Type Of Persistence Research Articles

The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3′ end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Gγ-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T β-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases.

Becoming a Founder: How Founder Role-Identity Affects Entrepreneurial Transitions and Persistence in Founding

By viewing organizational founding as involving a role transition, we highlight the challenges that potential founders face: 1) adjusting to the novel skills and social networks that underpin the new role, and 2) incorporating the new role into an overall self-concept that may consist of contradictory or competing identities. We develop the concept of founder role identity and delineate how two aspects, centrality and complexity, affect potential founders' ability to exit a current work role in order to undertake founding activities, an indicator of successful role transition. Founder centrality denotes the subjective importance of the founder role to an individual's self-concept, while complexity captures diversity and richness in the person's conceptions of the role. After a role transition occurs, we delineate how distinctive configurations of founder role identities influence the extend and type of persistence observed in the face of negative feedback so prevalent during the founding process. By explicitly considering persistence, we are able to link founder role identity to longer-term outcomes, including the overlooked condition of dormancy wherein a role transition has occurred but successful founding has not. Our theorizing seeks to redress an imbalance in theories explaining entrepreneurial activity by developing a more dynamic understanding of the founder's role in determining organizaional founding.

Practical ways of evaluating wind speed persistence

Wind speed persistence is a measure of the mean wind speed duration over a given period of time at any location. This definition implies that wind speed persistence means a positive serial correlation in time series. The wind speed persistence provides useful information about the general climatological characteristics of the wind persisting at a given location. Therefore, wind speed persistence should be taken into account in many studies such as weather forecast, site selection for wind turbines and synthetic generation of the wind speed data. On the other hand, if wind direction information is considered together with the wind speed then this type of persistence can be used for additional purposes such as forest fires, dispersion of the air pollutants, building ventilation, etc. In this study, three different methods with some modifications of the previous methods have been applied to the wind speed data obtained from the meteorology stations located at the northwest part of Turkey. These methods are based on autocorrelation function, conditional probability and the wind speed duration curves. It has been shown that the proposed methods clearly reflect the persistence properties of the wind speed in the study area.

Tissue Persistence and Prevalence of B19 Virus Types 1–3

Human parvovirus B19 is a minute ssDNA virus that causes a wide variety of diseases, including erythema infectiosum, arthropathy, anemias and fetal death. In addition to the B19 prototype, two new variants (B19 types 2 and 3) have been identified. After primary infection, B19 genomic DNA has been shown to persist in solid tissues of not only symptomatic but also of constitutionally healthy, immunocompetent individuals. The viral DNA persists as an intact molecule without persistence-specific mutations, and via a storage mechanism with life-long capacity. Thus, the mere presence of B19 DNA in tissue cannot be used as a diagnostic criterion, although a possible role in the pathology of diseases, for example through mRNA or protein production, cannot be excluded. The molecular mechanism, host-cell type and possible clinical significance of tissue persistence are yet to be elucidated.

Effect of Monitoring Bone Turnover Markers on Persistence with Risedronate Treatment of Postmenopausal Osteoporosis

Persistence with osteoporosis treatment is poor but is important for maximum benefit. The objective of the study was to assess the impact of physician reinforcement using bone turnover markers (BTMs) on persistence with risedronate treatment. This was a 1-yr multinational prospective, open-label, blinded study in 171 osteoporosis centers in 21 countries. A total of 2382 postmenopausal women (65-80 yr old) with spine/hip T-score -2.5 or less or T-score -1.0 or less with a low-trauma fracture. Intervention included calcium 500 mg/d, vitamin D 400 IU/d, and risedronate 5 mg/d for 1 yr. Centers were randomized to reinforcement (RE+) or no reinforcement (RE-). At 13 and 25 wk, reinforcement based on urinary N-telopeptide of type I collagen change from baseline was provided to the RE+ patients using the following response categories: good (>30% decrease), stable (-30% to +30% change), or poor (>30% increase). Persistence assessed with electronic drug monitors was measured. In the overall efficacy population (n=2302), persistence was unexpectedly high and was similar for both groups (RE-, 77%; RE+, 80%; P=0.160). A significant relationship between the type of message and persistence was observed (P=0.017). Compared with RE-, intervention based on a good BTM response was associated with a significant improvement in persistence [hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53-0.95]. Persistence was unchanged (HR 1.02; 95% CI 0.74-1.40) or lower (HR 2.22; 95% CI 1.27-3.89) when reinforcement was based on a stable or poor BTM response, respectively. Reinforcement was associated with a lower incidence of new radiologically determined vertebral fractures (odds ratio 0.4; 95% CI, 0.2-1.0). Reinforcement using BTMs influences persistence with treatment in postmenopausal women with osteoporosis, depending on the BTM response observed.

