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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified and characterized a Scottish individual with alpha thalassaemia, resulting from a de novo 48 kilobase (kb) deletion from the telomeric flanking region of the alpha globin cluster which occurred as a result of recombination between two misaligned repetitive elements that normally lie approximately 83 kb and 131 kb from the 16p telomere. The deletion removes two previously described putative regulatory elements (HS-40 and HS-33) but leaves two other elements (HS-10 and HS-8) intact. Analysis of this deletion, together with eight other published deletions of the telomeric region, showed that they all severely downregulated alpha globin expression. Together they defined a 20.4-kb region of the human alpha cluster, which contains all of the positive cis-acting elements required to regulate alpha globin expression. Comparative analysis of this region with the corresponding segment of the mouse alpha globin cluster demonstrated conserved non-coding sequences corresponding to the putative regulatory elements HS-40 and HS-33. Although the role of HS-40 as an enhancer of alpha globin expression is fully established, these observations suggest that the role of HS-33 and other sequences in this region should be more fully investigated in the context of the natural human and mouse alpha globin loci.
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PMID:De novo deletion within the telomeric region flanking the human alpha globin locus as a cause of alpha thalassaemia. 1261 24

There is a high prevalence of thalassemia in the South of China. To explore the genotype of alpha-thalassemia as well as the distribution of alpha globin gene mutation in the South of China, 356 patients with heterozygote alpha(+) thalassemia, heterozygote alpha(0) or homozygote alpha(+) thalassemia and 78 patients with HbH were analyzed. The gene diagnosis methods including Gap-PCR, nested-PCR, PCR-RE, PCR-SSCP, 4P-ASPCR and DNA sequence analysis were used. The results showed that among 356 patients, 295 patients with --SEA/alphaalpha (82.87%), 1 patient with alphaalpha/alpha-alpha(3.7) (0.28%), 3 patients with alphaalpha/alpha-alpha(4.2) (0.84%), 3 patients with alphaalpha/alpha(CS)alpha (0.84%), 1 patient with alphaalpha/alphaalpha(QS) (0.28%) and 2 patients with alphaalpha/alpha(Westmead) alpha (0.56%) were found. The homozygote with -alpha(4.2) or -alpha(3.7) was not found. In 78 patients with HbH, 29 patients with --SEA/alphaalpha(-3.7) (37.2%), 20 patients with --SEA/alphaalpha(-4.2) (25.6%), 19 patients with --SEA/alphaalpha(CS) (24.3%), 2 patients with --SEA/alphaalpha(QS) (2.6%) were detected, and other remaiming 8 patients were needed to be defined. Among the non-defined 8 patients, the synonymous mutation with C-->G transversion (GCC-GCG) at codon 65 in the exon 2 of alpha 2-globin gene was detected in 2 unrelated HbH patients came from Guangxi province. Whether it correlated with the phenotype of HbH disease or it is only a single nucleotide polymorphism site (SNPs), should be confirmed in the future. In addition, a set of gene diagnosis methods based on PCR to screen deletion and non-deletion genotypes of alpha-thalassemia in Chinese was improved. A new method, 4P-ASPCR, to detect Hb CS and Hb QS was also developed. The method was verified to be more accurate, time-saving and economic. In conclusion, the genotypes of alpha-thalassemia in Chinese are very complicated, the genotypes of alpha-thalassemia in Chinese need to be further studied, the results of this research probably have practical significance for the gene diagnosis or antenatal diagnosis of alpha-thalassemia in the South of China.
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PMID:[Study on gene mutations of alpha-thalassemia in the South of China]. 1266 91

