Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By using probes for epsilon-, Psibeta(1)-, and beta-globin genes, we found four additional polymorphic restriction sites that have frequencies >0.1 in persons of Mediterranean area origin, Asian Indians, and American Blacks. Three of these (HincII sites) and the two previously described polymorphic HindIII sites [one in intervening sequence (IVS) II of each gamma-globin gene] are distributed over 32 kilobases (kb) of DNA located 5' to the delta-globin gene. This region of DNA comprises two-thirds of the beta-globin gene cluster. Since each of these five polymorphic sites can be present (+) or absent (-), in theory there exist 32 possible combinations of sites (haplotypes). However, in Italians, Greeks, Indians, and Turks, 3 of the 32 haplotypes, (+----), (-+-++), and (-++-+), account for 92% of 89 beta(A) chromosomes examined. The observed frequencies for these haplotypes are 0.64, 0.15, and 0.13 in the populations studied, in contrast to expected frequencies (based on the observed gene frequencies at each of the five sites) of 0.20, 0.006, and 0.005, respectively. In American Blacks, a fourth haplotype, (----+), which is rare in non-Black populations, has a frequency of 0.37 in contrast to its expected frequency of 0.05. These results suggest a nonrandom association of DNA sequences over 32 kb 5' to the delta-globin gene in all populations studied. Two other polymorphic sites 3' to the delta gene (the newly discovered Ava II site in IVS II of the beta-globin gene and the BamHI site 3' to it) are nonrandomly associated with each other but randomly distributed with respect to the above haplotypes. This suggests that randomization of sequences has occurred within 12 kb of DNA between these two nonrandomly associated sequence clusters. Nonrandom association of polymorphic restriction sites has practical consequences in that it limits the usefulness of these additional HincII sites for prenatal diagnosis of hemoglobinopathies by linkage analysis. These sites provide little additional information for detection of beta-thalassemia, while the polymorphic Ava II site, which lies outside the nonrandomly associated sequences 5' to the delta gene, improves the test applicability from 52% to 70% of couples at risk.
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PMID:Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster. 627 83

Hemoglobin A2 levels in normal adults are rarely greater than 3.5%. In patients heterozygous for beta-thalassemia, they average about 5% but do not usually exceed 7%. We studied a family in which four patients with heterozygous beta-thalassemia had HbA2 levels of 8.4% to 11.2%. Globin biosynthesis studies and restriction endonuclease mapping of the alpha-globin loci showed homozygous or heterozygous alpha-thalassemia-2 as well as beta-thalassemia in some family members. The delta- and beta-globin genes were examined by using the restriction enzymes Eco RI, Pvu II, and Xba I, which cut both within and outside the coding portions of the delta- and beta-loci. Only the expected delta- and beta-globin gene containing fragments were present, excluding a crossover event producing a fusion gene that would code for delta-globin but possibly be under the regulatory influence of nucleotide sequences that control the expression of the beta-gene. This kindred provides evidence that in the presence of beta-thalassemia, expression of the delta-gene, beyond that commonly seen, is possible. This could be a direct result of the gene defect producing beta-thalassemia or be due to differences in the delta-globin gene linked to this beta-thalassemia gene. The interactions of alpha- and beta-thalassemia may alter tetramer assembly and increase HbA2 levels; however, this possibility seems less likely.
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PMID:Beta-thalassemia with exceptionally high hemoglobin A2. Differential expression of the delta-globin gene in the presence of beta-thalassemia. 628 19

The delta-globin genes of a normal Japanese and a Japanese patient with homozygous delta-thalassemia were cloned, and the nucleotide sequence of a region including the gene was determined. Comparison of the nucleotide sequences of these two individuals with that of pH delta 1, delta-globin clone from the gene library constructed by Maniatis et al., showed differences in the large intervening sequence (IVS 2), at positions 137, 151, 186, 188, 291, 292 and 540 as one base substitutions, at 339 and 823 as one base additions, at 548 as a one base deletion, and a 9 bp duplication between positions 651 and 659, and differences in the 3'-flanking sequence at 51 and 98 nucleotides 3' to the AATAAA sequence. However, in the region studied, no differences was observed in the nucleotide sequences of the normal subject and the patient with delta-thalassemia. Therefore, these differences may represent polymorphisms of the delta-globin gene present in Japanese individuals. These data suggest that IVS 2 is more divergent than other regions, and that a DNA region(s) other than the globin gene may affect expression of the gene.
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PMID:Structure of cloned delta-globin genes from a normal subject and a patient with delta-thalassemia; sequence polymorphisms found in the delta-globin gene region of Japanese individuals. 629 47

