Analysis of globin gene inversion reveals similarities with immunoglobulin rearrangement.
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Base Sequence↗
Biomedical subjects
D J Weatherall
Publications and source records attributed to D J Weatherall.
First trimester diagnosis of the hemoglobin disorders.
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Anemia, Sickle Cell↗
Vascular occlusion and infarction in sickle cell crisis and the sickle chest syndrome.
A young adult with homozygous sickle cell anaemia (Hb SS) suffered a fatal sickle cell crisis complicated by the sickle chest syndrome. At necropsy multiple large infarcts of the lung, bone marrow, and pituitary gland were found. The large majority of pulmonary infarcts were not associated with either gross or microscopic vaso-occlusion. These findings are discussed and correlated with past and current opinions of sickle cell crisis and the sickle chest syndrome.
Adult↗
Prenatal diagnosis of the common haemoglobin disorders.
New techniques of DNA analysis have been applied to the prenatal diagnosis of the common haemoglobin disorders. Currently, it is possible to provide a comprehensive programme for the prevention of these conditions, although this entails the use of several different techniques including globin chain synthesis analysis, direct identification of mutations with restriction enzymes, linkage analysis of restriction fragment length polymorphisms, and the use of oligonucleotide probes. At present, the best combination of these approaches has to be worked out for individual populations, but as the techniques of chorion villus sampling and DNA analysis improve it should be possible to rationalise these prenatal diagnosis programmes and thus make them simpler and less expensive.
Anemia, Sickle Cell↗
Alpha thalassemia changes erythrocyte heterogeneity in sickle cell disease.
Homozygous alpha-thalassemia has the beneficial effect in sickle cell anemia of reducing the hemolytic severity while changing several other hematological parameters. We examined in detail the cellular basis of some of these hematologic alterations. We find that the broad distribution in erythrocyte density and the large proportion of dense cells associated with sickle cell anemia are both reduced with coexisting alpha-thalassemia. Measurements of glycosylated hemoglobin levels as a function of cell density indicate that the accelerated increase in cell density, beyond normal cell aging, in sickle cell anemia is also reduced with alpha-thalassemia. The patients with homozygous alpha-thalassemia and sickle cell disease have slightly lower levels of hemoglobin F than the nonthalassemic sickle cell patients. Examination of hemoglobin F production revealed that the proportion of hemoglobin F containing reticulocytes remained unchanged, as did the proportion of hemoglobin F in cells containing hemoglobin F (F cells). Preferential survival of F cells occurs in sickle cell anemia, with or without alpha-thalassemia, and the slight difference in hemoglobin F levels appear to reflect differences in numbers of circulating F cells. Thus, in sickle cell disease with coexisting alpha-thalassemia, the change in the erythrocyte density profile, possibly due to inhibition of polymerization-related increases in cell density, explains the hematological improvement.
Anemia, Sickle Cell↗
The developmental genetics of human hemoglobin.
Clearly, it is impossible to combine the diverse information briefly outlined in this review to provide a coherent model of the regulation of globin gene expression during development. One of the great difficulties in this field is uncertainty as to whether the mutations which are associated with persistent gamma chain production or, for the matter, the experimental models which have been used to study the differential expression of the fetal and adult globin genes, have any real relevance to an understanding of the normal switching process. Probably they do, but only with respect to one aspect of what must be an extremely complex multi-step regulatory system. The consistent changes in chromatin and methylation state of the beta globin gene cluster which are associated with activation of the different gene loci at different stages of development provide an anatomical explanation for the activity of these loci but tell us nothing about their mode of regulation. However, the gene or chromosome transfer experiments suggest that there may be developmental-stage specific trans regulatory factors which may be involved in the regulation of these genes, presumably by interacting in some way with chromatin. This is a very promising lead. Equally interesting is the possibility that the upstream mutations which are being found in some of the forms of non-deletion HPFH could provide a clue as to the site of these interactions. Thus at least we have an indication of what might be the most productive area of investigation for trying to characterize the mechanisms of regulation at the chromosomal level. This may be as far as we can go in the immediate future. The central question remains, however. How is the differential expression of the globin genes during development actually timed? All we know at the moment is that it is related fairly closely to gestational age. The only experimental data relating to this question is derived from the sheep transplant model, and suggests that there might be some form of "developmental clock' built into the hemopoietic stem cell. Here we are in considerable difficulties because we don't have an obvious experimental model with which to analyze time-related events. None of the forms of HPFH is, strictly speaking, a heterochronic mutation.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Alpha zero-thalassemia due to recombination between the alpha 1-globin gene and an AluI repeat.
