Journal ArticleDOI
A Genetically Determined Disorder with Features both of Thalassaemia and Congenital Dyserythropoietic Anaemia
David J. Weatherall,J. B. Clegg,H. H. M. Knox-Macaulay,C. Bunch,C. R. Hopkins,I. J. Temperley +5 more
TLDR
The most likely molecular mechanisms for this disorder are either an ‘overproduction abnormality’ of α‐chain synthesis, or a defect in cell division leading to increased amounts of genetic material per cell, a mechanism postulated recently as a basis for the unusual distribution of red cell enzyme levels in congenital dyserythropoietic anaemia.Abstract:
Summary. What appears to be a hitherto unreported type of congenital anaemia has been found in six members of an Irish family. It is inherited in an autosomal dominant manner and is characterized by moderate anaemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphological abnormalities of the red cells (which are, however, well haemoglobinized), erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow, and in the peripheral blood after splenectomy. Potassium flux across the red cell membranes is increased and there is imbalanced globin chain synthesis with α-chain production exceeding that of β-chains by a factor of 2/1. Excess α-chains in the bone marrow form a pool of similar magnitude to that observed in β-thalassaemia heterozygotcs but the latter do not have red cell precursor inclusion bodies or the degree of ineffective erythropoiesis seen in the present cases. The most likely molecular mechanisms for this disorder are either an ‘overproduction abnormality’ of α-chain synthesis, or a defect in cell division leading to increased amounts of genetic material per cell, a mechanism postulated recently as a basis for the unusual distribution of red cell enzyme levels in congenital dyserythropoietic anaemia.read more
Citations
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Phenotype—genotype relationships in monogenic disease: lessons from the thalassaemias
TL;DR: Findings in the β-thalassaemias highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved.
Journal ArticleDOI
The Molecular Basis of β-Thalassemia
TL;DR: The β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects, which has provided a paradigm for understanding of much of human genetics.
Journal ArticleDOI
Molecular basis for dominantly inherited inclusion body beta-thalassemia.
S. L. Thein,C Hesketh,P. Taylor,I. J. Temperley,R. M. Hutchinson,John M. Old,William G. Wood,John B. Clegg,David J. Weatherall +8 more
TL;DR: It is suggested that the phenotypic difference between this condition and the more common recessive forms of beta-thalassemia lies mainly in the length and stability of the abnormal translation products that are synthesized and whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation.
Journal ArticleDOI
Recent developments in the molecular genetics of human hemoglobin
Journal ArticleDOI
Genetic insights into the clinical diversity of beta thalassaemia.
TL;DR: An overview of the b globin gene structure, function and expression is presented, followed by a short description of the clinical and haematological diversity encountered in b thalassaemia and the underlying pathophysiology.
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