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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemoglobin (Hb) Constant Spring is an alpha-thalassemic hemoglobinopathy that is a major cause of severe alpha-thalassemia in Southeast Asians. The difficulty of diagnosing Hb Constant Spring using standard electrophoretic methods has led to interest in DNA-dependent diagnostic methods. The methods developed have had to contend with the high degree of homology of the alpha 2-globin gene (the site of the Hb Constant Spring mutation) and the alpha 1-globin gene. We have developed a single reaction polymerase chain reaction-based method that uses asymmetric priming and a temperature shift to accomplish dual ends, selective amplification of alpha 2 but not alpha 1 DNA and discrimination of normal and Hb Constant Spring alpha 2 genes by allele-specific fluorescence polymerase chain reaction. Advantages of this method over previous approaches include avoiding radioisotopes, precluding the need for electrophoresis, and serving as its own control for successful amplification. It is readily applicable to routine diagnosis, population screening, and prenatal diagnosis.
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PMID:Asymmetrically primed selective amplification/temperature shift fluorescence polymerase chain reaction to detect the hemoglobin Constant Spring mutation. 171 43

During the past 15 years there have been remarkable advances in our understanding of the molecular biology of hemoglobin synthesis and the abnormalities in hemoglobinopathies and thalassemia. The globin genes were among the first mammalian structural genes that were cloned and the DNA sequence of the human globin gene clusters has since been completely delineated. During the last ten years, we have also learned of the many deletions and point mutations that give rise to hemoglobin-opathies and thalassemia. In addition, the sequences that control erythroid specific expression of the globin gene has also been revealed. These findings have contributed to our understanding of the pathophysiology of the diseases and have allowed the institution of accurate DNA diagnostic methods to be applied to prenatal diagnosis. As increased fetal hemoglobin synthesis is known to ameliorate the severity of the disease in disorders such as sickle cell anemia and thalassemia, agents which increase the level of fetal hemoglobin synthesis are being tested. Also, the discovery of DNA sequences and transacting factors which are responsible for high erythroid globin gene expression [4] may provide more effective means of gene therapy.
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PMID:Molecular biology of hemoglobin: its application to sickle cell anemia and thalassemia. 172 57

Prior to recent advances in the field of molecular biology, prenatal diagnosis of hemoglobinopathies was accomplished by direct analysis of the gene product(s) in samples obtained by fetoscopy or, more recently, percutaneous umbilical blood sampling. The use of the polymerase chain reaction enables quicker diagnosis than with indirect or cumbersome Southern blot techniques. This case, reporting a couple at risk for fetal sickle cell disease, is a model for rapid prenatal diagnosis and demonstrates the capabilities which exist in the military health care referral system. Within 24 hours of a couple's presentation for consultation and accomplishment of chorionic villus sampling (CVS), preliminary results of both cytogenetic and sickle cell status of an at-risk fetus were determined. Final analysis was accomplished by 48 hours. The combination of early referral, early sampling by CVS, and application of advances in DNA laboratory technologies offers tremendous improvements for care heretofore unavailable as a complete "package" in the military. The implications and limitations for prenatal testing for single gene disorders within the military medical health care system will be discussed.
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PMID:Molecular analysis and chorionic villus sampling (CVS): opportunities for rapid prenatal diagnosis in the military. 178 70

This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari, from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis, thalassemia-like bone changes, iron overload, high proportion of Hb F in the peripheral blood, reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes, and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents, even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation, thus making the proper diagnosis.
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PMID:Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy. 198 2

During a 10-month period, 10 couples originating from Africa (3), the tropics (1) and the thalassemia-belt region (6), living in Switzerland, requested prenatal diagnosis of hemoglobinopathies. Hb SS (twice), Hb Bart's (Hydrops fetalis) and beta-thalassemia major were diagnosed either by gene mapping or by direct detection of the mutations in DNA amplified by the PCR procedure. Whenever it was possible to obtain fetal blood or tissue, diagnosis was confirmed. In one Vietnamese man, concomitant existence of alpha-thal 1 with beta-thalassemia resulted in an unusually high Hb level because of balanced alpha and beta globin synthesis. The 10 couples examined originated from 7 different countries and presented at least 7 different Hb pathologies. This variety of pathologies represents the main difficulty for prenatal diagnosis of hemoglobinopathies in a non-endemic country. A diagnostic approach to overcome this problem is developed.
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PMID:Prenatal diagnosis of thalassemia and hemoglobinopathies in Switzerland. 200 49

