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D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 145 records · Page 8Linked to original sources
PubMed1987

Thalassaemia intermedia: interaction of the triple alpha-globin gene arrangement and heterozygous beta-thalassaemia.

Five patients with heterozygous beta-thalassaemia with an unusually severe clinical picture, low haemoglobin levels occasionally requiring blood transfusion, splenomegaly and unusually prominent basophilic stippling were found to have co-inherited a triple alpha-globin gene arrangement on one chromosome (alpha alpha alpha/alpha alpha). It seems probable that the expression of a single extra alpha-globin gene is sufficient in some patients with heterozygous beta-thalassaemia to give rise to a clinically significant degree of dyserythropoietic anaemia.

Adult↗
PubMed1987

Molecular pathology of single gene disorders.

Recent studies using recombinant DNA technology have led to an understanding of the basic molecular pathology of single gene disorders. Furthermore, methods are being developed for finding genes for conditions, whose underlying biochemistry is still not understood, or which may contribute to polygenic systems that underlie common diseases. As well as providing new approaches to carrier detection, prenatal diagnosis, and treatment of single gene disorders, these advances promise to provide important information about the pathophysiology of many common polygenic diseases.

Chromosome Aberrations↗
PubMed1987

High resolution gene mapping of the human alpha globin locus.

A combination of polymorphic DNA markers, cytogenetic analysis, and in situ hybridisation has been used for the high resolution assignment of the human alpha globin gene cluster on chromosome 16. Multiallelic DNA probes from within the alpha globin cluster were used to determine the number of copies of this locus in three cell lines containing trisomies of the short arm of chromosome 16 and one with a familial inversion, inv(16). The breakpoints in these rearrangements flank the alpha globin locus and locate a shortest region of overlap to 16p13.1. A meiotic crossover was also localised to this band. In situ hybridisation of biotinylated DNA probes to normal and inverted chromosomes 16 [inv(16)(p13.1;q22)] showed hybridisation sites at opposite ends of the chromosomes, consistent with this regional localisation.

Chromosome Inversion↗
PubMed1987

Non-deletion haemoglobin H disease in Papua New Guinea.

Analysis of DNA from members of a Melanesian family from Papua New Guinea with haemoglobin (Hb) H disease revealed that all four alpha globin genes are intact in affected subjects. Study of restriction enzyme site and length polymorphisms and the use of oligonucleotide probes indicated that the molecular basis of this Papuan form of non-deletion Hb H disease differs from the previously described Middle Eastern and Mediterranean types.

Female↗
PubMed1987

High frequency of beta thalassaemia in a small island population in Melanesia.

A study of the causes of anaemia in the south west Pacific archipelago of Vanuatu has identified one island, Maewo, where the carrier rate for beta thalassaemia exceeds 20%, one of the highest recorded incidences in the world. Homozygous beta thalassaemia is a major cause of infant mortality and a serious drain on health resources on this island. Interactions of beta thalassaemia with various forms of alpha + thalassaemia were common in this population. Coexistent alpha + thalassaemia leads to better haemoglobinised and larger red cells than are seen in simple beta thalassaemia heterozygotes and screening for the latter can only be reliably carried out by Hb A2 estimation.

Female↗
PubMed1987

Approach to the diagnosis of beta-thalassaemia by DNA analysis.

Over the last few years, the new techniques of DNA analysis have enabled efficient strategies for the detection and characterisation of the different mutations causing beta-thalassaemia of which a total of 41 have now been characterised. Since the majority of the beta-thalassaemia molecular defects are of the non-deletion type and not directly detectable by Southern blotting, a comprehensive approach to the identification of these mutations entails the use of several different techniques, including direct identification by restriction enzyme analysis and synthetic oligonucleotide probes, indirect identification by linkage analysis to restriction fragment length polymorphisms and globin chain synthesis analysis. As the majority of beta-thalassaemia in each population is accounted for by a few mutants, it should be possible to work out a combination of techniques to directly detect the majority of beta-thalassaemia in a defined population.

DNA↗
PubMed1987

Alpha-thalassaemia and the malaria hypothesis.

Recent population genetic studies of the distribution of alpha+-thalassaemia in Melanesia using DNA analysis have provided strong support for the hypothesis that high frequencies of this genetic disorder are the result of natural selection by malaria.

Age Factors↗
PubMed1987

Different hematologic phenotypes are associated with the leftward (-alpha 4.2) and rightward (-alpha 3.7) alpha+-thalassemia deletions.

