scholarly journals nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3625-3631 ◽  
Author(s):  
Robert S. Ohgami ◽  
Dean R. Campagna ◽  
Brendan Antiochos ◽  
Emily B. Wood ◽  
John J. Sharp ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Uptake ◽  
Genetic Locus ◽  
Failure To Thrive ◽  
Microcytic Anemia ◽  
Zinc Protoporphyrin ◽  
Hematopoietic Stem ◽  
Hypochromic Microcytic Anemia ◽  
Iron Deficient ◽  
Sparse Hair

AbstractHypochromic, microcytic anemias are typically the result of inadequate hemoglobin production because of globin defects or iron deficiency. Here, we describe the phenotypic characteristics and pathogenesis of a new recessive, hypochromic, microcytic anemia mouse mutant, nm1054. Although the mutation nm1054 is pleiotropic, also resulting in sparse hair, male infertility, failure to thrive, and hydrocephaly, the anemia is the focus of this study. Hematologic analysis reveals a moderately severe, congenital, hypochromic, microcytic anemia, with an elevated red cell zinc protoporphyrin, consistent with functional erythroid iron deficiency. However, serum and tissue iron analyses show that nm1054 animals are not systemically iron deficient. From hematopoietic stem cell transplantation and iron uptake studies in nm1054 reticulocytes, we provide evidence that the nm1054 anemia is due to an intrinsic hematopoietic defect resulting in inefficient transferrin-dependent iron uptake by erythroid precursors. Linkage studies demonstrate that nm1054 maps to a genetic locus not previously implicated in microcytic anemia or iron phenotypes.

Rsp1 Is Indispensable for mRNA Stability during Erythroid Terminal Differentiation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 532-532
Author(s):  
Meng Tian ◽  
Dean R. Campagna ◽  
Nathaniel Langer ◽  
Seong-Kyu Choe ◽  
Barry H. Paw ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Microarray Analysis ◽  
Mrna Stability ◽  
Iron Uptake ◽  
Positional Cloning ◽  
Terminal Differentiation ◽  
Microcytic Anemia ◽  
Zinc Protoporphyrin ◽  
Hypochromic Microcytic Anemia

Abstract Mouse models have proven invaluable for understanding erythropoiesis. Here, we describe an autosomal recessive inherited anemia in the mouse mutant hem6. Hematologic and transplantation analyses revealed a mild, congenital, hypochromic, microcytic anemia intrinsic to the hematopoietic system that is associated with a decreased red blood cell zinc protoporphyrin to heme ratio, indicative of porphyrin insufficiency. Iron uptake experiments showed that hem6 reticulocytes are defective in heme production, but not cellular iron uptake defects. Male hem6 mice are infertile due to defects in sperm structure and motility. Through positional cloning and BAC complementation, we identified the gene responsible for the hem6 anemia to be Rsp1 (RNAStabilityProtein1) on Chr.3. The anemia phenotype was reproduced by injecting zebrafish embryos with morpholinos specifically targeting the Rsp1 transcript. Multi-tissue, real-time PCR shows that Rsp1 is abundantly expressed in bone marrow and testis, which correlates with the anemia and infertility defects in the hem6 mutant. To further study the function of Rsp1, we conducted yeast two hybrid analysis, employing a human bone marrow library. We found that Rsp1 interacts with the poly (A)-binding protein cytoplasmic 1(PABPC1) and, using microarray analysis, showed that many abundant erythroid specific transcripts, including Hbb-b1, Hba-a1, Alas2, and Mitoferrin1, were significantly down regulated in hem6 reticulocytes. Since PABPC1 is responsible for stabilizing the Hba-a1 transcript [Wang et al. (1999) Mol Cell Biol19:4552–60 and Wang and Kiledjian (2000) Mol Cell Biol20:6334–41], we hypothesized that the relative deficiency in erythroid-specific mRNAs in hem6 reticulocytes might be due to decreased mRNA stability. Indeed, serial microarray analysis of reticulocytes aged in vitro showed that numerous, abundantly expressed erythroid-specific transcripts decayed at faster rates in hem6 reticulocytes compared to control reticulocytes. Furthermore, these mRNAs also have progressively shorter poly (A) tails, suggesting a mechanism for the increased rate of decay. In sum, the evidence supports the conclusion that Rsp1 is a regulator of mRNA stability and gene expression during the terminal differentiation of erythroid cells.

scholarly journals hem6: an ENU-induced recessive hypochromic microcytic anemia mutation in the mouse

