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Biomedical subjects

D J Weatherall

Publications and source records attributed to D J Weatherall.

At least 19 recordsLinked to original sources
PubMed1992

The spectrum of beta thalassaemia in Burma.

The molecular defects causing beta thalassaemia have been analysed in 85 unrelated Burmese patients. The patients included 14 with homozygous beta thalassaemia, 70 with HbE/beta thalassaemia and one with HbS/beta thalassaemia. Using a combination of allele-specific oligoprobe hybridization and direct sequencing of genomic DNA amplified by the polymerase chain reaction, 95/99 of the beta-thalassaemia alleles have been characterized. Six mutations have been identified of which three, the G-T at IVS-1 position 1, the G-C at IVS-1 position 5 and the deletion of TCTT in codons 41/42, accounted for 85% of the alleles. Despite the diversity of ethnic groups in Burma, the number of beta-thalassaemia alleles in Burma is relatively small. Thus, diagnosis of the majority of the beta thalassaemias would be possible using a limited number of oligonucleotide probes.

Alleles↗
PubMed1991

Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia.

In an attempt to determine the mechanism whereby thalassemia in its milder forms may protect against malaria, we have examined the expression of neoantigen at the surface of Plasmodium falciparum-parasitized thalassemic red cells. Neoantigen expression was estimated by measurement of antibody bound after incubation in serum from adults living in a malaria-endemic area, using a quantitative radiometric antiglobulin assay. We found that P. falciparum-parasitized alpha- and beta-thalassemic red cells bind greater levels of antibody from endemic serum than controls: mean binding ratios (+/- SE), respectively, for alpha- and beta-thalassemia compared with controls were 1.69 +/- 0.12 and 1.23 +/- 0.06 on a cell for cell basis, and 1.97 +/- 0.11 and 1.47 +/- 0.08 after a correction for surface area differences. Binding of antibody increased exponentially during parasite maturation. In addition, we found a small but significant degree of binding of naturally occurring antibody to parasitized red cells, the extent of which was also greater in thalassemia. The apparent protective effect of thalassemia against malaria may be related to enhanced immune recognition and hence clearance of parasitized erythrocytes.

Animals↗
PubMed1991

Characterization of the breakpoint of a 3.5-kb deletion of the beta-globin gene.

The precise extent and breakpoints of a deletion of the beta-globin gene in a Thai patient have been determined using direct sequencing of a PCR product. This lesion is not detectable by current screening methods using PCR to analyze the beta-globin genes and is, therefore, a potential source of error in the diagnosis and prenatal detection of beta-thalassemia.

Base Sequence↗
PubMed1991

The spectrum of beta-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis.

The beta-thalassaemia mutations in 702 unrelated carriers originating from seven different regions of the Indian subcontinent have been characterized using allele specific priming of the polymerase chain reaction (PCR). It was possible to identify the mutations in 688 (98%) of the individuals studied. Eleven different mutations were identified, of which five common ones accounted for 93.6%; namely the ones at IVS-1 position 5 (G-C), codons 8/9 (+G), IVS-1 position 1 (G-T), codons 41/42 (-CTTT) and the 619 bp deletion at the 3' end of the gene. The mutations at IVS-2 position 1 (G-A) and codon 30 (G-C), previously undescribed in Asian Indians, were found in two and six individuals respectively. Some regional variation in the distribution of beta-thalassaemia alleles was noted. These findings should prove useful for the development of a first trimester prenatal diagnosis programme based on direct detection of mutations.

Alleles↗
PubMed1991

Rare beta-thalassaemia mutations in Asian indians.

