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PubMed1992

Detection of beta and delta globin gene mutations by PCR and direct DNA sequencing in an individual with normal HbA2 beta thalassemia.

Normal HbA2 beta thalassemia in a Greek individual was shown to be due to co-inheritance of beta and delta thalassemias. The genetic defects were characterized by enzymatic amplification of the beta and delta globin genes and direct genomic sequencing. Two children with a typical high HbA2 beta thalassemia trait had inherited the beta thalassemia allele whilst a third child had low-normal HbA2 associated with delta+ thalassemia. Segregation patterns confirmed that the delta+/beta zero thalassemia defects were present in trans.

Adult↗
PubMed2000

Hb Bart's levels in cord blood and alpha-thalassemia mutations in Cyprus.

The purpose of this study was to examine the frequency of alpha-thalassemia in the population of Cyprus using cord blood samples. The levels of Hb Bart's were compared with the hematological indices and the results correlated with the presence of alpha-thalassemia mutations. The protocols for the polymerase chain reaction detection of the six most common alpha-globin mutations encountered in Cyprus were optimized, and the frequency of each mutation was determined through the screening of 495 random cord blood samples. The total allele frequency for the mutations examined was 10.6%, of which 1% is due to the triplication of the alpha-globin genes. The -alpha(3.7 kb) deletion accounts for 72.8% of all detectable mutations, while the--MED-I and -(alpha)-20.5 kb mutations account for 7.8%. The level of Hb Bart's and the MCV and MCH values in cord blood samples were found to correlate closely with the severity of alpha-thalassemia, although the -alpha(3.7 kb) deletion and perhaps other mild alpha-thalassemia mutations may not give detectable Hb Bart's levels. A reasonably accurate estimate of the alpha-thalassemia carrier frequency may be obtained from cord blood studies if Hb Bart's estimates are combined with hematological indices. When molecular methods are added, these give the best way to use cord bloods to survey populations for alpha-thalassemia.

Alleles↗
PubMed2000

Distribution of beta-thalassemia mutations in the Indian population referred to a diagnostic center.

Hemoglobinopathies are the most commonly inherited genetic disorders in India. Population screening has identified certain communities in India with high risk of beta-thalassemia, the prevalence of carrier status in some being as high as 17%. Over a period of 6 years we have conducted DNA analysis on 1,233 carriers of 23 beta-thalassemia mutations and Hb E, using the amplification refractory mutation system. The studies included analyses of five common mutations for Asian Indians, namely IVS-I-5 (G-->C), 619 bp deletion, IVS-I-1 (G-->T), and the frameshifts at codons 8/9 (+G) and 41/42 (-TTCT). The occurrence of these was seen in 1,066 (86.45%) of the carriers referred to us, the percentage of mutations varying between 5.03-42.58%. We found codon 15 (TGG-->TAG) in 47 (3.81%) samples which was also considered a common mutation in the Indian population. Rare beta-thalassemia mutations were found in 87 (7.06%) individuals. We have designed five new primers and modified four primers for nine rare mutations. These were seen in nine (0.73%) samples. The beta-thalassemia anomaly in 33 (2.68%) carriers remained uncharacterized. State-wide and community-wide distribution patterns of mutations indicated that IVS-I-5 (G-->C) is the most common beta-thalassemia allele in the Indian population. Sindhis settled in Gujrat, and Maharashtra and Lohanas from Gujrat showed a prevalence of the 619 bp deletion mutation in 49.2 and 45.5% carriers, respectively. High frequency of the IVS-I-1 (G-->T) mutation was also found in Sindhis (25.5%), Punjabi Hindus (34.7%), and Lohanas (31.2%). These studies of mutation patterns in different communities have helped us in the quick identification of beta-thalassemia mutations for prenatal diagnosis.

Alleles↗
PubMed1979

Immunologic diagnosis of alpha-thalassemia traits.

Frequently it is impossible to diagnose alpha-thalassemia-2 trait from hematologic findings, since the red cell morphology and the MCV are normal. In such cases, after the neonatal period Hb Bart's is not detectable by conventional electrophoreses and chromatography. Antibody against Hb Bart's was produced in rabbits by repeated injections with Hb Bart's from Hb Bart's hydropic fetuses. The antibody was specific for Hb Bart's without crossreaction with Hbs A, A2, E, F and H. By the capillary tube precipitin test Hb Bart's was demonstrable in 82% of 87 obligatory cases for alpha-thalassemia traits, 86% in alpha-thalassemia-1 trait and 79% in alpha-thalassemia-2 trait. The test was positive in 21% of the general subjects, corresponding to the prevalence of alpha-thalassemia in Bangkok. Thus the immunologic demonstration of Hb Bart's appears to offer a diagnostic screening test for alpha-thalassemia traits in the postneonatal period.