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4308-4313 ◽  
Author(s):  
Meng Tian ◽  
Dean R. Campagna ◽  
Lanette S. Woodward ◽  
Monica J. Justice ◽  
Mark D. Fleming
Keyword(s):  
Iron Uptake ◽  
Autosomal Recessive ◽  
Aminolevulinic Acid ◽  
Microcytic Anemia ◽  
Zinc Protoporphyrin ◽  
Mouse Mutant ◽  
Erythropoietic Protoporphyria ◽  
Enzymatic Assays ◽  
Hypochromic Microcytic Anemia ◽  
Uptake Studies

AbstractMouse models have proven invaluable for understanding erythropoiesis. Here, we describe an autosomal recessive, inherited anemia in the mouse mutant hem6. Hematologic and transplantation analyses reveal a mild, congenital, hypochromic, microcytic anemia intrinsic to the hematopoietic system that is associated with a decreased red blood cell zinc protoporphyrin to heme ratio, indicative of porphyrin insufficiency. Intercross matings show that hem6 can suppress the porphyric phenotype of mice with erythropoietic protoporphyria (EPP). Furthermore, iron uptake studies in hem6 reticulocytes demonstrate defective incorporation of iron into heme that can be partially corrected by the addition of porphyrin precursors. Gene expression and enzymatic assays indicate that erythroid 5-aminolevulinic acid synthase (Alas2) is decreased in hem6 animals, suggesting a mechanism that could account for the anemia. Overall, these data lead to the hypothesis that hem6 encodes a protein that directly or indirectly regulates the expression of Alas2.

Defective iron uptake by the duodenum of Belgrade rats fed diets of different iron contents

1996 ◽  
Vol 270 (5) ◽  
pp. G826-G832 ◽  
Author(s):  
P. S. Oates ◽  
E. H. Morgan
Keyword(s):  
Iron Content ◽  
Iron Uptake ◽  
Iron Transport ◽  
Iron Absorption ◽  
Microcytic Anemia ◽  
Deficient Diet ◽  
Hypochromic Microcytic Anemia ◽  
Iron Deficient

Homozygous Belgrade rats have an inherited hypochromic, microcytic anemia that is due to impaired iron transport into immature erythrocytes. There is also evidence for abnormal iron transport in other tissues such as the intestine. This study was aimed at investigating the intestinal defect in rats that had been fed diets for 12 days that are normal, low, or high in iron. The duodenal uptake, transfer, and absorption of Fe(III)-nitrilotriacetate and Fe(II)-ascorbate were studied using in vivo tied-off gut sacs in genetically normal rats and in heterozygous or homozygous Belgrade rats. In normal and heterozygous Belgrade rats, the handling of Fe(III) and Fe(II) was similar; uptake, transfer, and absorption of Fe(III) and Fe(II) changed inversely with the iron content of the diet. In contrast, in homozygous Belgrade rats the uptake of both Fe(III) and Fe(II) was markedly reduced and absorption of Fe(III) did not change when animals were fed an iron-deficient diet. Since absorption of Fe(II) was similar to Fe(III), there is no evidence that the defect in iron absorption is due to failure of a mechanism for reduction of Fe(III). The lowered uptake of Fe(III) and Fe(II) in homozygous Belgrade rats probably involves a defective iron carrier associated with the microvillous membrane of the duodenum.

HYPOCHROMIC MICROCYTIC ANEMIA OF INFANCY: IRON DEPLETION AS A FACTOR

PEDIATRICS ◽  
1956 ◽  
Vol 18 (6) ◽  
pp. 959-978
Author(s):  
Hugh W. Josephs
Keyword(s):  
Iron Deficiency ◽  
Severe Infection ◽  
Microcytic Anemia ◽  
Severe Anemia ◽  
Iron Depletion ◽  
Hypochromic Microcytic Anemia ◽  
Premature Babies ◽  
Number Of Factors ◽  
The Difference ◽  
Insight Into

In this work the author has attempted to gain insight into the significance of iron depletion by the use of 4 simple calculations, justification for which is found in recent articles. These are: (a) iron with which the infant is born; (b) iron retained from the food; (c) iron being used by the tissues and therefore unavailable for hemoglobin, and (d) iron combined with the total mass of hemoglobin. With these 4 figures it is possible to estimate the iron still potentially available for use (the "reserves" or "stones"). When the difference between a + b and c + d has reached about zero, depletion is considered to exist. The following characteristics of depletion may be emphasized: Depletion is the result of gain in weight and maximum possible usage of iron. It is therefore a normal result of growth and need not be associated with anemia. As soon as depletion has occurred, the organism is thereafter dependent on current absorption of iron. This is ordinarily sufficient, even with a diet of milk alone, to maintain an adequate concentration of hemoglobin after about 8 to 10 months of age. Severe anemia due to depletion alone is practically confined to premature babies whose relative gain in weight is rapid. Severe anemia in other than premature babies is the result of a number of factors by which iron becomes unavailable or is actually diverted from hemoglobin to storage. Response to iron medication is considerably better in infants with depletion than in those in whom some factor is present that interferes with iron utilization, and which is not connected by the mere giving of iron. The dependence on current absorption, whether the result of depletion or non-availability, introduces a certain precariousness which is apparently characteristic of this time of life. The organism gets along from day to day if nothing happens, but may not be able to meet an emergency, whether this appears as a rapid gain in weight, or a necessity to repair damage done by severe infection. If we consider iron deficiency as the cause of anemia, we can think of deficiency as due to a number of factors of which depletion is only one. The development and characteristics of depletion have been considered in this paper; other factors in iron deficiency will be considered in subsequent papers.

