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D J Weatherall

Publications and source records attributed to D J Weatherall.

461 records · Page 26Linked to original sources
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Alpha-thalassaemia caused by a polyadenylation signal mutation.

Most eukaryotic messenger RNAs have the sequence AAUAAA 11-30 nucleotides from the 3'-terminal poly(A) tract. Since this is the only significant sequence homology in the 3' non-coding region it has been suggested that it may be a recognition site for enzymes involved in polyadenylation and/or termination of polymerase II transcription. This idea is strengthened by observations on the effect of deletion mutations in or around the AATAAA sequence on polyadenylation of late simian virus 40 (SV40) mRNA; removal of this sequence prevents poly(A) addition. Naturally occurring variants of this hexanucleotide are rare and hitherto their functional significance has not been assessed. We have now identified a human alpha 2-globin gene which contains a single point mutation in this hexanucleotide (AATAAA leads to AATAAG). The paired alpha 1 gene on the same chromosome is completely inactivated by a frame-shift mutation. This unique combination has enabled the expression of the mutant alpha 2 gene to be studied in vivo where it has been found that the accumulated level of alpha 2-specific mRNA in erythroid cells is reduced. Furthermore, readthrough transcripts extending beyond the normal poly(A) addition site are detected in mRNA obtained from HeLa cells transfected with cloned DNA from the mutant alpha 2 gene, suggesting that the single nucleotide change in the AATAAA sequence is the cause of its abnormal expression.

Base Sequence↗
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A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16.

Adult polycystic kidney disease (APCKD) is a common and often lethal multi-organ disease with an autosomal dominant pattern of inheritance; approximately 1 in 1,000 people carry the mutant gene. The major pathological abnormality is the development and progressive enlargement of cysts in several organs including the liver, pancreas and spleen as well as the kidneys. The basic biochemical defect which leads to the formation of cysts remains unknown. Cyst development, which is not retarded by any known therapy, leads to irreversible renal failure and death at a mean age of 51 unless dialysis or transplantation are used. Patients with the disease account for 9% of chronic dialysis requirement. The first symptoms tend to occur in the fourth decade, after most patients have reproduced. Presymptomatic diagnosis depends on the ultrasonographic detection of cysts, but exclusion cannot be achieved by this means; 34% of at-risk patients in the second decade and 14% in the third will go on to develop cysts after negative diagnosis. The low sensitivity of diagnostic techniques in this critical age-range imposes severe limitations on genetic counselling and the condition cannot be identified prenatally. Hence we have searched for a linkage marker for APCKD; we show here that the APCKD locus is closely linked to the alpha-globin locus on the short arm of chromosome 16 (zeta = 25.85, theta = 0.05).

Chromosomes, Human, 16-18↗
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Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms.

The genetic relationships of human populations have been studied by comparing gene frequency data for protein and blood-group loci of different populations. DNA analysis now promises to be more informative since not only do the DNA coding sequences have more variation than their corresponding proteins but, in addition, noncoding DNA sequences display more extensive polymorphism. We have now studied the frequency of a group of closely linked nuclear DNA polymorphisms (haplotypes) in the beta-globin gene cluster of normal (beta A) chromosomes of individuals from eight diverse populations. We have found that all non-African populations share a limited number of common haplotypes whereas Africans have predominantly a different haplotype not found in other populations. Genetic distance analysis based on these nuclear DNA polymorphisms indicates a major division of human populations into an African and a Eurasian group.

Alleles↗
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Thalassemia and malaria: new insights into an old problem.

The hemoglobinopathies are probably the world's most common genetic diseases: The World Health Organization has estimated that at least 5% of the population are carriers for one or other of the most serious forms, the alpha- and beta-thalassemias and the structural variant hemoglobins S, C, and E, which are found at polymorphic frequencies in many countries. All these hemoglobinopathies are believed to provide protection against malaria, and it is thought that, in malarial regions of the world, natural selection has been responsible for elevating and maintaining their gene frequencies, an idea first proposed 50 years ago by J.B.S. Haldane. Epidemiological studies undertaken in the 1950s on hemoglobin S in Africa provided support for the "malaria hypothesis," but until recently it has proved extremely difficult to verify it for the thalassemias. The application of molecular methods has, however, provided new opportunities to address this old question. Population and molecular genetic analysis of thalassemia variants, and microepidemiological studies of the relationship between alpha-thalassemia and malaria in the southwest Pacific, have provided unequivocal evidence for protection. Surprisingly, some of this protection appears to derive from enhanced susceptibility in very young thalassemic children to both Plasmodium falciparum and, especially, P. vivax, and this early exposure appears to provide the basis for better protection in later life.

Africa↗
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The global problem of genetic disease.

Inherited haemoglobin disorders will undoubtedly cause an increasing health burden in many developing countries. Although much is known about their molecular pathology and the mechanisms for their phenotypic diversity, many important questions remain, not least the role of the environment in modifying the clinical course. Methods for screening these conditions are now well established and inexpensive and it is vital that they are applied to define the magnitude of the problem that will be posed by these conditions in the future. Similarly, they form the basis for widespread screening and counselling programmes directed at developing prenatal diagnosis expertise where this is not available. Answers to some relatively simple questions about the role of the environment could also make a major difference to the management of the haemoglobin disorders. There is a major case for the development of regional networks to apply such technology as has been developed for the control and prevention of the important haemoglobin disorders, particularly in Asian countries.

Developing Countries↗
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Iron overload and iron-chelating therapy in hemoglobin E-beta thalassemia.

Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.

Adult↗
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The phenotypic diversity of monogenic disease: lessons from the thalassemias.

Clearly, the thalassemias are associated with a remarkably diverse series of phenotypes. Much of this heterogeneity can be explained at the molecular level by variability of the primary mutation of the beta globin genes, and the effects of genetic variability at two other loci, that is the alpha and gamma gene loci. When all these factors are taken into consideration there still remains a considerable amount of phenotypic diversity that is not explainable in this way. It is becoming clear that there is potential for further diversity at unrelated loci that may modify the major complications of the disease. And there is yet another layer of potential genetic variability that reflects the way in which these diseases have come under intense selection by malaria over a relatively short period of time. Finally, there are many environmental and cultural factors that may modify a patient's reaction to the disease. It is apparent, therefore, that this group of monogenic diseases are highly diverse and that, although much of this heterogeneity can be ascribed to the action of one or two major modifying loci, phenotypic variability also reflects the action of even further genetic diversity stemming from the way this disease has spread and its evolutionary background. It is apparent, therefore, that when we start to dissect disease due to the action of multiple loci, together with a major environmental component, the situation will be infinitely more complex. Of course this should not stop us from attempting to isolate the major genes involved, but it is telling us that we should be very careful about making assumptions that we will be able accurately to predict phenotypes from genotypes; although we have made considerable progress toward this end for the thalassemias, even here we have to deal with a large number of genetic and environmental factors that may modify the primary action of mutations of the beta globin genes. It is issues of this kind that will set the limit on our current reductionist approach to the study of human disease and will make it all the more important that we develop a more holistic way of analyzing disease processes in the future.

Alleles↗