Animals↗
PubMed1980

The organization of the gamma-delta-beta gene complex in normal and thalassemia cells.

Restriction enzyme digestion analysis and direct human globin gene cloning have permitted analysis of the physical arrangement of nucleotide sequences within and surrounding the human globin genes. With these methods it has been shown that the linear arrangement 5' to 3' of the globin genes is G gamma-A gamma-delta-beta. The G gamma and A gamma genes are separated by about 3.5 kilobases (kb), while the A gamma and delta genes are 15 kb apart, and the delta and beta 6.5 kb apart. Each of these genes contains a large intervening sequence (IVS) of approximately 1 kb in precisely the same position between condons 104 and 105. In addition, each of these genes has a small IVS between codons 30 and 31. In homozygous delta beta thalassemia DNA, there is deletion of all of the normal delta and beta gene fragments. However, a new fragment 4.2 kb in size containing the 5' end of the delta globin gene is retained. Retention of this fragment in delta beta thalassemia, but not in HPFH is consistent with a role for sequences in this region for limiting gamma globin gene expression. Studies to date suggest that the beta + and beta 0 thalassemias will be due to a heterogeneous group of DNA defects affecting either beta globin gene transcription or beta mRNA processing. In most cases of beta + and beta 0 thalassemia DNA analyzed, there is no detectable deletion of beta or delta genes. In three India beta 0 patients, deletion of the 3' end of the beta gene has been found. Analysis of cloned beta globin genes from a patient with beta + thalasseia shows differences from normal in the fragments generated by restriction enzymes which cut frequently. Whether these differences are responsible for the defect in thalassemia or are polymorphisms unrelated to thalassemia remains to be determined.

Base Sequence↗
PubMed1982

Soluble and stroma-bound globin chains in mild and severe beta thalassemia.

In mild beta thalassemia hemoglobin levels are much higher than in severe beta thalassemia, yet black patients with the mild syndrome are as deficient in beta chain synthesis as severe thalassemia patients. The following studies were undertaken to determine if differences in the precipitation of excess alpha chain distinguishes these two groups of beta thalassemia homozygotes. The percentages of radioactive globin chain bound to erythroid cell stroma were determined in mild and severe thalassemia patients. Only the cells of splenectomized severe patients contained large amounts of stroma-bound globin radioactivity, the percentages in five such patients ranging from 6.7 to 13.9 (mean = 9.9). In four splenectomized patients with mild thalassemia the percentages ranged from 1.0 to 3.5 (mean = 1.9; p less than 0.005). This is the first observed difference in globin chain metabolism between these two groups of patients.

Adult↗
PubMed1988

The different types of alpha-thalassemia: practical and genetic aspects.

From May 1985 to October 1987, 1,564 Southeast Asians living in Hawaii were screened for hereditary anemias. Microcytosis was determined by electronic red cell indices and morphology; iron deficiency was ruled out by normal red cell distribution width and normal protoporphyrin levels; Hb E was determined by electrophoresis; beta-thalassemia (thal) heterozygotes were identified by raised Hb A2 on column chromatography. alpha-Thalassemia heterozygotes were diagnosed by exclusion. Family studies helped identify or confirm diagnoses, especially for the alpha-thal-2 heterozygotes (-alpha/alpha alpha) and homozygotes (-alpha/-alpha). Provisional diagnoses are being checked by DNA analyses. Iron deficiency prevented detection of possibly coexisting alpha-thalassemias in 97 individuals. Technical problems included the obscuring of standard criteria for recognizing the alpha-thal variants by the presence of Hb E or beta-thal. In such cases, alpha-thal could only be detected by family studies or DNA analyses. Problems with hemoglobin (Hb) electrophoresis included Hb H migrating beyond the edge of the strip if incubation was not closely monitored, and difficulty in detecting the small amounts of unstable Hb Constant Spring. DNA analyses also had limitations, since the nondeletion alpha-thalassemias would not be detected by routine Southern blotting. DNA analyses suggested that about 50% of presumed alpha-thalassemias were alpha-thal-2 (-alpha/alpha alpha) variants, and a corresponding number of alpha-thal-2 variants were among the apparent normals. Gene frequencies in the unselected Lao subjects were approximately 0.2 for Hb E, at least 0.1 for (-alpha), usually a rightward (alpha -3.7) type, 0.04 for (-), and 0.01 for a beta-thal. Multistep screening for the alpha- and beta-thalassemias was an effective and efficient strategy.