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of β-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of δβ-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of α-thal trait is 1.5%, of which α-thal-2 is 1.45% and α-thal-1 is 0.05%. The molecular basis of the different forms of β-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 β-thal chromosomes have been studied. Fifteen different β-thal mutations have been detected, four of which [IVS-I-110 (G→A), IVS-I-6 (T→C), IVS-I-1 (G→A), codon 39 (C→T)] account for 85% of all β-thal chromosomes. Among the Albanians, 48 β-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, −30 (T→A), IVS-I-110, IVS-I-1] account for 85% of all β-thal chromosomes. Four new mutations [−101 (C→A), −87 (C→G), −30, polyadenylation signal (poly A) (AATAAA→AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with δβ-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of δβ-thal) was discovered. Molecular analyses of α-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA→AATGAA), and Hb Icaria [α142, Term→Lys, TAA→AAA (α2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different α chain variants among 10 families, seven different β chain variants among 33 families, two γ chain variants in two newborns, one variant with an extended α chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.

The Venezuelan Type of Nondeletional Hereditary Persistence of Fetal Hemoglobin Is Due C →T Mutation at Nucleotide -211 of the Aγ Globin Gene.

Hereditary Persistence of Fetal Hemoglobin (HPFH) is a clinically benign condition characterized by continuous synthesis of fetal hemoglobin (Hb F) in adult life without major related hematological changes. The nondeletional HPFH is characterized by hemoglobin F level between 5% and 30%, in heterozygotes state. This condition has been observed among Blacks, Italians, Greeks, English and Chinese. Two different forms are known, characterized by the type of chain involve, either Gγ or Aγ. Several point mutations in the promoter region of the Aγ globin gene have been identified in ndHPFH: −202, −198, −196, −195, −117, −114, deletion 4pb (−222 −225) and −158.The propositus is a 36 year old black female with a moderate increased level of Hb F, also her sister and her sibling had the same condition. She was discovered during studies due to the presence of splenomegaly and gastroesophageal reflux. The Hbs A, A2 and F were eluted and quantified by cation exchange high-performance liquid chromatography (HPLC-CE), using Beta Tal short program, Variant BioRad (Hercules, California, USA). DNA was isolated from peripheral blood leukocytes by a salting-out extraction procedure. The Aγ and Gγ promoters globins gene were amplified independently by PCR and the presence of the HPFH mutation was determined by denaturing gradient gel electrophoresis technique (DGGE) as previously described Gottardi et al., (1992). The Aγ promoter globin gene was sequenced in three members of the family using the BigDyeTM Terminator Cycler Sequencing Kit and the ABI PRISMTM 310 Genetic Analyzer (PE Applied Biosystems, Foster City, CQ, USA).Her hematological studies revealed Hb: 14.2 g/dl, Hcto: 41.1 %, MCV: 94.4 fl, MCHC: 34.5 fl, Hb A: 81.9 %, Hb A2: 2.1 % and Hb F: 6.3 %. The sibling hematological finding was Hb: 13.1 g/dl, Hcto: 41.8 %, MCV: 83.7 fl, MCHC: 31.3 fl, Hb A: 83.2 %, Hb A2: 3.2 % and Hb F: 5.1. The sister was Hb: 14.3 g/dl, Hcto: 46.4 %, MCV: 105.9 fl, MCHC: 30.8 fl, Hb A: 83.7 %, Hb A2: 3.3 % and Hb F: 2.7 %. No spleen enlargement was seen in the other two affected members of the family. The DGGE results in the Aγ promoter, suggested the presence of a non-deletion form of HPFH in heterozygotes state. The Aγ promoter region revealed the presence of a substitution C→T at position −211. This mutation does not modify any restriction site.To our knowledge the −211 (C→T) mutation in the Aγ promoter have not been reported previously. Since modulation of g-globin gene expression in adults could provide a therapeutic intervention in hemoglobinopathy, the study of the molecular mechanisms generating HPFH is medically relevant.

