker AP, et al.
Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the Ferroportin 1 gene (SLC11A3).
Blood
2002;100:695-697
9.
Wallace DF, Pedersen P, Dixon JL, et al.
Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis.
Blood.
2002;100:692-694 10. Fleming RE, Sly WS. Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. J Clin Invest. 2001;108:521-522[CrossRef][Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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