Asia, Southeastern↗
PubMed1988

Overview of the beta thalassemias: genetic and clinical aspects.

There has been much progress in basic studies of the beta-thalassemia disorders in recent years, as well as in the practical aspects of prenatal diagnosis and clinical management. Alterations in a single or a few nucleotides account for most of the types of beta-thalassemia syndromes that have been characterized, and a variety of deletions have been found associated with beta O thalassemia, delta beta thalassemia, gamma delta beta thalassemia, and hereditary persistence of fetal hemoglobin (HPFH). Studies of nondeletional types of HPFH have revealed several single base changes 5' to the G gamma and A gamma genes, suggesting that these regions may be of major importance in the switchover from fetal to adult hemoglobin synthesis and in the relative production of the G gamma and A gamma globin chains during development. Evaluation of restriction enzyme polymorphisms and the assignment of haplotypes in the beta-like globin region of chromosome 11 have allowed delineation of the origin and distribution of thalassemia mutations, and have provided an important means for prenatal diagnosis. These studies have accumulated much new information about the function and expression of eukaryotic genes, and have served as a model for the investigation of human genetic disorders. The clinical management of patients with Cooley's anemia has benefited greatly from changes in transfusion practice, clear guidelines for splenectomy, and the availability of effective chelation therapy for iron overload. Current basic and clinical studies may lead to new approaches to management, treatment and eventual cures for this disease, including safe bone marrow transplantation, oral chelation treatment, and gene therapy.

Fetal Hemoglobin↗
PubMed1991

The G----A mutation at position +22 3' to the Cap site of the beta-globin gene as a possible cause for a beta-thalassemia.

We describe the occurrence of a chromosome with a G----A mutation at position +22 relative to the Cap site that was found in five patients with beta-thalassemia. All patients had a common type of beta-thalassemia mutation on the second chromosome, namely the frameshift at codon 8 (-AA), the IVS-I-110 (G----A) and the IVS-II-1 (G----A) mutations. The beta genes of two patients, including the 5' and 3' untranslated regions, were completely sequenced and no other mutations, except a few polymorphic sites, were observed. Dot-blot analyses failed to demonstrate this G----A mutation at +22 in nearly 400 beta-thalassemia chromosomes and 180 normal chromosomes. Heterozygotes have the features of a high Hb A2-beta-thalassemia heterozygosity, although the hematological parameters might be less abnormal than observed in heterozygotes for the more common beta-thalassemia mutations. The possibility has been presented suggesting that this mutation might impair the binding of mRNA to ribosomes. Another mutation in this segment of DNA, i.e. a C----G mutation at position +20, is observed exclusively on a chromosome which also carries the C----G mutation at IVS-II-745. It is postulated that the +20 C----G mutation accentuates the beta-thalassemia condition caused by the IVS-II-745 mutation; the mechanism might be similar to that suggested for the G----A at +22 mutation.

Alleles↗
PubMed1994

Distribution of beta-thalassemia mutations in three Asian Indian populations with distant geographical locations.

We have identified the beta-thalassemia alleles in 47 pediatric patients with transfusion-dependent thalassemia major from a clinic in New Delhi and in 105 heterozygous relatives. Surprisingly, only five mutations were present in 94 beta-thalassemia chromosomes with frequencies from 10 to 32%. This observation greatly facilitated the initiation of a prenatal diagnostic program. Similar studies were conducted for seven Asian Indian patients from Calgary, Canada, seven Asian Indian patients from Durban, South Africa, and from heterozygous relatives, and persons with a beta-thalassemia trait who were not related. Besides beta-thalassemia alleles, common to Asian Indian beta-thalassemia patients, some unexpected alleles were observed in the patients from South Africa, including a newly discovered frameshift at codon 15 (-T).

Alleles↗
PubMed1997

A significant beta-thalassemia heterogeneity in the United Arab Emirates.