scholarly journals Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6418-6425 ◽  
Author(s):  
Lara Krieg ◽  
Oren Milstein ◽  
Philippe Krebs ◽  
Yu Xia ◽  
Bruce Beutler ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Absorption ◽  
Osmotic Fragility ◽  
Microcytic Anemia ◽  
Deficiency Anemia ◽  
Α Subunit ◽  
Hypochromic Microcytic Anemia ◽  
Gastric Proton Pump ◽  
Potassium Atpase

Abstract Iron is an essential component of heme and hemoglobin, and therefore restriction of iron availability directly limits erythropoiesis. In the present study, we report a defect in iron absorption that results in iron-deficiency anemia, as revealed by an N-ethyl-N-nitrosourea–induced mouse phenotype called sublytic. Homozygous sublytic mice develop hypochromic microcytic anemia with reduced osmotic fragility of RBCs. The sublytic phenotype stems from impaired gastrointestinal iron absorption caused by a point mutation of the gastric hydrogen-potassium ATPase α subunit encoded by Atp4a, which results in achlorhydria. The anemia of sublytic homozygotes can be corrected by feeding with a high-iron diet or by parenteral injection of iron dextran; rescue can also be achieved by providing acidified drinking water to sublytic homozygotes. These findings establish the necessity of the gastric proton pump for iron absorption and effective erythropoiesis.

Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3985-3987 ◽  
Author(s):  
Monika Priwitzerova ◽  
Guangjun Nie ◽  
Alex D. Sheftel ◽  
Dagmar Pospisilova ◽  
Vladimir Divoky ◽  
...  
Keyword(s):  
Protein Expression ◽  
Iron Uptake ◽  
Chinese Hamster ◽  
Microcytic Anemia ◽  
Homozygous Mutation ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Hypochromic Microcytic Anemia ◽  
Functional Consequences ◽  
Uptake Activity

We have previously described a case of severe hypochromic microcytic anemia caused by a homozygous mutation in the divalent metal transporter 1 (DMT1 1285G > C). This mutation encodes for an amino acid substitution (E399D) and causes preferential skipping of exon 12 during processing of the DMT1 mRNA. To examine the functional consequences of this mutation, full-length DMT1 transcript with the patient's point mutation or a DMT1 transcript with exon 12 deleted was expressed in Chinese hamster ovary (CHO) cells. Our results demonstrate that the E399D substitution has no effect on protein expression and function. In contrast, deletion of exon 12 led to a decreased expression of the protein and disruption of its subcellular localization and iron uptake activity. We hypothesize that the residual protein in hematopoietic cells represents the functional E399D DMT1 variant, but because of its quantitative reduction, the iron uptake activity of DMT1 in the patient's erythroid cells is severely suppressed.

Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2089-2091 ◽  
Author(s):  
Flavia Guillem ◽  
Sarah Lawson ◽  
Caroline Kannengiesser ◽  
Mark Westerman ◽  
Carole Beaumont ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Microcytic Anemia ◽  
Deficiency Anemia ◽  
Nonsense Mutations ◽  
Hepcidin Expression ◽  
Hypochromic Microcytic Anemia ◽  
Iv Iron ◽  
Membrane Bound ◽  
Inherited Mutations ◽  
Iron Utilization

Abstract Genetic causes of hypochromic microcytic anemia include thalassemias and some rare inherited diseases such as DMT1 deficiency. Here, we show that iron deficiency anemia with poor intestinal absorption and defective iron utilization of IV iron is caused by inherited mutations in TMPRSS6, a liver-expressed gene that encodes a membrane-bound serine protease of previously unknown role that was recently reported to be a regulator of hepcidin expression.

scholarly journals Optimization of Epoetin Therapy with Intravenous Iron Therapy in Hemodialysis Patients

