Major rearrangement in the human beta-globin gene cluster.
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Chromosome Deletion↗
Biomedical subjects
J B Clegg
Publications and source records attributed to J B Clegg.
Molecular basis for mild forms of homozygous beta-thalassaemia.
Five Cypriots homozygous for beta +-thalassaemia have inherited deletion or non-deletion forms of alpha-thalassaemia that seem to have modified the usually severe clinical picture to that of mild thalassaemia intermedia. These observations have important implications for the antenatal diagnosis of beta-thalassaemia.
Adolescent↗
Screening procedures for quantitative abnormalities in hemoglobin synthesis.
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Clinical Laboratory Techniques↗
Embryonic erythroid differentiation in the human leukemic cell line K562.
K562 human leukemia cells synthesize embryonic hemoglobins after culture in the presence of hemin. We have rigorously identified these hemoglobins by globin chain analysis and peptide mapping. No adult hemoglobin could be detected, and beta-globin synthesis was less than 2 ppm of total protein synthesis. Persistent embryonic globin gene expression is known to occur as a consequence of globin gene deletions. However, restriction endonuclease mapping showed that the globin gene complexes in K562 cells are indistinguishable from normal. Hemin increased the rate of embryonic globin synthesis. The pattern of hemoglobin synthesis proved to be stable when cells from different laboratories were compared. One line, however, synthesized large amounts of Hb X and very little Hb Portland in response to hemin. Hb X has been previously detected in human embryos; we show here that it has the composition epsilon 2 gamma 2 and is diagnostic of imbalanced chain synthesis or "zeta thalassemia." We have identified several agents that induce hemoglobin synthesis in K562 cells. Different inducers induced different patterns of embryonic hemoglobin synthesis but never any adult hemoglobin synthesis.
Cell Differentiation↗
Structure of the zeta chain of human embryonic hemoglobin.
The complete amino acid sequence of the zeta chain of human embryonic hemoglobin has been determined. It differs from human alpha globin at 57 of the 141 residues and several of the replacements are at positions of structural or functional importance, particularly in relationship to the Bohr effect and high intrinsic oxygen affinity which are characteristic of embryonic hemoglobins. The zeta-globin sequence is more closely related to other mammalian embryonic alpha-like globins than to human alpha, suggesting that there have been strong selective pressures to maintain these embryo-specific globins since their emergence several hundred million years ago.
Amino Acid Sequence↗
Genetic and molecular diversity in nondeletion Hb H disease.
Restriction endonuclease mapping of nondeletion alpha-thalassemia determinants from a variety of racial groups showed no detectable abnormalities within a 40-kilobase region of the zeta-alpha globin gene cluster. By using a zeta-specific probe, we defined three different types of interactions that give rise to Hb H disease, each involving a nondeletion alpha-thalassemia haplotype. mRNA analysis showed further diversity within these groups, indicating that there are at least three nondeletion determinations.
Chromosome Deletion↗
The genetics and molecular basis of alpha thalassaemia in association with Hb S in Jamaican Negroes.
We have studied seven Jamaican Negro families in whom the genes for alpha thalassaemia and the sickle cell mutation (betas) were independently segregated. Using a combination of techniques we identified two alpha thalassaemia phenotypes which resemble the severe (alpha thalassaemia 1) and mild (alpha thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of alpha thalassaemia with the genotype in this population. Furthermore, since in each family alpha thalassaemia was present in association with the gene for the sickle cell mutation we have determined the proportion of Hb S in the peripheral blood of individuals with the alpha alpha/alpha alpha, -alpha/alpha alpha and -alpha/-alpha genotype who are also heterozygous for the betas mutation. Genetic analysis in these families shows that in each case subjects with the alpha thalassaemia 1 phenotype are homozygous for the alpha thalassaemia 2 defect (-alpha/-alpha). We have found no instances of the genotype --/alpha alpha in this population which may explain the rarity of the severe alpha thalassaemia syndromes in Jamaica. Restriction mapping data in the alpha thalassaemia 2 homozygotes from this population shows that the (-alpha/) haplotype results from a deletion of one of the linked pair of alpha globin genes and that this has probably arisen by an unequal crossover between non-homologous alpha genes.
Black People↗
The molecular basis for the haemoglobin Bart's hydrops fetalis syndrome in Cyprus.
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Chromosome Aberrations↗
A new triplicated alpha-globin gene arrangement in man.
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Chromosome Deletion↗
The molecular basis of hemoglobin Grady.
DNA from individuals heterozygous for the extended alpha-chain variant Hb Grady were studied by gene counting and restriction enzyme analysis. Neither method indicated the presence of an extra (fifth) alpha gene, which argues that if this variant arose by unequal crossing over, the event most likely involved mispairing between alleles rather than between the separate alpha 1 and alpha 2 loci.
Chromosome Mapping↗
A new genetic basis for hemoglobin-H disease.
We studied 11 families with alpha-thalassemia from the Qatif population of eastern Saudi Arabia to determine the genetic and molecular basis of hemoglobin-H disease, which is being encountered in this area with increasing frequency. The results show that there are two common alpha-thalassemia haplotypes, a deletion (-alpha/) determinant and a nondeletion (alpha alpha T/) determinant, which interact to produce a series of overlapping phenotypes. The most severe, hemoglobin-H disease, results from the homozygous state for the nondeletion determinant--a pattern of inheritance not previously recognized for this condition. Its molecular and genetic properties are thus different from those that produce the condition in Oriental or Mediterranean populations.
Child↗
Defective synthesis of HbE is due to reduced levels of beta E mRNA.
