X‐Linked Hypochromic Anaemia of Mice

Abstract

MANY different imitations giving rise to anaemia in mice have now bccn rcportcd and their genctic and hacmatological features have recently been reviewed (Russell and Bcrnstein, I 966; I'inkerton and Bannerman, 1967). In some instances, such as the hereditary spherocytosis of the deer mouse and the autoimmune hacmolytic anaemia of the NZUjB1 strain of house mouse, they mimic human disorders, and their study offers the possibility of insight into mechanisms of human disease. Other mutants provide the opportunity to isolatc and study single, genetically-controlled, steps in haemopoiesis. Sex-linked (or, preferably, X-linked) anaemia of mice (gene symbol, sla) first appeared in the male offspring of the daughter of a male who was irradiated with 5 0 0 r. of X-rays, and this finding and the results of subsequent linkage studies were reported by Falconer and Isaacson (1962). Grewal (1962) gave a general description of the anaemia and compared it with thalassaemia. We have reported preliminary findings on the nature and mechanism of the anaemia Cooper, 1964, 1966; Pinkerton, Kreimer-Uirnbaum and Bannerman, 1966), and we now describe in detail the haematological findings, including the effects of age and various forms of treatment, and discuss possible analogies between X-linked mouse anaemia and the human hypochromic anaemias. MATERIALS AND METHODSThc mice studied were descendants of a small breeding stock from a mixed strain, kindly presented by Dr. D. S. Falconer. Most of the investigations reported here have been carried out on animals inbred from the original stock by brother-sister matings. It has sometimes been necessary to use as controls normal first generation hybrid males from crosses with the inbred C~7B1/6 Jax strain; this has been occasioned by the presence in our original stock of the X-linked mutation, 'Brindled', lethal shortly after birth in the male, in repulsion to sla (to which it is quite closely linked; Falconer and Isaacson, 1962). Although strain differences may affect the blood picture in mice (Russell, Neufeld and Higgins, 1951), careful comparison between normal non-anaemic males of our partially inbred strain and the first generation hybrids with the C57B1/6 Jax strain revealed no detectable differences.The animals were maintained on Rockland rat and mouse diet, the constitution of which is shown in Table I; tap water was given ad libitum Body weights were regularly recorded to the nearest 0.1 g.Serial observations were made from the time of weaning (21-28 days) to more than 300 days of age in 64 anaemic hemizygous male mice, 45 homozygous female mice, 69 heterozygous female carriers and I I I normal male mice of the mixed strain or the hybrid mentioned above.

Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency

“…The data show that both sla and iron-deficient mice had iron deficiency anemia and low liver iron stores. Although anemia in sla mice improves with age, our results and previous reports 21,37 show persistent anemia at 6 months of age. It is important to note that the iron deficiency, as measured by liver iron stores, in sla mice is even more severe than control mice on an iron-deficient diet.…”

“…[41][42][43] As noted in previous studies, the hemoglobin levels gradually increase with age in sla mice and the difference between wild-type and sla mice narrows. 21,37 However, the sla mouse continues to have significantly lower hemoglobin levels beyond 1 year of age. 21,37 Despite the recovery in hemoglobin levels, sla mice continue to be severely iron deficient as shown in this and previous studies.…”

“…21,37 However, the sla mouse continues to have significantly lower hemoglobin levels beyond 1 year of age. 21,37 Despite the recovery in hemoglobin levels, sla mice continue to be severely iron deficient as shown in this and previous studies. 38 In our study, sla mice have even lower liver iron levels than wild-type mice on an iron-deficient diet.…”

Age-related changes in iron homeostasis in mouse ferroxidase mutants

“…Defects in two multi-copper ferroxidases, ceruloplasmin and hephaestin, lead respectively to the contrasting phenotypes of iron overload and deficiency in mice. Previous studies of the sex-linked anemia (sla), a genetic mouse model of iron deficiency with a defect in hephaestin, found that hemoglobin levels gradually increase with age (Bannerman and Cooper 1966;Bannerman and Pinkerton 1967) although they continue to be iron deficient (Pinkerton et al 1970). In contrast, 10-12 week old ceruloplasmin-deficient mice had increased spleen and liver iron (Harris et al 1999).…”

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice

“…42,43 Sla mice are iron deficient at birth and weaning and have a severe hypochromic microcytic anemia. 44 The severity of the anemia decreases with age, 45 although the animals remain iron deficient. 9,46 Despite this defect, sla mice absorb sufficient iron for normal development and reproduction.…”