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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↗
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

Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type.

Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa.

Adult↗
PubMed1985

Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients.

We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozygotes, and the Senegal haplotype in sickle cell anemia patients are all linked to high G gamma-globin expression. In addition, haplotypes IX and Senegal, but not haplotype III, have high Hb F levels. All of these haplotype have a common subhaplotype (+- ) in the gamma-globin gene region. In addition, haplotypes IX, III, and Senegalese sickle cell anemia patients exhibit hematological amelioration of their disease. Conversely, haplotypes I, V, and A in thalassemia patients, which also have a common subhaplotype (-----), and the Benin subhaplotype (--++-) in sickle cell anemia patients are all associated with low G gamma-globin and low Hb F levels. Low G gamma-globin expression in the adult is associated with two haplotypes that are not common between thalassemia and sickle cell anemia patients. We conclude that the determinant for high G gamma-globin expression is haplotype-linked to common and genetically dominant subhaplotypes in the two diseases. The total Hb F level, unlike the high G gamma-globin expression, however, is linked to haplotypes but not to subhaplotypes, thus dissociating the two genetic effects.

Anemia, Sickle Cell↗
PubMed1985

[Genetic polymorphism of drepanocytosis].

The pathophysiological mechanism of sickle cell anemia has been thoroughly studied and is now well understood, in contrast to the extreme clinical heterogeneity of the disease. A possible genetic explanation for this diversity arose from the discovery of an HpaI restriction polymorphism 3' to the beta globin gene, in linkage disequilibrium with the Hb S mutation. This linkage is unequally distributed among ethnic groups in Africa and predominantly found in Central West Africa. A multipolymorphic analysis spanning 60 Kb of the beta globin gene cluster demonstrated that the sickle mutation arose at least 3 times in 3 different geographical areas (Atlantic West Africa, Central West Africa and Equatorial Central Africa) and expanded by malaria selection. Two genetic factors seem to have epistatic effects which differ when comparing the two first groups. The alpha thalassemia gene (-alpha) is distributed equally among African Black control populations (0.10). The frequency is significantly higher in the SS patients of the Benin area (Central West Africa), whereas it is unmodified in the patients of Senegal (Atlantic West Africa). Alpha thalassemia does not seem therefore to have exercised the same selective effect in this latter group. Secondly, fetal hemoglobin is quantitatively and qualitatively different in both groups. A high G gamma phenotype (greater than 60%) is found in Senegal, whereas a low G gamma phenotype is constant in Benin, without overlap between the two series. The total production of fetal hemoglobin is statistically higher, although only moderately, so in the first group.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa, Central↗