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D Labie

Publications and source records attributed to D Labie.

At least 37 records · Page 2Linked to original sources
PubMed1989

A gene conversion located 5' to the A gamma gene in linkage disequilibrium with the Bantu haplotype in sickle cell anemia.

Cloning and sequencing of the gamma-globin gene of a sickle cell anemia patient homozygous for the Bantu haplotype has revealed a gene conversion that involves the replacement of an A gamma sequence by a G gamma sequence in the promoter area of the A gamma gene. This event is similar to another gene conversion believed to be responsible for the very high homology between gamma-globin genes, suggesting that the promoter area of these genes is prone to this type of genetic rearrangement. Further analysis demonstrated that the chromosome bearing this gene conversion has a very high frequency among Bantu chromosomes and a very low or nil frequency in other haplotypes linked to the beta s gene. No correlation was found between the G gamma/A gamma ratio and the presence of the gene conversion among Bantu haplotype patients, thus excluding a portion of the gamma gene sequence in the determination of this ratio.

Anemia, Sickle Cell↗
PubMed1989

Nucleotide variations in the 3' A gamma enhancer region are linked to beta-gene cluster haplotypes and are unrelated to fetal hemoglobin expression.

Molecular cloning and sequence analysis of a nondeletion form of Sicilian beta o hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C----T at -158 5' to G gamma, T----C at +2285, C----A at +2476, and A----G at +2676, all 3' to A gamma. The latter three variations in the putative A gamma enhancer are identical to those observed in the case of Seattle HPFH. However, a severe beta o-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variation, albeit an inefficient HbF production. We conclude that the variations in the A gamma enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the beta-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black beta c-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between A gamma and psi beta, which is thus in linkage disequilibrium with the variations in the A gamma enhancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1989

Haplotypes in tribal Indians bearing the sickle gene: evidence for the unicentric origin of the beta S mutation and the unicentric origin of the tribal populations of India.

To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the beta gene cluster in beta S-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the beta S gene are linked in 91% of the cases to the "Asian" (Arab-Indian) haplotype (although 25% of the haplotypes had the epsilon polymorphic site negative, making the 5' portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high G gamma expression (67.2 +/- 5.9%) and a high percentage of Hb F (15.5 +/- 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to beta S in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the beta S gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (-alpha) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The beta S gene linkage to a high Hb F-expressing haplotype and the high incidence of alpha-thalassemia predict a mild phenotypical expression of sickle cell anemia in India.

Anemia, Sickle Cell↗
PubMed1989

The enhancer-like sequence 3' to the A gamma gene is polymorphic in human populations.

Cloning and sequencing of the enhancer 3' of the A gamma globin gene of a particularly low G gamma and HbF sickle cell anemia (SCA) patient unexpectedly revealed three base changes (T----C, C----A, and A----G at sites +2285, +2460, and +2676) previously associated with the Seattle-type HPFH, thus leading the authors to suspect that the three mutations were polymorphic. The determination of the incidence of the mutations among various ethnic groups allowed the authors to conclude that this is a widely spread polymorphism, thus excluding any role of these base changes in the determination of the hereditary persistence of fetal hemoglobin (HPFH) phenotype. The origin of these three mutations is not clear because they appear linked, and the same bases (C, A, G) are found in homologous position in the 3' of the normal G gamma gene. As C, A, G at positions +2285, +2460, and +2676 are found with a 100% frequency in African SS patients and presumably among normal Africans (to explain the extremely high frequency among normal American blacks), it is likely that this was the sequence preceding the division of races. The presence of T, C, and A at the same positions apparently occurred after the divergence between blacks and the other races, that is, within the last 1 million years.

Base Sequence↗
PubMed1988

Beta S gene in Sicily is in linkage disequilibrium with the Benin haplotype: implications for gene flow.

Hemoglobin beta-like gene cluster haplotypes defined by restriction enzyme polymorphic sites are useful in determining the origin of the beta S gene found in several human populations. We present here evidence that the beta S gene found among Sicilians is associated with the same haplotype observed among sickle cell anemia patients from Central West Africa. In addition, this haplotype is either nonexistent or very rare among normal Sicilian individuals. We conclude that the beta S gene was introduced to Sicily from North Africa and that the gene flow originated in Central West Africa and traveled north through historically well-defined trans-Saharan commercial routes.

Anemia, Sickle Cell↗
PubMed1988

Analysis of crossover type in the alpha -3.7 haplotype among sickle cell anemia patients from various parts of Africa.

The frequency of alpha+-thalassemia has been determined in African populations carrying beta S-chromosomes of different origins. All these alpha+ thalassemias result from a right-ward deletion. Restriction mapping of the alpha -3.7/haplotype with the enzyme ApaI only showed the presence of a type I crossover. RsaI polymorphism at the 5' end of Z alpha 2 is largely represented in the normal population (gene frequency 23%) but, in our series, never associated with the alpha -3.7/haplotype.