A unique beta 0-thalassaemia in a Dutch family results in fetal haemoglobin expression comparable to that of delta 0 beta 0-thalassaemia. Haemoglobin analysis and restriction endonuclease mapping studies of DNA suggest that the beta-globin gene is entirely deleted, but that the delta-globin gene is intact. The 5' break point of the deletion is 3-4 kilobases 3' to the delta-globin gene, while the 3' break point is 6-7 kilobases 3' to the beta-globin gene (relative to the normal DNA restriction map). The result is a approximately 10 kilobase deletion of DNA whose 3' end point may lie very close to that for one delta 0 beta 0-thalassaemia, within a cluster of Kpn I-family repetitive sequences. The Dutch beta 0-thalassaemia deletion is thus the shortest one which, in the absence of additional chromosomal rearrangements, results in enhancement of gamma-chain synthesis above that seen for haemoglobin Lepore. These data support the hypothesis that the region of DNA 3' to the beta-globin gene may be important to the developmental regulation of fetal gamma versus adult beta chain production.
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PMID:Dutch beta 0-thalassaemia: a 10 kilobase DNA deletion associated with significant gamma-chain production. 631 97

The synthesis of delta-globin is directed by a gene whose inherent characteristics permit only limited expression, a gene resembling in some respects that of beta +-thalassemia. The existence of delta O-thalassemia and the presence of delta-globin genes in this condition recall the molecular findings in most types of beta O-thalassemia. The delta-globin and beta +-thalassemia genes may be evolving pseudogenes. Those for delta O and beta O-thalassemia are, in functional sense, already pseudogenes in that they closely resemble functional genes but lack a discernible protein product. In time they should accumulate sufficient changes in their nucleotide sequences which will make them more analagous to what we now recognize as pseudogenes. the selective pressure of Falciparum malaria infection may help maintain the beta-thalassemia "pseudogene" in many populations.
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PMID:beta-thalassemia-? Selected pseudogenes. 682 Jan 19

A novel deletion in the human beta-globin gene cluster associated with increased levels of fetal hemoglobin (HbF) in adult life was molecularly characterized in a member of a family of Eastern European descent. The phenotype of the deletion, documented in five members of the family, shows mild hypochromia and microcytosis (mean corpuscular Hb, 24 to 25.9 pg; mean corpuscular volume, 74 to 78.5 fL) but high production of HbF (13% to 24%) with heterocellular distribution (36% to 86% F cells). Extensive restriction enzyme mapping of the beta-globin cluster and sequencing of the region encompassing the breakpoints showed that the deletion starts 1,612 bp upstream of the cap site of the delta-globin gene, and terminates within the first intron of the beta-globin gene, deleting 9.1 kb of DNA. This length is definitely shorter than the average 12.0 kb of the previously characterized (delta beta) zero-thalassemias. The 5' breakpoint of the new deletion is close to that of the Yugoslavian delta beta-thalassemia deletion, whereas the 3' breakpoint is very close to those of the Turkish and the Greek beta zero-thalassemia deletions. The breakpoints of the deletion occur within a direct repeat containing a tetranucleotide exhibiting homology to a donor-splice site, and is symmetrically flanked by a set of 13- and 14-bp homologous complementary sequences, respectively. It is likely that the deletion may be the result of an "illegitimate" or "nonhomologous" recombination event to which these two short sequences may have contributed. It is of interest that the novel deletion (9.1 kb) is comparable to the Italian HPFH-5 deletion (12.9 kb), regarding both the size and the position of the breakpoints. However, the HPFH-5 deletion includes sequences flanking the breakpoints that are preserved in the new deletion. Considering the resulting two discrete phenotypes (ie, delta beta-thalassemia v HPFH), it can be hypothesized that the deleted sequences in the Italian HPFH-5 mutation may harbor regulatory elements that exert a negative control on the gamma-globin gene expression.
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PMID:Eastern European (delta beta) zero-thalassemia: molecular characterization of a novel 9.1-kb deletion resulting in high levels of fetal hemoglobin in the adult. 784 5