The Dubai Thalassemia Center has identified 35 different beta-thalassemia mutations in 570 chromosomes from the United Arab Emirates population using gene amplification, hybridization with specific labeled oligonucleotide probes, sequencing of amplified DNA, restriction enzymes, and amplification refractory mutation system techniques. This large number of mutations which represent 21% of the total beta-mutations discovered worldwide reflects the heterogenous nature of the population living in the United Arab Emirates (1). We found that 50% of our beta-thalassemia patients have a concomitant alpha-thalassemia; namely the -alpha 3.7 kb deletion. Co-inheritance of alpha-thalassemia especially in the form of two alpha-globin gene deletions have an ameliorating effect on the phenotype presentation of our beta-thalassemia. Nine patients (one homozygote and eight compound heterozygotes) were identified with Hb Monroe (IVS-I,-1 (G-->C)), a thalassemic hemoglobin characterized by an Arg-->Thr substitution in codon 30 of the beta-globin gene. In addition, one of the patients was a compound heterozygote for Hb Tacoma [IVS-I, +1 (G-->C)]; a point mutation affecting the third nucleotide of codon 30 (G-->C) causing an Arg-->Ser replacement.

Adolescent↗
PubMed1999

Co-inherited Gilbert's syndrome: a factor determining hyperbilirubinemia in homozygous beta-thalassemia.

BACKGROUND AND OBJECTIVE: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter. DESIGN AND METHODS: We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia. RESULTS: In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype. INTERPRETATION AND CONCLUSIONS: These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co-inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders.

Gilbert Disease↗
PubMed1999

Beta-thalassemia and pulmonary function.

BACKGROUND AND OBJECTIVE: The survival of patients with beta-thalassemia major and intermedia has improved considerably. This has focused attention on the long-term sequelae of the disease itself and its treatment. The effect of hemosiderosis in major organs (heart, liver, etc) are well-recognized, but the pathophysiology of any lung damage is less clearly understood. We studied lung function changes in 32 patients with beta-thalassemia. DESIGN AND METHODS: Respiratory function tests, CO diffusion and arterial blood gas analysis were performed on 19 patients with beta-thalassemia major (9 F, 10 M) and 13 with beta-thalassemia intermedia (6 M, 7 F). All investigations were performed 24 hours before the patients received a blood transfusion or when they were in a stable state hematologic condition. Echocardiography was performed in all patients and the ejection fraction was employed as a measure of cardiac function. RESULTS: No patient had clinical signs of pulmonary dysfunction. Pulmonary function tests, however, showed a reduction of all main parameters (TLC, FVC, FEV1 and RV) in most patients with beta-thalassemia major, indicating a restrictive type of dysfunction. The pulmonary function of patients with beta-thalassemia intermedia seemed to be preserved. Arterial blood gas values were within the normal range, while in some subjects CO diffusion approached the lower limits of normality. There was no evidence that the observed abnormalities in pulmonary function were secondary to congestive heart failure. INTERPRETATION AND CONCLUSIONS: Iron deposition due to repeated blood transfusions may play a central role in determining lung alterations although the majority of patients are well chelated, suggesting that more than one causal mechanisms could be involved.

Adolescent↗
PubMed2001

[Analysis of the non-deletion alpha-thalassemia mutations by PCR temperature gradient gel electrophoresis].

OBJECTIVE: To develop a PCR-temperature gradient gel electrophoresis(TGGE) method applied to screening for the point mutations causing the non-deletion alpha-thalassemia. METHODS: The entire alpha2-globin gene fragment (1085 bp) was selectively amplified from human genomic DNA with different genotypes of alpha-thalassemia and a 543 bp fragment spanning the exon 2 and exon 3 of the alpha2-globin gene was amplified with a pair of nested primers. The condition of perpendicular and parallel TGGE for the two different fragments in length was optimized and the candidate mutant was confirmed by DNA sequencing. In pilot study, 15 samples with suspected non-deletion alpha-thalassemia were screened for point mutations in alpha-globin gene. RESULTS: Hb Constant Spring (Hb CS) and Hb Quong Sze (Hb QS), two most commonly types of the non-deletion alpha-thalassemia distributed in Chinese, and a rare type of the Hb Westmead mutation, alpha2 CD122 CAC-->CAG(His-->Gln) could be detected by PCR-TGGE. Among those 15 samples screened for alpha-thalassemia mutation were 10 samples with Hb CS mutation, 2 samples with Hb QS mutation, 2 samples with Hb Westmead mutation, and a previously unreported one, alpha2 CD31 AGG-->AAG(Arg-->Lys), confirmed by DNA sequencing. CONCLUSION: The present PCR-TGGE method could be a useful tool for the molecular screening for the point mutations causing alpha-thalassemia and alpha-globin gene polymorphism.

Electrophoresis↗
PubMed1975

Comparison of methodologies for thalassemia screening by Hb A2 quantitation.