Analysis of the mechanism of action of the Brazilian type (Agamma-195 C --> G) of hereditary persistence of fetal hemoglobin.

We report an in vitro expression study of the Agamma-globin gene promoter containing the Agamma-195 C --> G mutation that causes the Brazilian type of hereditary persistence of fetal hemoglobin (HPFH). To demonstrate that this mutation results in increased promoter strength, we evaluated the mutant promoter linked to the hypersensitive site-2 of the locus control region with the luciferase reporter gene system and examined protein interactions by eletrophoretic mobility shift assay. The transient expression was studied in three cell lines: K562, HEL and 293, and indicated increased promoter activity of the promoter containing the Brazilian mutation in all cell lines. The protein-DNA interaction showed that, in contrast to the Agamma-198 T --> C mutation which has increased affinity for the Sp1 protein and creates a motif that behaves like a novel CACCC box in the gamma promoter, the Brazilian HPFH mutation decreases the affinity at the Sp1 protein and does not act as a CACCC motif. These results suggest that this mutation may act to increase the Agamma-globin chain production. In addition, the mechanism by which this increased production occurs is different to that of the -198 mutation. Other proteins may be involved in the overexpression of the gamma-globin chain and/or may be dependent upon the DNA structure.

The Cretan type of non-deletional hereditary persistence of fetal hemoglobin [A gamma-158C-->T] results from two independent gene conversion events.

We report a new type of non-deletional hereditary persistence of fetal hemoglobin that is due to a C-->T transition at position -158, relative to the Cap site of the human Agamma-globin gene. This mutation was identified in three unrelated adult cases presenting slightly elevated levels of fetal hemoglobin (Hb F), i.e. 2.9-5.1%, and normal hematological indices. Our sequencing results, from both polymerase chain reaction-amplified and subcloned DNA fragments, indicate that the A gamma -158C-->T mutation occurred by two independent gene conversion events in the three cases studied. In addition, hematological and molecular data, including restriction fragment length polymorphism haplotyping in the beta-globin gene cluster, extended haplotype analysis inside the gamma-globin gene region and routine analysis of three tandem repeat loci (D1S80, 3'HVR/apoB and F8vWf), led us to conclude that the A gamma -158C-->T mutation in one of the three cases occurred recently in the parental germ line (P=99.47%), representing the first example of a de novo gene conversion event identified in humans.

Haplotype analysis and Agamma gene polymorphism associated with the Brazilian type of hereditary persistence of fetal hemoglobin.

We have identified three unrelated individuals and three members of a family with the non-deletion form of Agamma-hereditary persistence of fetal hemoglobin (HPFH). Molecular analysis showed that each individual is a heterozygote for a previously described -195 Agamma (C-->G) mutation. The beta-globin gene cluster was studied using the polymerase chain reaction and related techniques. Haplotyping using nine restriction sites identified two closely related chromosomes with the -195Agamma mutation, differing only in a single site 3' to the beta-globin gene. Further analysis of beta-globin framework indicated that the HPFH allele segregates with haplotype V, according to Orkin's classification. The second haplotype probably originated by a point mutation or DNA rearrangement of a pre-existing -195Agamma chromosome. We also determined the sequences from -622 to +55 bp upstream to the Agamma gene and part of the Agamma IVS-2. We found four polymorphisms associated to the -195Agamma promoter region. All -195Agamma chromosomes had a G at positions -588 and +25 relative to the Agamma gene. One individual was also homozygous for polymorphisms at -398 (G-->A), and another at -369 (C-->G). Cloning and sequencing of the polymorphic patterns of the 3' region of Agamma IVS-2 showed that the mutated allele is linked to beta-globin chromosome B. Some correlations between chromosome characteristics and Agamma point mutations were also observed.

Detection of non-deletional type of hereditary persistence of fetal hemoglobin (HPFH) condition associated with 619 bp β°-thalassemia deletion

DNA samples from a family (parents and a son) with hereditary persistence of fetal hemoglobin (HPFH) condition were subjected to amplification of a 1.214 kbp DNA fragment from β-globin gene using polymerase chain reaction (PCR). The aim of this study was to identify the type of HPFH i.e. deletional or non deletional. Non deletional type of HPFH was identified in two samples and moreover, these samples were found to be associated with 619bp β(°)-thalassemia deletion. This is the first report on the association of non deletional HPFH with 619bp β(°)-thalassemia deletion.