We have compared the phenotypes of the two common deletion forms of alpha+-thalassemia by analysis of umbilical cord blood samples from Melanesia. Homozygotes for the leftward, 4.2-kilobase, deletion (-alpha 4.2) had significantly higher levels of Hb Bart's at birth than homozygotes for the rightward, 3.7-kilobase, deletion (-alpha 3.7). Compound heterozygotes for each deletion had intermediate values. Although deletion forms of alpha 0 thalassemia were not found in this survey, nondeletion alpha-thalassemia was present at low frequency. Since the predominant rightward deletion in this population, -alpha 3.7III, entirely removes the alpha 1-gene and the 4.2-kilobase deletion deletes the alpha 2-gene, these data indicate that the alpha 2-globin gene has a higher output than the alpha 1-gene, on single alpha-gene chromosomes.

Chromosome Deletion↗
PubMed1987

Fetal hemoglobin levels and beta (s) globin haplotypes in an Indian populations with sickle cell disease.

To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta(0), 7 A beta, (0) and 12 AA) Indians from the state of Orissa. The beta(s) globin gene was found to be linked almost exclusively to a beta(S) haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta(s) haplotype). By contrast, the majority of beta A and beta(0) thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta(s) globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.

Adolescent↗
PubMed1987

Raised Hb F levels in sickle cell disease are caused by a determinant linked to the beta globin gene cluster.

A haplotype of restriction fragment length polymorphisms in the beta S globin gene cluster was determined in six different African and Asian ethnic groups with sickle cell disease. The geographical distribution of a particular haplotype, designated Asian beta S haplotype, coincides with the occurrence of raised Hb F levels in sickle cell disease. Detailed hematologic and genetic studies of a large geographically isolated group of Orissan Indian patients with sickle cell disease and a mixed Asian Indian group with homozygous beta thalassemia provided evidence that the determinant responsible for raised Hb F levels is linked to the beta globin gene cluster. The possible nature of this determinant is discussed.

Africa↗
PubMed1987

Polynesian origins and affinities: globin gene variants in eastern Polynesia.

Analysis of copy number variants of the duplicated alpha-, zeta-, and gamma-globin genes in eastern Polynesians revealed a high frequency of both triplicated-zeta-gene chromosomes and a specific alpha thalassemia deletion. This deletion and a novel restriction-enzyme-site polymorphism associated with a zeta zeta zeta chromosome are found only in Melanesians and Polynesians. Analysis of alpha-globin restriction-enzyme haplotypes indicated further similarities to Melanesians but suggested an additional non-Melanesian genetic component in eastern Polynesia. Several globin gene alleles showed evidence of marked frequency fluctuations due to genetic drift.

Alleles↗
PubMed1987

Heterogeneity and origins of the alpha-thalassemias.

The alpha-globin gene cluster is far from static. It shows remarkable diversity within and among populations, both in gene number and in the pattern of polymorphisms involving the hypervariable regions. The deletions that have given rise to alpha(0)-thalassemia appear to have resulted from rare genetic events, and the affected chromosomes have been distributed among localized populations by selection. On the other hand, the deletions that have given rise to at least one of the alpha(+)-thalassemias seem to have occurred on multiple occasions in different populations. The genesis of this condition, the most common single gene disorder, may reflect the concerted evolution of the alpha-globin genes, and the alpha(+)-thalassemias may have arisen as a by-product of this evolutionary process. The existence of such a polymorphic gene family and the fact that its mutations are the most common single gene disorders in man provide us with a remarkable, natural model for studying population genetics at the molecular level. Further analysis of this cluster may provide valuable information about the timing of racial diversions, population movements, and the molecular events that have helped to maintain such high gene frequencies for some of the mutations of these loci.

Biological Evolution↗
PubMed1986

First-trimester fetal diagnosis for haemoglobinopathies: report on 200 cases.

First-trimester prenatal diagnosis by DNA analysis was found to be possible in 224 (80%) of 281 families at risk of having a child with beta-thalassaemia major. 200 prenatal diagnoses, mainly for beta-thalassaemia or sickle-cell anaemia, were made by means of chorionic villus sampling and fetal DNA analysis. The overall fetal loss rate was 6.7%, the majority being in the first half of the programme. There was one misdiagnosis. Prenatal diagnosis was also carried out successfully for both pairs of twins in two pregnancies. Comparison of these results with 53 prenatal diagnoses made with DNA prepared from amniotic fluid suggests that the first-trimester procedure is more reliable. If further experience confirms that chorionic villus sampling has an acceptably low risk for both mother and fetus it will largely replace other methods for prenatal diagnosis of the haemoglobin disorders and other single-gene conditions.

Amniotic Fluid↗