An efficient, reliable, inexpensive screening test for beta-thalassemia triat is required before the National Cooley's Anemia Control Act can be carried out. Densitometry of hemoglobin samples separated by cellulose acetate has become a routine procedure to quantitate Hb A2 and thereby indicate beta-thalassemia trait carriers. To determine the utility of densitometry in quantitation of Hb A2, we evaluated three densitometers marketed in the United States. Individuals with genetically proved beta-thalassemia trait and normal Hb AA controls were studied. Two analytic procedures (elution and column chromatography) for Hb A2 quantitation were used as reference methods. Densitometry was shown to be unsatisfactory for detecting beta-thalassemia-trait carriers. We recommend that a unified approach to the detection of anemia, which would include thalassemia trait, be developed in the United States rather than free-standing thalassemia screening centers and clinics.

Chromatography, Gel↗
PubMedDate not supplied

Analysis of thalassemia syndromes and abnormal hemoglobins in patients from the Aegean region of Turkey.

Turkey is located in a geographic area of the world where thalassemia syndromes and abnormal hemoglobins are common. In this study we aimed to evaluate the thalassemia syndromes and abnormal hemoglobins in patients from the Aegean region of Turkey. Among the patients admitted to our Pediatric Hematology or Hematology Clinic between January 1997-September 1999, hemoglobin electrophoresis of 3,228 cases investigated for anemia was done using high performance liquid chromatography. Beta thalassemia trait was diagnosed in 21.1%, beta thalassemia major in 0.2%, S-beta thalassemia in 0.37%, Hb D in 0.37%, Hb S trait in 0.32%, Hb E in 0.18%, Hb O-Arab in 0.12%, Hb G-Copenhagen in 0.09%, Hb D-Iran in 0.06%, Hb Lepore in 0.06%, Hb Hasharon in 0.03%. Our results demonstrate that people in the Aegean region of Turkey have a wide spectrum of thalassemia syndromes and abnormal hemoglobins.

Child↗
PubMed2001

The use of the amplification refractory mutation system (arms) in the detection of rare beta-thalassemia mutations in the Malays and Chinese in Malaysia.

Molecular characterization and prenatal diagnosis for beta-thalassemia can be carried out using the Amplification Refractory Mutation System (ARMS). The ARMS is a rapid and direct molecular technique in which beta-thalassemia mutations are visualized immediately after DNA amplification by gel electrophoresis. In the University of Malaya Medical Center, molecular characterization and prenatal diagnosis for beta-thalassemia is carried out using ARMS for about 96% of the Chinese and 84.6% of the Malay patients. The remaining 4% and 15.4% of the uncharacterized mutations in the Chinese and Malay patients respectively are detected using DNA sequencing. DNA sequencing is an accurate technique but it is more time-consuming and expensive compared with the ARMS. The ARMS for the rare Chinese beta-mutations at position -29 (A-->G) and the ATG-->AGG base substitution at the initiator codon for translation in the beta-gene was developed. In the Malays, ARMS was optimized for the beta-mutations at codon 8/9 (+G), Cap (+1) (A-->C) and the AATAAA-->AATAGA base substitution in the polyadenylation region of the beta-gene. The ARMS protocols were developed by optimization of the parameters for DNA amplification to ensure sensitivity, specificity and reproducibility. ARMS primers (sequences and concentration), magnesium chloride concentration, Taq DNA polymerase and PCR cycling parameters were optimized for the specific amplification of each rare beta-thalassemia mutation. The newly-developed ARMS for the 5 rare beta-thalassemia mutations in the Chinese and Malays in Malaysia will allow for more rapid and cost-effective molecular characterization and prenatal diagnosis for beta-thalassemia in Malaysia.

Base Sequence↗
PubMed2002

Homozygosity for nondeletion delta-beta(0) thalassemia resulting in a silent clinical phenotype.

The clinical phenotype of homozygous beta thalassemia varies in severity from the mild thalassemia intermedia to the severe thalassemia major. This variability depends largely on the molecular heterogeneity of beta thalassemia defects. We report the first case of a homozygous state for nondeletion Sardinian delta-beta(0) thalassemia, which resulted in a symptomless clinical phenotype with a peculiar hemoglobin (Hb) pattern (99.8% Hb F and 0.2% Hb A(2)). The molecular defect was characterized by the presence of 2 nucleotide substitutions: -196C>T in the promoter of the Agamma-globin gene and beta 39C>T nonsense mutation. The absence of typical beta thalassemia clinical findings was due to the high Hb F output, which compensated for the absence of beta chains. The near absence of Hb A(2) may have resulted from either alterations in the globin gene transcriptional complex with preferential activation of gamma-globin genes and suppression of delta-globin genes or preferential survival of red blood cells with the highest Hb F content and low Hb A(2) level.

Female↗