Cultured human myocardial fibroblasts of pediatric origin: Natural human interferon-α is more effective than recombinant interferon-α 2a in carrier-state coxsackievirus B3 replication

Cultured human myocardial fibroblasts of pediatric origin seem to be a useful species-specific model for studying various heart diseases which involve the myocardial interstitium, for example enterovirus heart disease. Cells were propagated from small samples of human ventricular tissues (0.2 g) obtained from standard surgical procedure for the correction of Fallot-tetralogy. Cultured cells exhibited typical fibroblastoid morphology over a period of 4 months and were uniformly immunoreactive with a monoclonal antibody directed against prolyl-4-hydroxylase, a marker enzyme of fibroblasts. Infection of cell cultures with coxsackievirus B3, a cardiotropic enterovirus, resulted in a typical carrier-state type of virus persistence. Average virus titers of 2.3 x 10(5) plaque-forming units/ml (SD = 9.9 x 10(4)) were maintained over a period of up to 10 weeks by productive infection of about 8-10% of the cell population. Coxsackievirus B3 carrier cultures of human myocardial fibroblasts were used to evaluate in vitro the long-term antiviral effects of recombinant interferon alpha-2a and natural human interferon-alpha. Recombinant interferon-alpha reduced virus yields by 90% with a concentration of 423 IU/ml, whereas with natural interferon-alpha a 90% reduction of virus yields was achieved with concentrations as low as 21 IU/ml. Antiviral effects of both recombinant and natural interferon-alpha were highly specific and not related to inhibition of cell-proliferation (< 50% with interferon-alpha concentrations as high as 6250 IU/ml). Since effective concentrations of interferon-alpha can be easily attained in vivo with subcutaneous application, interferon-alpha (in particular: natural interferon-alpha) may become useful in the treatment of patients with enterovirus myocarditis and enterovirus induced dilated cardiomyopathy.

Does precipitation pattern foretell climatic shift over Punjab state ?

ABSTRACT. Statistical analysis of 82-years (1901-1982) record of precipitation from 27 rain-recording stations in Punjab state of lndia has been carried out to assess the climate shift if any in the state. The central part of the study is the trend and spectrum analysis of annual. monsoon and winter rainfall of different stations in the region. It is seen that frequency distribution of 19 rainfall series out of 81 series is normally distributed. Maikov linear type of persistence is observed in some of the rainfall series. Marin-Kendall test indicates the decreasing trend in winter rainfall of all the stations and is found to be significant in case of Amritsar, Taran Taran, Tanda, Ludhiana and Ranike. Low-pass filter reveals that trend is not linear but oscillatory consisting of periods of 10 years or more. It is seen that winter rainfall of most of the stations exhibits the decreasing trend from 1935-40 to 1965-70. It is also revealed by the low-pass filter curves that winter rainfall of all t1le sla1ions remained below average from 1960 till the end of the study period.&#x0D; The spectral analysis indicates a significant cycle of 4.1 to 27 years in some of the stations and Quasi-Biennial Oscillations (QBO) over many stations.&#x0D;

Nondeletional type of hereditary persistence of fetal haemoglobin: molecular characterization of three unrelated Thai HPFH.

The beta-globin gene clusters of three unrelated Thai families with a nondeletional type of hereditary persistence of fetal haemoglobin (HPFH) were studied using polymerase chain reaction-related techniques. All appeared to have normal nucleotide sequences from the Cap site to position -400 of both the G gamma- and A gamma-globin genes. Two individuals suspected of having a beta-thalassaemia gene linked to the high HbF condition also had a normal beta-globin gene sequence, spanning from position -108 from the Cap site to the polyadenylation site. Deletion of four nucleotides, AGCA, at positions -225 to -222 of one A gamma-globin allele was detected in one subject and was confirmed by dot-blot hybridization. Restriction fragment length polymorphisms in the beta-globin gene cluster showed that the 5' haplotype (-+-++) and the presence (+) of an Xmm 1 polymorphic site at -158 of the G gamma-globin gene are associated with the high F phenotype in these families. Direct sequencing of the 5' hypersensitive-2 (5' HS-2) site of the locus control region (LCR) showed that this Xmn 1 (+) site is also linked to a specific rearrangement of TA repeats (TA)9CACATATACG(TA)10, in HS-2 segment.