Haemoglobin E (alpha 2 beta 2(26)Glu leads to Lys) is one of the commonest haemoglobin variants. There are an estimated 30 million carriers of the beta E gene in South-East Asia, where they comprise more than 50% of the population in some areas; however, the reasons for this high frequency have never been adequately explained. Homozygotes for HbE may be midly anaemic, but they do not have any clinical disability. However, individuals heterozygous for both beta E and beta thalassaemia (HbE/beta thalassaemia) have a severe clinical disorder which in some cases may approach that seen in homozygous beta thalassaemia and which is by far the commonest form of symptomatic thalassaemia in the Indian subcontinent and South-East Asia. Haemoglobin E is the only common structural variant which interacts with beta thalassaemia to produce a severe disorder and the underlying mechanism of the interaction is not known. We have studied several homozygotes and heterozygotes for HbE and show here that the beta E chain is inefficiently synthesized and produces the phenotype of a mild form of beta thalassaemia; hence, when inherited together with beta thalassaemia it causes a marked beta-chain deficit. Furthermore, the mechanism for the defective production of beta E chains seems to be a reduction of beta E mRNA, a most unexpected finding in a disorder caused by a single amino acid substitution and presumably by a single nucleotide change in the DNA of the beta globin gene.
Globins↗
Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex.
A new deletion causing alpha thalassemia has been characterised in a Greek family. Detailed mapping of the alpha gene complex shows that the deletion extends for 5.2 kb and removes the whole of the alpha 2 gene and the 5' end of the alpha 1 gene. The affected chromosome, therefore produces no normal alpha chains and results in a phenotype of alpha thalassemia 1.
Chromosome Deletion↗
Haemoglobin Bart's hydrops syndrome in Greece.
A case of haemoglobin Bart's hydrops syndrome was characterised in a Greek family with a history of three other fetuses with hydrops. Family studies showed that both the mother and father carried alpha-thalassaemia genes, and globin-chain synthesis analysis of the present fetus showed a total absence of alpha-chain production. The haemoglobin composition of the fetus was similar to that seen in cases in south-east Asia, and analysis of DNA from the Greek case confirmed the total deletion of the alpha-chain genes. The extent of the deletion, however, differed from that seen in south-east Asian cases and included the loss of one of the embryonic zeta-chain genes. Thus the severe form of alpha-thalassaemia occurs in Greece but has arisen independently from the similar condition in south-east Asia. The condition must be considered in any woman of this racial background who gives a history of unexplained stillbirths.
Adult↗
A novel alpha-globin gene arrangement in man.
The human genome has two linked alpha-globin genes on chromosome 16. Deletion of one or more of them, as occurs in alpha-thalassaemia, leads to a reduced output of alpha-globin mRNA in proportion to the number of alpha-globin genes lost. In some racial groups deletion of one of the pair of alpha-globin genes may result from unequal crossing over between the genes on homologous chromosomes by a mechanism resembling that postulated for the formation of the delta beta fusion genes of the Lepore haemoglobins. By analogy, the opposite chromosome in this cross-over should have three alpha-globin genes just as the 'anti-Lepore chromosome has three non-alpha chain genes. We describe here a Welsh family in which three members have five alpha-globn increased alpha mRNA output and it may therefore produce the phenotype of mild beta-thalassaemia.
DNA Restriction Enzymes↗
Gene deletions in alpha thalassemia prove that the 5' zeta locus is functional.
The deletions in the zeta-alpha globin gene cluster in two infants with the hemoglobin Bart's hydrops fetalis syndrome (homozygous alpha thalassemia 1) have been mapped by restriction endonuclease analysis using a zeta-specific probe. DNA from a Thai infant lacked the psi alpha 1 gene and both alpha genes, but the zeta genes were present. A Greek infant's DNA had also lost the 3' zeta 1 gene. Because zeta globin was synthesized in the infant's cord blood, this indicates that the 5' zeta 2 gene recently identified by Lauer et al. [Lauer, J., Shen, C. J. & Maniatis, T. (1980) Cell, in press] must be functional.
Chromosome Deletion↗
Determination of alpha thalassaemia phenotypes by messenger RNA analysis.
The possibility of using alpha/beta globin messenger RNA (mRNA) ratios to distinguish between the carrier states for different forms of alpha thalassaemia has been explored. Alpha/beta globin mRNA ratios were determined in the red cells of a series of normal individuals and in members of four Cypriot families, one Thai and one Chinese family in which at least one person has haemoglobin H disease. It was found that there was a clear distinction in the ratios between normals, alpha thalassaemia 1 carriers, alpha thalassaemia 2 carriers, and those with haemoglobin H disease. This method should be a valuable addition to haematological analysis, haemoglobin synthesis and restriction mapping of DNA for the further elucidation of the genetics of alpha thalassaemia.
DNA↗
Detection of alpha thalassaemia in Negro infants.
A prospective study of 2191 Negro infants in Jamaica showed that approximately 7% of them had detectable levels of Hb Bart's (gamma 4) in the neonatal period. The red cell indices, globin chain biosynthesis and restriction endonuclease mapping of DNA from these infants were used to determine the significance of Hb Bart's at birth. The results indicate that the genotypes alpha alpha/alpha alpha, -- alpha/alpha alpha and -- alpha/ -- alpha are associated with 0%, 0.1-2%, and greater than 2% Hb Bart's respectively. Although trace amounts of Hb Bart's may be associated with the genotype -- alpha/alpha alpha this is not always the case and therefore haemoglobin analysis in the neonatal period cannot be used to diagnose this genotype with any certainty.
Black People↗