A form of alpha zero-thalassemia found in subjects of Mediterranean origin has been analyzed by gene mapping and DNA sequencing. Homozygotes have the hemoglobin Bart's hydrops fetalis syndrome, while compound heterozygotes for this defect and alpha+-thalassemia have hemoglobin H disease. It results from a deletion that removes 20.5 kilobases of DNA from within the alpha-globin gene cluster. Sequence data from the regions adjacent to the breakpoint indicate that the recombination event that caused this deletion occurred between the alpha 1-gene and an unusual AluI sequence located between the embryonic zeta genes.
Chromosome Deletion↗
Melanesians and Polynesians share a unique alpha-thalassemia mutation.
Several genetic markers that provide information on population migrations and affinities have been detected by studies of proteins and cellular antigens in blood. Analysis of DNA polymorphisms promises to yield many further population markers, and we report here the distribution of a new alpha-globin gene deletion (-alpha 3.7 III) detected by a restriction enzyme mapping. This is found frequently in Melanesians and Polynesians but not in five other populations in which alpha-thalassemia is prevalent. We used restriction enzyme haplotype analysis to support a single origin for this mutation and propose that it is a useful population marker. Its geographical distribution supports a route through Island Melanesia for the colonizers of Polynesia.
Chromosome Deletion↗
Prenatal diagnosis of inherited blood diseases.
Many common genetic disorders of the blood can be identified in utero, either by fetal blood sampling, biochemical analysis of amniotic fluid cells or directly by studying DNA obtained from amniotic fluid cells or chorion biopsy. With the development of gene probes for most of the important genetic disorders of the blood there will be a gradual transition from fetal blood sampling and amniocentesis to chorion biopsy as the major approach to prenatal diagnosis of haematological disorders. Since the carrier states for many of these conditions can be identified at the antenatal clinic by a careful family history and a few relatively simple blood tests the outlook for prevention of many of the important genetic disorders of the blood is extremely promising.
Amniocentesis↗
DNA in medicine. Implications for medical practice and human biology.
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Chromosome Mapping↗
A new DNA polymorphism for prenatal diagnosis of beta-thalassaemia in Mediterranean populations.
The prevalence of a new polymorphism for the restriction enzyme Ava II in the psi beta-gene of the beta-globin gene cluster was determined in Mediterranean families with at least one beta-thalassaemia homozygote. The polymorphic site was absent in 54/115 beta-thalassaemic chromosomes but only in 4/120 normal chromosomes. The difference in frequencies of this polymorphism between normal and thalassaemic chromosomes greatly increases the feasibility of prenatal diagnosis of beta-thalassaemia by DNA analysis in this population.
Asia, Western↗
Genetic disorders of human haemoglobin as models for analysing gene regulation.
The genetic and acquired disorders of human haemoglobin provide a diverse group of naturally occurring models for analysing the regulation of protein synthesis. They include structural haemoglobin variants, thalassaemias, which are conditions in which there is a reduced rate of globin chain production, and hereditary persistence of foetal haemoglobin (HPFH) in which there is an inherited abnormality in the switch from foetal to adult haemoglobin synthesis. The thalassaemias result from a diverse series of cis acting lesions of the globin genes which include deletions, insertions, frame shift mutations, and point mutations involving transcription, messenger RNA processing, initiation, termination, poly A addition and globin chain stability. Many forms of HPFH are due to deletions of the beta-like gene cluster; it has been suggested that they may involve regions of the cluster which are involved in the regulation of the foetal to adult globin chain switch. So far, however, no regions of this type have been identified with certainty. The varieties of HPFH not associated with major gene deletions, or those caused by genetic determinants that are not linked to the globin gene clusters, and some of the acquired forms of alpha thalassaemia associated with mental retardation or leukaemia, may be more useful models for studying the regulation of the globin genes, particularly their developmental control.