The -158 (C--&gt;T) promoter mutation is responsible for the increased transcription of the 3' gamma gene in the Atlanta type of hereditary persistence of fetal hemoglobin

The Atlanta type of hereditary persistence of fetal hemoglobin (HPFH) is characterized by a mild elevation of Hb F (2% to 5% in heterozygotes), almost exclusively of the G gamma type (more than 90%). Gene-mapping analysis has identified this condition as a -G gamma-G gamma- arrangement with the -158 (C--&gt;T) substitution in the promoters of both G gamma genes. We have reevaluated this condition in members of two families. Sequence analysis identified only two changes in the 3′ gamma gene as compared with the A gamma gene from a chromosome with haplotype no. 3 (or Senegal), namely the -158 (C--&gt;T) promoter mutation and the C--&gt;G change in codon (CD) 136, which accounts for the -G gamma- G gamma- phenotype. The absence of any other nucleotide (nt) substitution provides genetic evidence that the -158 (C--&gt;T) change is primarily responsible for the elevated Hb F levels associated with this condition. A quantitative reverse transcription/polymerase chain reaction (RT/PCR) procedure, presented in detail in this report, was developed to determine the effect of this mutation on the transcription of individual gamma genes in four individuals with the Atlanta type of HPFH. Both gamma-globin genes, ie, the (5′) G gamma and the (3′) G gamma-Atlanta genes of the Atlanta type of HPFH chromosome, expressed elevated amounts of transcripts, which were present in nearly equal amounts. This shows that the -158 (C--&gt;T) mutation exerts its effect on the transcriptional rate of the gene with which it is associated.

The -158 (C → T) Promoter Mutation Is Responsible for the Increased Transcription of the 3'γ Gene in the Atlanta Type of Hereditary Persistence of Fetal Hemoglobin

The Atlanta type of hereditary persistence of fetal hemoglobin (HPFH) is characterized by a mild elevation of Hb F (2% to 5% in heterozygotes), almost exclusively of the G gamma type (more than 90%). Gene-mapping analysis has identified this condition as a -G gamma-G gamma- arrangement with the -158 (C-->T) substitution in the promoters of both G gamma genes. We have reevaluated this condition in members of two families. Sequence analysis identified only two changes in the 3' gamma gene as compared with the A gamma gene from a chromosome with haplotype no. 3 (or Senegal), namely the -158 (C-->T) promoter mutation and the C-->G change in codon (CD) 136, which accounts for the -G gamma-G gamma- phenotype. The absence of any other nucleotide (nt) substitution provides genetic evidence that the -158 (C-->T) change is primarily responsible for the elevated Hb F levels associated with this condition. A quantitative reverse transcription/polymerase chain reaction (RT/PCR) procedure, presented in detail in this report, was developed to determine the effect of this mutation on the transcription of individual gamma genes in four individuals with the Atlanta type of HPFH. Both gamma-globin genes, ie, the (5') G gamma and the (3') G gamma-Atlanta genes of the Atlanta type of HPFH chromosome, expressed elevated amounts of transcripts, which were present in nearly equal amounts. This shows that the -158 (C-->T) mutation exerts its effect on the transcriptional rate of the gene with which it is associated.

The mystery of the mycobacterial ‘persistor’

