Year: 2005
Type: letter
Abstract: Analysis of the E399D mutation in SLC11A2In a recent Blood article, Mims and colleagues 1 reported the phenotype of a patient with anemia and iron overload who was homozygous for a novel mutation in the iron transporter SLC11A2 (DMT1).SLC11A2 (solute carrier family 11, member 2) is the only known transporter involved in cellular iron uptake in mammals.We recently showed that Slc11a2 was critical for both intestinal iron absorption and erythroid iron assimilation in mice. 2 Slc11a2 Ϫ/Ϫ mice died within the first few days of life with severe systemic iron deficiency and consequent anemia.Animals lacking Slc11a2 only in the intestine had a similar but less severe phenotype that could be rescued by parenteral iron administration.Lethally irradiated wild-type animals transplanted with Slc11a2 Ϫ/Ϫ hematopoietic stem cells were anemic (hemoglobin [Hgb] 8.53 Ϯ 0.20 g/dL, mean corpuscular volume [MCV] 26.33 Ϯ 0.59; n ϭ 6) compared with animals that had received wild-type cells (Hgb 13.20 Ϯ 0.13, MCV 50.32 Ϯ 0.63; n ϭ 5) 8 to 12 weeks after transplantation (P Ͻ .001).However, liver iron stores were increased, with liver nonheme iron averaging 109.6 g/g wet weight (n ϭ 2) in animals that received transplants versus 63.0 g/g wet weight in controls (n ϭ 2) 12 weeks after transplantation and later. 2 This phenotype, observed in mice lacking Slc11a2 only in hematopoietic cells, was strikingly similar to that in the human patient.The human mutation reported by Mims et al has 2 molecular consequences.First, it favors the production of a splice isoform missing exon 12, which encodes the eighth predicted transmembrane segment of SLC11A2.Second, transcripts retaining exon 12 encode an E399D substitution.To attempt to understand why the phenotype resulting from the human mutation differed from that seen in mice lacking Slc11a2, we analyzed the functions of the 2 mutant gene products (Figure 1).SLC11A2 that lacked exon 12 was poorly expressed in transiently transfected HEK293T cells and had little, if any, iron transport activity.In contrast, the E399D mutant protein showed expression that was comparable to the wild-type protein and had substantial iron transport activity.We infer that tissues expressing only the exon 12-deleted form would lack SLC11A2 activity and that tissues expressing the E399D form would have SLC11A2 activity in proportion to the amount of protein present.While it is possible that humans have a distinct, unknown iron uptake activity that is absent in mice, as proposed by Mims et al, we favor a different hypothesis.If the patient expressed substantial amounts of functional E399D SLC11A2 in the intestine, her increased liver iron stores could be explained by the combined effects of enhanced intestinal absorption in response to anemia and redistribution of iron from the erythron to the liver.
Source: Blood
Authors: Hiromi Gunshin, Jie Jin, Yuko Fujiwara, Nancy C. Andrews
Institutions: Boston Children's Hospital, Harvard University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2042689970