John A. Edwards

Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia.

Summary Intestinal iron absorption was studied in mice with hereditary microcytic anemia (gene symbol mk), an autosomal recessive trait characterized by hypochromia and microcytosis. In vivo studies by means of whole body counting following the intragastric administration of radioiron showed impaired intestinal absorption of iron. Further in vitro studies using the everted duodenal loop technique, demonstrated a defect in the mucosal uptake of iron. Hereditary microcytic anemia should, therefore, provide a valuable model for the study of the mechanisms controlling intestinal iron absorption.

Hereditary defect of intestinal iron transport in mice with sex-linked anemia

Iron transport by everted duodenal sacs in vitro was studied in mice with sex-linked anemia (gene symbol sla) (an inherited iron deficiency anemia), in normal mice, and in normal mice on iron-deficient and iron supplemented diets. Although the over-all mucosal uptake of iron was the same in sla and normal sacs, transport of iron to the inside of the sac was much decreased in sla. The iron transport defect in sla was emphasized by the fact that genotypically normal mice on an iron-deficient diet demonstrated greatly increased iron transport. Electrophoretic analysis of protein extracted from sla and normal sacs showed only one iron-binding fraction. The sla and normal fractions had the same mobility and corresponded in position to the major band of horse ferritin. It thus appears that the iron deficiency of sla is due to a genetically determined defect in mucosal iron transport and that this defect is not associated with any demonstrable abnormality of a major iron-binding protein.

A new familial syndrome characterized by pigmentary retinopathy, hypogonadism, mental retardation, nerve deafness and glucose intolerance

Three siblings with retinitis pigmentosa, deafness and mental retardation were studied. Physical abnormalities included nystagmus, acanthosis nigricans and multiple keloids. The two male siblings had gynecomastia, small testes and mild subvirilization whereas the only indication of hypogonadism in the female sibling was oligomenorrhea. Testosterone levels in the males, which were in the low to low normal range, were increased by the administration of large doses of chorionic gonadotropin. The two affected males had elevated plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels which were decreased by the administration of testosterone and increased by the administration of clomiphene. One sibling had mild obesity and diabetes mellitus, one had moderate obesity, normal glucose tolerance and hyperinsulinism and the third had abnormal glucose tolerance and hyperinsulinism. This familial syndrome is distinct from either the Laurence-Moon, Bardet-Biedl or Alström disorders and provides further evidence of genetic heterogeneity in this group of autosomal recessive traits.

Hereditary microcytic anaemia in the mouse; studies in iron distribution and metabolism

Summary. Iron distribution and metabolism have been studied in hereditary iiiicrocytic anaemia of tlie mouse (gene symbol mk), an autosonial recessive trait cliaractcrizcd by hypoclironiia and microcytosis. Evidence of iron deficiency was hutid in the forin of depleted body stores, hyposidcraemia, an increased total iron biiiding capacity of tlic plasma and a high free erythrocyte‐protoporyhyrin level. I lowcvcr, the failure to find citlicr rapid clearance and high utilization of tracer doses of 59Fe or a complete response to pareliteral iron treatment indicated that simple iron deficiency was not the cause of tlie anaemia. It is suggested that generalized impairmcn t in tlie cellular uptake of iron involvingthe transfer of iron from the intestinal lumen to tlic mucosa and from tlie plasma to the erythroblast may provide a unitary explaiiation of licreditary microcytic anaemia.

Iron metabolism and absorption studies in the X-linked anaemia of mice.

Summary. The X‐linked anaemia of mice (gene symbol, sla) is hypochromic and microcytic, and the stainable iron stores are reduced. Chemical estimates of total body iron content and serum iron concentration show low values and the total serum iron binding capacity is elevated in anaemic mice. Rapid plasma iron clearance and increased iron utilization provide further confirmation of iron deficiency in anaemic animals. Alterations in activity of haem‐containing enzymes have been sought in the heart, liver and kidney of anaemic mice, and slightly decreased activity found only in kidney cytochrome oxidase.