Africa↗
PubMed1988

DNA haplotype distribution in Algerian beta thalassaemia patients. An extended evaluation by family studies and representative molecular characterization.

An evaluation of beta thalassaemia mutations and the associated chromosomal haplotypes has been made among Algerian thalassaemic patients in this extended series. The major features of our findings are: (i) due to elevated proportion of consanguinity, the frequency of true homozygotes for a defect is high; (ii) Despite this high homozygosity within families, the number of molecular defects resulting in beta thalassaemia are very heterogeneous within this population. This is exemplified not only by the high heterogeneity of haplotypes and associated mutations, but also by the definition of several new haplotypes, among which two of them were found to be associated with novel mutations. Family studies have been performed in parallel to evaluate the degree of feasibility of antenatal diagnosis in this population.

Algeria↗
PubMed1988

Structural analysis of the 5' flanking region of the beta-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa.

Haplotype analysis of the beta-globin gene cluster shows two regions of DNA characterized by nonrandom association of restriction site polymorphisms. These regions are separated by a variable segment containing the repeated sequences (ATTTT)n and (AT)xTy, which might be involved in recombinational events. Studies of haplotypes linked to the sickle cell gene in Africa provide strong argument for three origins of the mutation: Benin, Senegal, and the Central African Republic. Nevertheless, the haplotype determination does not give any information about the variable segment and does not totally exclude the possibility of recombination leading to different haplotypes linked to the mutation. The structure of the variable segment in the three African populations was studied by S1 nuclease mapping of genomic DNA, which allows a comparison of several samples. A 1080-base-pair DNA segment was sequenced for one sample from each population. S1 nuclease mapping confirmed the homogeneity of each population with regard to both (ATTTT)n and (AT)xTy repeats. We found three additional structures for (AT)xTy correlating with the geographic origin of the patients. Ten other nucleotide positions, 5' and 3' to the (AT)xTy copies, were found to be variable when compared to homologous sequences from human and monkey DNAs. These results allow us to propose an evolutionary scheme for the polymorphisms in the 5' flanking region of the beta-globin gene. The results strongly support the hypothesis of three origins for the sickle mutation in Africa.

Africa↗
PubMed1988

Interaction of deletional alpha-thalassaemia with sickle cell beta-thalassaemia and its influence on foetal haemoglobin expression.

A rare association of three haemoglobin defects, viz: traits for deletion form of alpha-thalassaemia, beta-thalassaemia, and sickle cell gene, in a family of French West Indies origin, was studied both at phenotype and genotype levels. In this sickle cell beta-thalassaemia, interacting alpha-thalassaemia is shown to influence the foetal haemoglobin expression. A reverse relationship between the foetal haemoglobin level and the number of alpha genes was observed.

Anemia, Sickle Cell↗
PubMed1988

[Hereditary persistence of fetal hemoglobin associated with mutation above the gamma gene].

Fetal hemoglobin is normally present but as an extremely minor constituent in red cells during adult life. Its persistence or reappearance in various conditions is encountered mainly in the course of major hemoglobinopathies, but can also exist in the absence of any pathological symptom, defining the group of the so called Hereditary Persistence of Fetal hemoglobin (HPFH). We report here a case of G gamma beta + HPFH due to a C----G mutation 202 bp 5' to the Cap Site of the G gamma gene, in a region of major importance for controlling the gamma gene expression.

Chromosome Aberrations↗
PubMed1987

The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between G gamma and HbF level.

Previous work has demonstrated that the HbS gene has appeared and expanded three times in Africa in three separate geographic locations and that these three distinct mutational events can be identified by linked DNA polymorphic sites (haplotypes) surrounding the abnormal gene. We have reported that the Senegalese and Beninian haplotypes differ in G gamma expression, mean percentage of HbF, and percentage of dense cells. We now report on the third haplotype, the Bantu, and find that it has intermediate features, namely, the high mean percentage of HbF and low percentage of dense cells associated with the Senegalese haplotype, but with a low percentage of G gamma expression similar to the Beninian haplotype. The distribution of percent HbF is quite different from Senegal haplotype-bearing sickle cell anemia patients since it covers a much wider range. The low G gamma expression is also different from the Beninians since it contains a significant and unique cluster of individuals with lower than 38% G gamma. Interestingly, among the Bantu there is a strong correlation between HbF levels and G gamma expression, which is not seen with the other haplotypes. These findings open the possibility that among the Bantu haplotype-bearing individuals two chromosomal types exist that define different levels of G gamma and HbF expression. Further structural exploration of these two potential subhaplotypes is needed.

Anemia, Sickle Cell↗
PubMed1987

[Analysis of the recombination zone in hereditary persistence of fetal hemoglobin with fetal gene rearrangement of the G gamma-G gamma-A gamma type].

