Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3)

Abstract

Summary. Iron overload may predominantly involve parenchymal or reticuloendothelial cells, the prototype of parenchymal iron overload being HFE-related genetic haemochromatosis. We studied a family with autosomal dominant hyperferritinaemia in whom the proband showed selective iron accumulation in the Kupffer cells on liver biopsy. Analysis of L and H ferritin genes excluded mutations responsible for hereditary hyperferritinaemia/cataract syndrome or similar translational disorders. Sequence analysis of the ferroportin gene (SLC11A3) in four individuals with hyperferritinaemia singled out a three base pair deletion in a region that contains four TTG repeats. This mutation removes a TTG unit from 780 to 791, and predicts the loss of one of three sequential valine residues 160-162. Denaturing high performance liquid chromatography can be used for its detection. SLC11A3 polymorphism analysis indicates that this probably represents a recurrent mutation due to slippage mispairing. Affected individuals may show marginally low serum iron and transferrin saturation, and young women may have marginally low haemoglobin concentration levels. Serum ferritin levels are directly related to age, but are 10-20 times higher than normal. Heterozygosity for the ferroportin Val 162 deletion represents the prototype of selective reticuloendothelial iron overload, and should be taken into account in the differential diagnosis of hereditary or congenital hyperferritinaemias.

Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice

“…Fpn1 has been implicated in turnover of iron recovered from scavenged red blood cells in reticuloendothelial macrophages of the splenic red pulp and hepatic Kupffer cells (Abboud and Haile, 2000;Yang et al, 2002). The essential role of Fpn1 in iron homeostasis has been revealed by mutations in human FPN1, leading to autosomal dominant iron overload in reticuloendothelial macrophages (Montosi et al, 2001;Njajou et al, 2001;Cazzola et al, 2002;Devalia et al, 2002;Arden et al, 2003;Rivard et al, 2003;Jouanolle et al, 2003). This unique pattern of iron accumulation caused by a mutation in FPN1, comprising type IV hereditary hemochromatosis, contrasts distinctly to the primarily parenchymal accumulation seen in the more common, recessively inherited HFEassociated hemochromatosis (type I) (for a review, see Ajioka and Kushner, 2002).…”

Identification of New Mutations of the HFE, Hepcidin, and Transferrin Receptor 2 Genes by Denaturing HPLC Analysis of Individuals with Biochemical Indications of Iron Overload

“…Denaturing HPLC (DHPLC) allows rapid DNA scanning (28 ) and has already been applied to the study of the HFE (29 ), ferritin (30 ), and ferroportin 1 genes (20 ). It shows promise as a suitable technique for studying the genetic basis of HH and iron overload.…”

Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease

“…30 Molecular analysis of the human ferroportin gene (FPN1, HFE4) was carried out as follows: each exon, including intron-exon boundaries, was polymerase chain reaction (PCR) amplified, and direct sequencing analysis carried out on an ABI Prism 310 automated sequencer. Primers and PCR conditions were used as described in Cazzola et al 8 Serum iron parameters were determined using standard laboratory techniques (Abbott, Vienna, Austria).…”

“…[1][2][3][4][5][6][7][8][9] Clinically, ferroportin disease is rarely associated with hepatic cirrhosis, and the principal pathological finding is iron deposition predominantly in cells of monocytic macrophage lineage-mainly and conspicuously Kupffer cells within the liver.…”

“…3,8,10,11 Deletion of this amino acid causes loss of function and when studied in vitro causes accumulation of iron in cultured cells. 12 FPN1 is a putative transmembrane iron channel implicated in the egress of iron from duodenal enterocytes, macrophages, hepatocytes, and placenta (reviewed in McKie and Barlow 13 ).…”