This chapter reviews general aspects of the normal human haemoglobins which include those predominantly present in the embryo, the fetus and newborn baby, and in the normal adult. Special emphasis is given to factors which affect the levels of fetal haemoglobin in the adult because increased percentages of Hb F can be of great benefit to adults with certain haemoglobinopathies such as sickle cell anaemia and beta-thalassaemia. A review of the numerous Hb variants published since the discovery of Hb S in 1959 reveals a steady stream of newly detected abnormalities; most of these are the result of single-point mutations in the alpha-, beta-, gamma-, or delta-globin genes. Of the more than 600 variants listed in a repository, some 200 have clinical significance because of a decreased stability, a change in functional properties, among others. Methodology developed for the detection and quantitation of normal and abnormal Hb components has been greatly modified during the past 30 years; isoelectrofocusing and different fast developing micro chromatographic procedures are the methods of choice. Analyses of DNA isolated from the white cells has become most useful for the final characterization of the variants; this methodology consists of amplification of a desired segment of DNA and identification of a mutation with labelled oligonucleotide probes. Additional methods include sequence determination of this amplified DNA and identification of known mutations with an allele specific amplification procedure.
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PMID:The structure and function of normal and abnormal haemoglobins. 768 97

We describe an African-American child with beta-thalassemia intermedia. Molecular studies revealed that the proband is a compound heterozygote for the -29 (A-->G) beta (+)-thalassemia mutation and an extensive deletion involving the delta- and beta-globin genes. The proband's mother is a simple carrier of the deletion and exhibits the phenotype of delta beta-thalassemia rather than hereditary persistence of fetal hemoglobin. The deletion spans 11,767 bp, with the 5' deletion endpoint located 2,455 bp upstream of the delta-globin gene mRNA Cap site and the 3' endpoint located 441 bp downstream of the termination codon of the beta-globin gene. Based on this information, we have developed a polymerase chain reaction strategy for the rapid detection of this delta beta-thalassemia deletion.
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PMID:Delta beta-thalassemia in an African-American: identification of the deletion endpoints and PCR-based diagnosis. 771 43

In a 2.5-month-old infant with beta-thalassaemia major, DNA analysis of the gamma-beta region revealed homozygosity for two large deletions removing the entire psi beta and beta regions including their 5' promoter regions but leaving the delta gene intact. The downstream deletion was predicted to be 7.6 kb in length extending from a point 1.5 kb on the 3' side of the delta-globin gene to about 1.8 kb on the 3' side of the beta-globin gene. The upstream deletion, which was also about 7.6 kb, extended from a point 1.5 kb on the 5' side of the psi beta-globin gene to about 4.5 kb on the 3' of the psi beta gene. The delta-globin gene was intact. From the phenotypic expression of the disease it is concluded that removal of the psi beta gene probably prevents derepression of the gamma gene that has previously been observed in the absence of the promoter region of the beta gene and the switch mechanism from gamma to beta gene expression may take place earlier than expected.
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PMID:A new Turkish type of beta-thalassaemia major with homozygosity for two non-consecutive 7.6 kb deletions of the psi beta and beta genes and an intact delta gene. 787 80

In this paper we have reviewed the social and technical aspects of carrier screening and prenatal diagnosis of the inherited haemoglobinopathies. The characteristics of programmes based on carrier screening and prenatal diagnosis ongoing in a number of at-risk Mediterranean populations have been described. The most relevant and common aspects of these programmes are the continuous educational campaign directed to the population at large, the voluntary basis and non-directive counselling. The target population has been most commonly couples before or after marriage. The vast majority of couples counselled accepted prenatal diagnosis. All programmes have encountered a high degree of success as indicated by the marked reduction in the birth rate of infants with thalassaemia major. No significant adverse effects have been reported. A programme with similar characteristics and for which the preliminary results are encouraging, is operating for sickle cell anaemia in the Cuban population. In a population with high frequency of hydrops fetalis, screening for deletion alpha-thalassaemia is recommended to prevent the negative effects on a pregnant woman of the presence of an hydropic fetus. Thalassaemia carrier screening is now carried out by automatic red cell indices and HbA2 determination. Definition of atypical cases may require iron studies, globin chain synthesis determination and/or alpha, beta- and delta-globin gene analysis. Identification of the carrier state is followed by definition of the mutation on enzymatically amplified DNA. Known mutations may be detected by restriction endonuclease analysis, non-denaturing polyacrylamide gel electrophoresis, allele-specific primers or allele-specific probes. The most promising procedures, which are also amenable to complete automation are reverse oligonucleotide hybridization and primer-specific amplification. Unknown mutations are defined by denaturing gradient gel electrophoresis, single-strand conformation polymorphism analysis, and chemical mismatch cleavage analysis followed by direct sequencing. The same methods on enzymatically amplified chorionic villus DNA are used for prenatal diagnosis. The potential pitfall resulting from maternal contamination can be avoided by careful dissection of the maternal decidua from the chorion and by the simultaneous amplification of a suitable polymorphism.
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PMID:Screening and prenatal diagnosis of the haemoglobinopathies. 839 56


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