We describe a family of Italian origin in which the father and his two children had hypochromia and microcytosis with normal iron status. All individuals underwent an uneventful clinical course and required no treatment. To investigate the molecular basis of this phenotype, which is a prerequisite for further genetic counselling, we revealed that all affected family members are carriers of a common form of alpha+ thalassaemia resulting from the deletion of 3.7 kb of the alpha-globin cluster (alphaalpha/-alpha3.7). However, this genotype alone could not account for the phenotype presenting in this family. Further characterization of the alpha-globin genes demonstrated an additional AC deletion in the vicinity of the initiation codon of the -alpha3.7 allele. This secondary mutation causes an additional impaired translation of the affected allele producing increased globin chain imbalance. This leads to a more severe phenotype, as heterozygotes for such mutation (alphaalpha/-alphaT) have hypochromic microcytosis and abnormal globin chain synthesis that mimic alpha0 thalassaemia trait (--/alphaalpha). Accurate genotyping of alpha globin determinant is absolutely required as there is a possibility that an interaction of this unusual double mutation with other common alpha0 thalassaemias (--/-alphaT) can give rise to a very severe, probably fatal, alpha thalassaemia.
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PMID:Dinucleotide deletion in -alpha3.7 allele causes a severe form of alpha+ thalassaemia. 1289 Jan 55

Hb H disease is generally associated with moderate to severe anemia but rarely requires regular blood transfusion. We recently studied two apparently unrelated patients with transfusion-dependent Hb H disease. Hemoglobin studies demonstrated Hb H and Hb Bart's without other detectable abnormal globin species. Extensive molecular analyses of the alpha globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for alpha0 thalassemia (--(SEA)) and a novel point mutation, a thymidine insertion after codon 131 of the alpha1 gene. The resulting frameshift gives rise to a highly unstable alpha globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual alpha1 globin variant clearly causes alpha thalassemia, but the unexpectedly severe phenotype suggests that this mutation may have additional effects on red cell physiology. A PCR-based (ARMS) assay was developed for rapid detection of this novel mutation, and this might be useful to study the prevalence of this novel mutation which poses potentially significant clinical consequences in populations of Southeast Asia. Detecting carriers of this mutation using the molecular diagnostic procedures described will provide the means to screen and prevent a potentially severe form of alpha thalassemia in Thailand.
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PMID:Co-inheritance of Hb Pak Num Po, a novel alpha1 gene mutation, and alpha0 thalassemia associated with transfusion-dependent Hb H disease. 1497 97

The coinheritance of beta-thalassemia major with the genotype of Hb H disease is extremely rare, with few reported cases. We investigated the hematological, biochemical, biosynthetic, molecular and pathophysiological parameters to evaluate a rare male patient with this compound syndrome. The patient was studied at first diagnosis during hospitalization at 50 years of age and subsequently followed up for more than a year. Examinations included full hematological, biochemical, biosynthetic, molecular, pathophysiological and clinical parameters. Besides standard parameters, we additionally measured reticulocyte hemoglobin content (CHr), erythropoietin (Epo), soluble transferrin receptors (sTfR), oxygen pressure at 50% hemoglobin saturation (P50), 2,3-bisphosphoglycerate (2,3-BPG), total glutathione (GSHt), oxidized glutathione (GSSG), malonyldialdehyde (MDA), nontransferrin-bound iron (NTBI), vitamins A and E. The male patient was first hospitalized for a 2-day period at 50 years of age, following the finding of marked anemia (hematocrit 20%) during a blood test to investigate the cause of fatigue in the absence of weight-loss or other notable symptomatology. He had never been transfused, maintaining Hb 85-95 g/l. Definitive diagnosis was achieved through DNA studies, which showed coexistence of beta-thalassemia major (IVSI-6 T > C/IVSI-I G > A) with Hb H disease (-alpha(3.7)/-(Med)). Alpha/non-alpha globin chain biosynthesis was completely balanced. Parameters demonstrated a well-compensated anemia with ineffective erythropoiesis and oxidative stress, which was ameliorated following splenectomy. In conclusion, this case is a remarkable example that the coinheritance of severe forms of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to almost complete balance the symptoms of classic thalassemia syndromes.
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PMID:A rare example that coinheritance of a severe form of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to balance the phenotype of classic thalassemic syndromes. 1500 25

Thalassemias are a group of genetic hemolytic disorders with varying phenotypes. In this study, the frequency of alpha globin gene deletions was studied in the beta-thalassemia trait, the mildest form of the disorder. Eleven out of 33 (33%) individuals were positive for alpha(-3.7 kb) deletions. None of the subjects was positive for the Southeast Asian deletion. Such a high frequency for alpha deletions has not been reported earlier in thalassemia minor. Hematological parameters are compared, and implications of this finding for genetic counseling are discussed.
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PMID:High frequency of deletional alpha-thalassemia in beta-thalassemia trait: implications for genetic counseling. 1522 73