Over the past 20 years we have studied 1781 patients with beta-thalassemia syndromes of which 1481 Yugoslav, 166 Bulgarian, 102 Turkish and 32 Albanian. In this paper we summarize the data on the heterogeneity and molecular basis of beta-thal, delta beta-thal and Lepore hemoglobinopathy in these four nationalities living in Yugoslavia and Bulgaria. Beta-thalassemia is the most frequent form of thalassemia in all four nationalities. At the phenotypic level 9 different forms were detected, while at the genotypic level 17 different mutations were characterized. DNA analysis of 377 beta-thal chromosomes showed that in Yugoslav 5 mutations (IVS I#110, IVS I#6, IVS I#1, Codon #39 and Poly A (A----G)) account for 83% of the beta-thal genes, while in Bulgarian 6 mutations (IVS I#110, Codon #39, IVS II#6, IVS II#745, Codon #8 and Codon #8/9) account for 76% of the beta-thal genes. In Turkish the most common mutation is IVS I#110, followed by IVS I#6, IVS II#1 and Codon #8, while in Albanian IVS I#110, Codon #39 and IVS I#6 are prevalent. Delta beta-thalassemia is the second most common form of thal in Yugoslav (10.8%) and Bulgarian (4.2%) but not in Turkish and Albanian. At the phenotypic level 6 different forms were detected, while at the molecular level 3 different deletions (approximately 15 kb, approximately 23 kb, and approximately 148 kb) were characterized. Hb Lepore is the third most common hemoglobinopathy among Yugoslav (9.6%) and most probably Bulgarian (3.67%). This condition was observed in homozygous (n 7) and heterozygous (n 124) state, and in association with beta zero-thal (n 5), beta(+)-thal (n 11), (delta beta)zero-thal (n 1), and Hb Beograd (n 1). Haplotype analysis of 29 lepore chromosomes from 9 unrelated families showed that Hb Lepore is associated with haplotype V.
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PMID:Beta-, delta beta-thalassemia and Hb lepore among Yugoslav, Bulgarian, Turkish and Albanian. 208 80

DNA isolation and Southern Blot analysis are two of the many techniques currently being used routinely by molecular biologists to discover genetic defects that affect human health. Together these two techniques have greatly aided in the growing knowledge of genetics on a molecular level. Southern blotting can be used to discern genetic deletions, alterations, or amplifications that are not detectable by cytogenetic methods. Several examples of the clinical applications of these methods are discussed in Table 4. Southern analysis has been recently used: (1) to facilitate prenatal diagnosis of sickle cell hemoglobinopathies, (2) to demonstrate human papillomavirus DNA integration in the genome of cervical cancer cells and (3) to demonstrate that oncogene amplification in the tumors of patients with node positive breast cancer correlates inversely with prognosis. Each of these examples not only have diagnostic value for patient care but also may help begin to understand the very basis of the disease processes themselves.
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PMID:DNA isolation and Southern analysis: a clinician's view. 215 12

With the goal of using adeno-associated viruses (AAV) as the gene-transfer vector for gene therapy of hemoglobinopathies, human beta-globin cDNA was ligated downstream from the P40 promoter of the AAV type-2 (AAV2) genome. To circumvent difficulties of cloning DNA containing palindromic sequences, two of which exist in the termini of AAV genome, a step-wise approach handling one palindrome at a time was devised to construct the chimeric expression vector. Electroporation of the construct into human 293 cells (embryonal kidney cell line) resulted in expression of the cloned human beta-globin cDNA, as evidenced by the synthesis of transcripts hybridizable to human beta-globin cDNA probe. Addition of the 3'-end region of AAV DNA that contains both the transcription termination signal and origin of DNA replication for AAV to the construct permitted the recombinant AAV genome to be rescued and replicate in the cell.
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PMID:Construction and replication of an adeno-associated virus expression vector that contains human beta-globin cDNA. 216 23

The polymerase chain reaction (PCR) is a newly developed molecular biology technique that can significantly amplify DNA or RNA. The process consists of repetitive cycles of specific DNA synthesis, defined by short stretches of preselected DNA. With each cycle, there is a doubling of the final, desired DNA product such that a million-fold amplification is possible. This powerful method has numerous applications in diagnostic pathology, especially in the fields of microbiology, forensic science, and hematology. The PCR may be used to directly detect viral DNA, which may facilitate the diagnosis of acquired immune deficiency syndrome (AIDS) or other viral diseases. PCR amplification of DNA allows detection of specific sequences from extremely small samples, such as with forensic material. In hematology, PCR may help in the diagnosis of hemoglobinopathies or of neoplastic disorders by documenting chromosomal translocations. The new PCR opens exciting new avenues for diagnostic pathology using this new technology.
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PMID:Theory and applications of the polymerase chain reaction. 218 Feb 80

A region of DNA located far upstream of the human beta-globin locus is critically involved in the regulation of the beta-globin gene family. Recent experiments in transgenic mice suggest that switching from fetal to adult globin gene expression during human development results from competition among individual globin gene family members for interaction with sequences in this region. The phenotypes of patients with defined hemoglobinopathies support this hypothesis.
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PMID:Human globin locus activation region (LAR): role in temporal control. 220 10


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