Base Sequence↗
Independent recombination events between the duplicated human alpha globin genes; implications for their concerted evolution.
We have examined the molecular structure of the human alpha globin gene complex from individuals with a common form of alpha thalassaemia in which one of the duplicated pair of alpha genes (alpha alpha) has been deleted (-alpha 3-7). Restriction mapping and DNA sequence analysis of the mutants indicate that different -alpha 3.7 chromosomes are the result of at least three independent events. In each case the genetic crossover has occurred within a region of complete homology between the alpha 1 and alpha 2 genes. Since the -alpha chromosomes may reflect the processes of crossover fixation and gene conversion between the two genes, their structures may provide some insight into the mechanism by which the concerted evolution of the human alpha globin genes occurs.
Base Sequence↗
Prenatal diagnosis of thalassaemia.
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DNA↗
Alpha thalassaemia in Papua New Guinea.
Haemoglobin Bart's was detected in cord blood samples from 81% of 217 infants born in Madang on the north coast of Papua New Guinea. Analysis of the alpha globin genes of 30 infants and adults from the same region showed that all but 3 were heterozygous or homozygous for the deletion form of alpha + thalassaemia. None of 18 cord blood samples from infants born in Goroka in the Eastern Highlands Province had haemoglobin Bart's, and in each case the alpha globin genes were normal. Preliminary geographical and linguistic analyses of both groups suggest that the prevalence of alpha thalassaemia may be related to altitude rather than to linguistic grouping and hence that resistance to malaria may be at least one reason why alpha thalassaemia is so common in some populations.
ABO Blood-Group System↗
The molecular basis of alpha-thalassaemia in Thailand.
The molecular basis of alpha-thalassaemia has been established in 48 Thai subjects with Hb H disease and 15 with the Hb Bart's hydrops fetalis syndrome. This study has shown that in this population there are at least 18 different types of chromosome carrying seven independent alpha-thalassaemia mutations one of which is a novel deletion removing the entire alpha-globin gene complex. Although there are a limited number of alpha-thalassaemia determinants in the Thai population, there is a remarkable degree of variation in the genetic markers which flank them. These markers may be of value in establishing the evolutionary history of the alpha-thalassaemias.
Chromosome Deletion↗
The deoxyuridine suppression test in severe anaemia following Plasmodium falciparum malaria.
Haematological studies in a group of Gambian children with severe anaemia due to Plasmodium falciparum malaria revealed marked dyserythropoietic changes in erythroblasts and evidence of increased ineffective erythropoiesis. In some cases, the bone marrow also showed a few giant metamyelocytes and ring sideroblasts. The results of deoxyuridine suppression tests indicated that these haematological disturbances were not a consequence of vitamin B12 or folate deficiency within marrow cells.
Anemia↗
Erythroid differentiation in CGL cells from a patient with blast crisis.
A 60-year-old patient with Ph1 + ve CGL presented with blast crisis. The leukaemic blast cells resembled erythroblasts and had 51 chromosomes with two Ph1. Cells obtained from peripheral blood, marrow and a pleural effusion were cultured under a variety of conditions. After 2-3 weeks in culture, the model 51-chromosome line persisted but many of the cells displayed erythroid morphology and differentiated to resemble mature normoblasts, strongly positive on o-tolidine +ve staining. Haemoglobin analysis by starch gel and globin synthesis studies demonstrated only fetal haemoglobin (HbF) synthesis in the cultured cells whilst the patient's reticulocytes synthesized very little HbF. Restriction enzyme mapping of DNA from the cultured cells showed that beta-globin genes were still present in these cells even though they were not expressed.
Bone Marrow↗