A simple and an efficient oligonucleotide array was developed to identify common severe determinants of alpha (alpha) thalassemia. A total of 14 probes were designed to detect the most frequently three deletions (-alpha(3.7), -alpha(4.2), -(SEA)) and two non-deletions (alpha(Quong Sze), alpha(Constant Spring)). PCR products were amplified from human genomic DNA and allowed to hybridize with the oligonucleotide array. Hybridization was detected by fluorescence scanning, and alpha globin genotypes were assigned by quantitative analysis of the hybridization results. The efficiency and specificity of identifying alpha globin genotypes using the oligonucleotide arrays was evaluated by blinded analysis of 690 samples from unrelated individuals. The oligonucleotide array method described in this paper provides unambiguous detection of complex combinations of heterozygous, compound heterozygous and homozygous alpha thalassemia genotypes. The experimental results demonstrate that this methodological approach may be applied for screening and for hemological diagnosis in population at large.
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PMID:Oligonucleotide array for detection of common severe determinants of alpha thalassemia. 1560 20

-alpha3.7 is a common deletional alpha-thalassemia-2 in China. According to different recombination sites,-alpha3.7 can be divided into -alpha3.7I,-alpha3.7IIand -alpha3.7III. The frequency and population distribution of these -alpha3.7 are quite different. In this study,we detected 56 patients among Chinese population of -alpha3.7 defect in alpha globin gene by PCR method, then the PCR product was digested by the restriction enzyme ApalI and BalI. The sub-typing result shows that in the 56 cases of -alpha3.7 defect,54 out of 56 is -alpha3.7I,2 out of 56 is -alpha3.7II and none of -alpha3.7III is detected. This result enriches the data about the alpha thalassemia genotypes of Chinese people.
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PMID:[Detection and analysis of the sub-types of -alpha3.7 in Chinese]. 1563 51

During a study of the molecular basis for severe forms of beta thalassemia in Sri Lanka, 2 patients were found to be heterozygous for beta thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated alpha globin genes in combination with heterozygous beta thalassemia. The other is homozygous for a triplicated alpha globin gene arrangement and heterozygous for beta thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe beta thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended alpha globin gene interactions and in dominant beta thalassemia, raising the possibility that increased levels of HbF production in beta thalassemia may require mutations at both beta globin gene loci.
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PMID:A novel molecular basis for beta thalassemia intermedia poses new questions about its pathophysiology. 1594 92

Hemoglobinopathies are an important inherited disorder with a high prevalence in Southeast Asia. Hemoglobin Suan-Dok is an example of a hemoglobinopathy that was first identified and described in Thailand. It has been identified as an unstable hemoglobin variant associated with alpha-thalassemia. The role of the hemoglobin instability in Hb Suan-Dok in the altered red cell morphology in comparison to the thalassemia-like deficit of alpha globin mRNA has not been entirely resolved and needs additional structural study for clarification. In this study the amino acid sequence of human alpha globin was extracted using ExPASY and compared with that obtained from the Hb Suan-Dok disorder. The derived sequences, alpha globin chains in both the normal and Hb Suan-Dok disorder, were used for further investigation of the tertiary structures. Modeling these proteins for the tertiary structure was performed using the CPHmodels 2.0 Server. For comparison the tertiary structure of human alpha globin chains in normal and hemoglobin Suan-Dok are calculated and presented. Based on this information, there was no significant difference between the predicted alpha globin tertiary structures of normal hemoglobin and Hb Suan-Dok. Therefore, from this study we can state that the tertiary structure of alpha globin is not significantly affected by the mutation in the Hb Suan-Dok disorder and that the effect of this hemoglobin abnormality may be silent. The data suggests that the thalassemic defect associated with the Suan-Dok mutation results from another unidentified process rather than the structural aberration and that the finding of a thalassemic picture might be due to another undetectable inherited hemoglobin disorder.
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PMID:Modeling for tertiary structure of globin chain in Hemoglobin Suan-Dok disorder. 1601 64


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