THE EFFECT OF HEMIN ON GLOBIN SYNTHESIS AND IRON UPTAKE BY RETICULOCYTES OF THE BELGRADE RAT

The anemia of the Belgrade laboratory rat is an autosomal recessive trait (gene symbol b)-determined by a radiation-induced mutation (l-31 . It is characterized by red-cell hypochromia and microcytosis, reti~ulocytosis, hyperfe~nemia, absent tissue iron stores and high levels of free erythrocyte protoporphyrin 12-41. Uptake of iron by b/b reticulocytes in vitro is about 25% normal, and synthesis of globin is about 50% normal 151. The primary defect therefore appears to be a defiled delivery of iron to the erythroid cell 1.51. A primary defect in globin synthesis, however, with a secondary effect on iron uptake has not been entirely excluded. The present study demonstrates that exogenous hemin partially corrects the globin synthesis defect of b/b reticulocytes. Since the iron delivery step is bypassed with exogenous hemin, this observation provides indirect evidence that the primary abnormality is one of diminished delivery of iron to the erythroid cell.

HEREDITARY ANAEMIAS IN LABORATORY ANIMALS

Some 20 different licrcditary disorders of the red cells in animals other than man liave now becii described (Russcll & Berimein, 1966; Russell, 1970; Bannerman ct nf, 1973b). They offer excelleiit opportunities to elucidate physiological and pathological aspects of hacmopoiesis (Russell, 1963 ; Bannerman, 1974). Workers at thc Jackson Laboratory, espccially Dr E. S. Russell and her co-workers, have made a particular contribution to this ficld, not only in expcrimcnts, but in maintaining mutant mouse stocks and making tliem available to the scientific community. Tlie advantages of investigating a liercditary disease in a sinall laboratory animal are easily sceii. Tlie mouse is particularly useful, siiicc tlic generation time is short, and genetic tests can bc relatively easily and quickly carried out. A large populatioii can be maintained in a small space at modest cxpciisc. Since many of tlic mousc mutations are availablc on inbred strain backgrounds, irrclcvant variation due to diffcrciiccs at otlier loci is minimal. Transplantation experiments can bc done between highly coiigciiic normal aiid affected individuals. Most of the anaemias have been dcscribcd in mice aiid rats, but several are now known in dogs. They fall into four groups (Table I) : ( I ) stcm cell disorders; (2) hypochromic aiiacmias; (3) haemolytic anaemias; (4) a small misccllaiieous group. I17 this Aiiiiotation, only some recciit aspccts of the first tliree groups will be considcred; more complete reviews with full refereiiccs have been cited above.

In Search of the Etiology of Alzheimer’s Disease

Alzheimer’s disease is defined by a characteristic neuropathology consisting of neurofibrillary tangles made up of intraneuronal paired helical filaments and straight filaments, and senile plaques made up of a core of extracellular amyloid fibrils surrounded by dystrophic neurites and glial cells, the accumulation of the same amyloid fibrils in cerebral and meningeal microvessels and loss of neurones. This neuropathology predominantly affects the frontal, parietal and temporal cortex, and hippocampus.

Haemoglobin metabolism in mice with a hereditary iron deficiency anaemia (sla/Y)

1. 1. Haemoglobin was labelled in vivo in normal mice and in mice with iron deficiency anaemia due to the X-linked gene mutation, sla. 2. 2. Two main red cell populations are found in normal mice, one subject to accelerated destruction and the second with a longer finite life span. 3. 3. In iron deficient sla / Y mice, haem and globin labelling indicate random haemolysis and shortened red cell survival. 4. 4. Specific activity curves of faecal urobilinogen show complex “early” labelling patterns. They confirm mean red cell survival in both normal and anaemic mice. and indicate increased ineffective erythropoiesis in the sla/Y animals with iron deficiency.