2000 ◽  
Vol 11 (3) ◽  
pp. 530-538
Author(s):  
ANATOLE BESARAB ◽  
NEETA AMIN ◽  
MUHAMMAD AHSAN ◽  
SUSAN E. VOGEL ◽  
GARY ZAZUWA ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Serum Ferritin ◽  
Transferrin Saturation ◽  
Intravenous Iron ◽  
Hemodialysis Patients ◽  
Chronic Hemodialysis ◽  
Control Group ◽  
Zinc Protoporphyrin ◽  
Study Group ◽  
Iron Deficient

Abstract. Iron deficiency limits the efficacy of recombinant human erythropoietin (rhEPO) therapy in end-stage renal disease (ESRD) patients. Functional iron deficiency occurs with serum ferritin >500 ng/ml and/or transferrin saturation (TSAT) of 20 to 30%. This study examines the effects of a maintenance intravenous iron dextran (ivID) protocol that increased TSAT in ESRD hemodialysis patients from conventional levels of 20 to 30% (control group) to those of 30 to 50% (study group) for a period of 6 mo. Forty-two patients receiving chronic hemodialysis completed a 16- to 20-wk run-in period, during which maintenance ivID and rhEPO were administered in amounts to achieve average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl. After the run-in period, 19 patients randomized to the control group received ivID doses of 25 to 150 mg/wk for 6 mo. Twenty-three patients randomized to the study group received four to six loading doses of ivID, 100 mg each, over a 2-wk period to achieve a TSAT >30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 mo. Both regimens were effective in maintaining targeted hemoglobin levels. Fifteen patients in the control group and 17 patients in the study group finished the study in which the primary outcome parameter by intention to treat analysis was the rhEPO dose needed to maintain prestudy hemoglobin levels. Maintenance ivID requirements in the study group increased from 176 to 501 mg/mo and were associated with a progressive increase in serum ferritin to 658 ng/ml. Epoetin dose requirements for the study group decreased by the third month and remained 40% lower than for the control group, resulting in an overall cost savings in managing the anemia. Secondary indicators of iron-deficient erythropoiesis were also assessed. Zinc protoporphyrin did not change in either group. Reticulocyte hemoglobin content increased only in the study group from 28.5 to 30.1 pg. It is concluded that maintenance of TSAT between 30 and 50% reduces rhEPO requirements significantly over a 6-mo period.

scholarly journals Zinc protoporphyrin as screening test in female blood donors

1998 ◽  
Vol 44 (4) ◽  
pp. 800-804 ◽  
Author(s):  
Else J Harthoorn-Lasthuizen ◽  
Jan Lindemans ◽  
Mart M A C Langenhuijsen
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Serum Ferritin ◽  
Blood Donors ◽  
Deficiency Anemia ◽  
Zinc Protoporphyrin ◽  
Ferritin Concentration ◽  
Iron Deficient ◽  
Serum Ferritin Concentration ◽  
Low Serum

Abstract Erythrocyte zinc protoporphyrin (ZPP) was measured in 102 women blood donors to evaluate its usefulness in screening for evolving iron deficiency anemia, a reason for the deferral of donors. The results were compared with serum ferritin determinations. Five women were deferred before their first donation and eight women were deferred after one or two donations. Women with increased ZPP values all had low serum ferritin concentrations, indicating iron-deficient erythropoiesis that was caused by iron depletion. The positive predictive value of an increased ZPP in predicting deferral of the donor after one or two donations was 75%, whereas a serum ferritin concentration ≤12 μg/L predicted deferral in 26% of the donors. The results indicate that the ZPP test can be recommended as a feasible and inexpensive predonation test to determine a subset of donors with iron-deficient erythropoiesis at risk of developing iron deficiency anemia.

Differential Diagnosis of Hypochromic Microcytic Anemia

1980 ◽  
Vol 1 (7) ◽  
pp. 196-222
Keyword(s):  
Iron Deficiency ◽  
Lead Poisoning ◽  
Microcytic Anemia ◽  
Beta Thalassemia ◽  
Age Group ◽  
Peak Incidence ◽  
Hypochromic Microcytic Anemia ◽  
Alpha Thalassemia ◽  
History Of ◽  
Thalassemia Trait

The only hypochromic microcytic anemias in young children are iron deficiency, lead poisoning, and thalassemia. Clinical features helpful in the diagnosis include the following. Iron deficiency: peak incidence from 1 to 2 years of age, diet deficient in iron, or ingestion of more than one quart of milk per day. Alpha-thalassemia trait: occurs in any age group and predominantly in Oriental, black, and Mediterranean races. Beta-thalassemia trait occurs in children more than 6 months of age and predominately in black and Mediterranean races. Lead poisoning: peak incidence from 6 months to 4 years of age and a history of pica. It occurs largely in urban children.

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