Five beta-thalassaemia mutations hitherto undescribed in Asian Indians were identified in beta-thalassaemia carriers originating from the Indian subcontinent by direct sequencing of their beta-globin genes which were amplified by the polymerase chain reaction (PCR). A T-G substitution at IVS 2 position 837, which probably creates an alternative acceptor splice site and a T insertion in codon 88, resulting in a shift in the reading frame with a premature stop codon, are new beta-thalassaemia mutations. The others were framshift codon 5 (-CT), IVS 1 position 110 (G-A) and IVS-1 minus 1 (G-A) which have been described previously in other populations. These results complete the characterization of the beta-thalassaemia mutations in 708 carriers of Asian Indian origin and will enable a comprehensive programme of carrier screening and prenatal diagnosis of beta-thalassaemia in this population.

Alleles↗
PubMed1990

Rapid detection and prenatal diagnosis of beta-thalassaemia: studies in Indian and Cypriot populations in the UK.

The application of the amplification refractory mutation system (ARMS) to the detection of individual beta-thalassaemia mutations in heterozygous parents and "at risk" fetuses has been assessed in Indian and Cypriot immigrant populations in the UK. 100 first trimester prenatal diagnoses have been done, entailing the detection of 17 different mutations. The method, which allows the determination of the mutations in both parental and fetal DNA on the same day, should have wide application to the carrier detection and prenatal diagnosis of monogenic diseases with heterogeneous molecular defects.

Cyprus↗
PubMed1990

Molecular basis for dominantly inherited inclusion body beta-thalassemia.

Analysis of the molecular basis of dominantly inherited beta-thalassemia in four families has revealed different mutations involving exon 3 of the beta-globin gene. 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, in particular, whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation.

Amino Acid Sequence↗
PubMed1990

A chronic granulomatous syndrome of unknown origin.

A small clinically distinct group of patients with widespread tissue granulomata are described. The principal presenting symptoms are malaise, fever, and weight loss, although a wide variety of complaints are documented. Pulmonary involvement is uncommon. The granulomata are noncaseating with a few multinucleate giant cells and some surrounding chronic inflammatory infiltrate. There is no evidence of an associated arteritis. The disease has a relapsing and remitting course and although it may require treatment with immunosuppressive drugs, particularly if the kidneys are involved, the prognosis is relatively good. We propose that this entity be called granulomatous syndrome of unknown origin. The characteristics that set this syndrome apart from the other granulomatous vasculitides are discussed. The current limited understanding of granuloma formation does not allow us to propose a definite etiology for this condition. It is emphasized that it is not helpful to encompass it within a label of sarcoidosis. First, it may only serve to confuse the doctor in assessing and treating this very particular group of patients. Secondly, it may hinder future attempts to understand the different pathogenetic mechanisms underlying the various conditions in which granulomata may arise.

Adolescent↗
PubMed1990

Globin genes in Micronesia: origins and affinities of Pacific Island peoples.

DNA polymorphisms and copy-number variants of alpha-, zeta-, and gamma-globin genes have been studied in seven Micronesian island populations and have been compared with those in populations from Southeast Asia, Melanesia, and Polynesia. Micronesians are not significantly different from Polynesians at these loci and appear to be intermediate between Southeast Asians and Melanesians. There is evidence of significant Melanesian input into the Micronesian gene pool and of substantial proto-Polynesian contact with Melanesia.

Black People↗
PubMed1990

Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex.

We have identified five unrelated patients, all of north European origin, who have hemoglobin H (Hb H) disease and profound mental handicap. Surprisingly, detailed molecular analysis of the alpha globin complex is normal in these subjects. Clinically, they present with a rather uniform constellation of abnormalities, notably severe mental handicap, microcephaly, relative hypertelorism, unusual facies and genital anomalies. Hematologically, their Hb H disease has subtly but distinctly milder properties than the recognized Mendelian forms of the disease. These common features suggest that these five "nondeletion" patients have a similar underlying mutation, quite distinct from the 16p13.3 deletion associated with alpha thalassemia and mild to moderate mental retardation described in the accompanying paper. We speculate that the locus of this underlying mutation is not closely linked to the alpha globin complex and may encode a trans-acting factor involved in the normal regulation of alpha globin expression.

Adolescent↗