The term ‘persistence’ was first applied to mycobacteria by McCune and his colleagues in 1966 in reference to the capacity of tubercle bacilli in tissues to survive in the presence of bactericidal concentrations of antituberculosis agents.‘,* Although the great majority of tubercle bacilli in a lesion are killed within a week or two by the drugs used in modern short-course chemotherapy, it is necessary to continue such therapy for at least 5 months to be sure that the few remaining bacilli are eliminated. The need for such a costly and prolonged course of therapy, which must usually be administered under supervision, is one of the major obstacles to the control of tuberculosis worldwide.3 The nature of ‘persistors’ is unknown but it is generally assumed that they are in a state of dormancy which renders them functionally resistant to antituberculosis agents except rifampicin to which they are sensitive but only if and when they undergo short bursts of metabolic activity.4 Another type of mycobacterial persistence is that which is responsible for the endogenous reactivation of tuberculosis years or even decades after the primary infection. Indeed, such bacterial persistence is crucial to the epidemiological features of tuberculosis and without it the disease would probably not exist. Again, we have no knowledge of the nature of these persisting bacilli. Nor do we know whether they are similar to those that persist during chemotherapy. It is usually considered that these persistors lie dormant within the scars of primary foci. Such presumed dormancy may be the result of a metabolic adaptation to anaerobiasis or of the mycobacteriostatic effects of macrophages. The former is suggested by the finding that cells of M. tuberculosis in the anaerobic conditions in the sediment of liquid cultures remain viable for long periods yet do not replicate.’ It was later found that such adaptation to anaerobiasis involved changes in oxygen-dependent metabolic pathways and it was suggested that these changes might facilitate the phenomenon of dormancy in vivo.h

Hemoglobinopathies in Yugoslavia: an update.

This paper summarizes information on the epidemiology and molecular basis of hemoglobinopathies in Yugoslavia. Over the past 25 years, population surveys of more than 28,000 school children from all over the country, except Slovenia, have shown that the average incidence of beta-thalassemia (beta-thal) trait is 1.2%, ranging from 2.9% in the south (Macedonia) to 0.8% in the northwest (Croatia). The frequency of delta beta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.4%. Screening of 6,400 newborns has shown that the frequency of alpha-thal trait is 1.6%. The molecular basis of the different forms of beta-thal among Yugoslavians has been almost completely defined. Over 250 beta-thal chromosomes have been studied, and in over 90% the molecular defect was determined. Eighteen different beta-thal mutations have been detected, three of which (IVS-I-110, G-->A; IVS-I-6, T-->C; IVS-I-1, G-->A) account for more than 70% of all beta-thal chromosomes. Four new mutations [-87 (C-->A); IVS-II-850 (G-->C); initiation codon mutation T-->C; poly A (AATAAA-->AATGAA)] and one new deletion (1605 bp) have been characterized. Molecular analyses of DNA from over 30 unrelated cases with delta beta-thal have shown that this condition is mainly caused by a 13 kb deletion (Sicilian type); in one family a deletion of > 18 to 23 kb (Macedonian type), and in another family a deletion of 148 kb (Yugoslavian type of epsilon gamma delta beta-thal) of the globin gene complex was discovered. Limited studies of alpha-thal in Yugoslavia have shown the following types of molecular defects: approximately 20.5 kb deletion, approximately 17.5 kb deletion, -3.7 kb deletion, 5 nucleotide (nt) deletion, and Hb Icaria. The incidence of abnormal hemoglobins (Hbs) in Yugoslavia is 0.3%. Five different alpha chain variants among 21 families, 15 different beta chain variants among 53 families, one delta chain variant in one family, one variant with a deleted residue in one family, and two types of Hb Lepore among 122 families, have been observed.

The Georgia type of nondeletional hereditary persistence of fetal hemoglobin has a C---T mutation at nucleotide-114 of the A gamma-globin gene [letter

The Georgia type of nondeletional hereditary persistence of fetal hemoglobin has a C---T mutation at nucleotide-114 of the A gamma-globin gene [letter

An Aγ Type of Nondeletional Hereditary Persistence of Fetal Hemoglobin With a T→ C Mutation at Position -175 to the Cap Site of the Aγ Globin Gene

The nondeletional types of hereditary persistence of fetal hemoglobin (ndHPFH) concern the continued synthesis of hemoglobin (Hb) F with either G gamma or A gamma chains in amounts varying from 5% to 30%. Several mutations have been identified in either the A gamma or G gamma promoter which are considered causative to the continued production of one of the two gamma chains because the substitutions occur in sequence motifs essential for the expression characteristics of the gamma-globin gene in the 3' position. We report the discovery of a T----C mutation at position -175 in the A gamma promoter which was associated with a greatly increased level of Hb F (with mainly A gamma) and a decreased level of Hb A in the one (Black) heterozygote who had a beta c gene in trans. The same mutation has been observed in the G gamma promoter of a Black heterozygote who had high levels of Hb F with G gamma chains only. A detailed comparison between these two individuals indicated significant differences in the levels of Hb F and Hb A which may result from an additional mutation at position -158 in the G gamma promoter.