An increased synthesis of fetal hemoglobin in adult life is a common feature of the genetically determined severe disorders like beta thalassemia and sickle cell anemia. A continued synthesis of fetal hemoglobin in adults is also characteristic of clinical or subclinical syndromes like respectively delta beta thalassemia or hereditary persistence of fetal hemoglobin (HPFH). These disorders are highly heterogeneous with respect to their molecular defects as well as to the composition of Hb F. We report here a novel case of hereditary persistence of fetal hemoglobin in heterozygous state discovered by chance, in a young perfectly healthy french man. The gamma chain of his fetal hemoglobin was almost entirely composed of G gamma chains. Molecular analysis of the DNA revealed the existence of triplicated gamma genes on one chromosome with the genotype arrangement of G gamma-G gamma-A gamma. A polymorphic Xmn I restriction site (at position -158 5' to the cap site) was present in 5' of both of these G gamma genes. The presence of this site in front of G gamma gene had previously been shown to be associated both with high G gamma phenotype constitutively and also with high fetal hemoglobin level only in case of anemic stress. In the absence of any anemic stress in this individual, the constitutive increase of both fetal hemoglobin and G gamma chains could be due to the presence of a chromosome with triplicated arrangement of gamma genes. The classical triplication (G gamma-A gamma-G gamma-A gamma) does not result in HPFH phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Differences in DNase I sensitivity and methylation within the human beta-globin gene domain and correlation with expression.

We have analysed the chromatin features of DNA regions encompassing human epsilon, G gamma, A gamma, delta and beta globin structural genes in fetal and adult erythroid cells on the one hand and adult lymphocytes on the other. Highly purified nuclei from these cells were submitted to DNase I digestion and the kinetic data were obtained from the percentage of residual hybridization of defined regions in Southern blots. Our results, as others have shown by different approaches, indicate that the structural genes of the beta-globin cluster are generally more sensitive to DNase I in the erythroid cells than in non-erythroid cells. Thus a domain of DNase I sensitivity related to the committed state is defined. In addition we show that within this DNase-I-sensitive beta cluster domain, individual genes of the cluster are arranged in subdomains of differential DNase I sensitivity, which correlate with their expression status. Furthermore the differential expression of the two fetal genes in the fetal stage is shown to be directly proportional to the degree of hypomethylation of these genes.

Adult↗
PubMed1986

Heterogeneity of sickle cell disease as shown by density profiles: effects of fetal hemoglobin and alpha thalassemia.

Factors that modify the intraerythrocytic concentration of hemoglobin S may influence the clinical expression of the disease. Using the phthalate ester method, the red blood cell density has been studied as a function of the mean corpuscular hemoglobin concentration. Four parameters have been used to compare the density distribution of the erythrocytes: D50 (median cell density), R60 (density range in which the middle 60% of the cells are found), F4 and F5 (proportion of cells with density greater than 1.110 and 1.120 g/ml). Compared to normal controls the density distribution of sickle red cells is heterogeneous, reproducible for the same patient (except in case of crisis), while different from one to another. The R60 is correlated with the percentage of dense cells, and the highest values for both R60 and dense cells are found when hemoglobin F is less than 10%. The highest values for the median cell density and dense red cells, but not for R60 which is normal, are observed in S/C patients. In sickle cell anemia patients, the median cell density values are not very different from the normal ones. The highest levels of hemoglobin F are found in this median subpopulation of red cells, while they are very low in the densest cells. R60 and the percentage of dense cells are not affected by the association of sickle cell disease with the deletion of one alpha gene. Their values are very near the normal ones in the case of an association with beta thalassemia or homozygous alpha thalassemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Sickle Cell↗
PubMed1985

[Homozygous beta-thalassemia in Algeria. Study of 50 cases].

The clinical and laboratory data recorded at first presentation in 50 homozygous beta-thalassaemic untransfused children seen at the National Transfusion Centre, Algiers, are reported. These children came from 38 families, including 25 with consanguinous parents. Pallor was observed in all cases but jaundice and asthenia were present in only 11 and 10 children respectively. Splenomegaly was frequent (45 cases), as were skeletal changes mainly in the skull and face (35 cases). Haemoglobin levels ranged from 2.4 to 9.6 g/dl and MCV from 71 to 89 fl. Among these 50 patients, 34 had beta + thalassaemia and 16 beta 0 thalassaemia. Levels of foetal haemoglobin (Hb F) were similar in both groups but clinical symptoms appeared earlier in beta 0 thalassaemia patients. Thirty-seven cases were diagnosed as thalassaemia major and 6 as thalassaemia intermedia. Comparison of various parameters between siblings (20 children belonging to 9 families) showed no differences between Hb F and Hb A2 levels and clinical courses. These findings should be taken into consideration for the prenatal diagnosis of beta-thalassaemia.

Algeria↗