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D Labie

Publications and source records attributed to D Labie.

At least 19 recordsLinked to original sources
PubMed2002

Two novel CD1 E alleles identified in black African individuals.

CD1 gene (CD1A to CD1E) products are involved in non-peptide antigen presentation, such as lipids and glycolipids, to T cells. With a similar function to MHC, namely antigen presentation, these genes nevertheless displayed a much lower level of polymorphism as compared to MHC. We report here two additional CD1E variants identified in black African individuals, designated herein CD1E*05 and CD1E*06. While the former differs from the common (wild type) allele sequence by two substitutions at nucleotide positions 217 and 229 of exon 2, the latter only by a single base change at position 91 of exon 3. These substitutions lead to amino acid changes at position 73 and 77 of the alpha1 domain in the former and at position 30 of the alpha2 domain in the latter. Identification of these additional variants suggests that the CD1 locus, especially the CD1E gene, is much more polymorphic than previously assumed.

Africa↗
PubMed1999

Genetic variations in human fetal globin gene microsatellites and their functional relevance.

Short tandem repeats are abundantly present within the genome. They are commonly used as polymorphic markers but their potential functional role is poorly documented. Several of these microsatellites have been described within the beta-globin locus and some could be involved in controlling gene expression. Our purpose was to investigate the extent and significance of the (TG)n(CG)m dinucleotide repeat polymorphisms in the two gamma-globin gene IVS2s. Two groups of subjects were studied: a group of 63 beta-thalassaemic patients presenting either with a severe Cooley's anaemia (n=50) or with thalassaemia intermedia (TI, n=13), and a control group of 60 unrelated healthy individuals. A high heterogeneity of the polymorphic repeats was demonstrated, extending the range of the published alleles from 13 to 22 and allowing a first attempt at making a phenotype/genotype correlation. One specific allele, (TG)13 in the Agamma-gene, was highly enriched in the TI patients (46.1% vs 2.9% of the Cooley's anaemia cases, P < 0.0002, and 23.3% in the normal controls, P < 0.008) and preferentially observed in TI patients with a high haemoglobin F (Hb F). Transient transfection assays in K562 cells, with the growth hormone gene as a reporter, showed a positive regulatory action mediated by a (TG)13-containing 243 nt IVS2 fragment. Finally, a first set of mobility shift experiments with erythroid (K562 and MEL) and nonerythroid (HeLa) cell lines showed binding of erythroid component(s) in this DNA region and the binding pattern was modified upon induction of MEL cells by DMSO. Thus, our in vivo and in vitro data raise the question of a possible contribution of the gamma-gene IVS2s polymorphic microsatellites to the variable Hb F synthesis in the major haemoglobinopathies: a well known, puzzling and still unanswered question.

Cell Line↗
PubMed1999

Long-term hydroxyurea treatment in young sickle cell patients.

Hydroxyurea is the first drug that, under well-organized, large-scale trials in adults, has shown a beneficial effect on the clinical course of sickle cell disease. Several small-scale trials have been conducted in children, but they used different therapeutic schedules, and only one was a single-blind crossover trial. Still, children are clearly good responders to the treatment because a rapid clinical improvement was observed, with decreased frequencies of vaso-occlusive crises, acute chest syndromes, and transfusion requirements. Despite large interindividual variations, virtually all the children studied increased their fetal hemoglobin, mean corpuscular volume, and total hemoglobin. Follow-up varied from 6 months to 59 months. More than in adults, the fetal hemoglobin increase was sustained, and few side effects were observed. Large-scale, placebo-controlled studies seem no longer needed. Guidelines concerning patient selection, dosing schedules, and monitoring protocols as well as exhaustive registries for the detection of long-term side effects are necessary.

Adolescent↗
PubMed1999

[Molecular and cellular pathophysiology of sickle cell anemia].

The beta S mutation responsible for sickle cell disease (SCD) was identified in 1949. This mutation always consists in a T for A substitution at codon 6 of the beta-globin chain. Deoxygenated HbS becomes polymerized, producing erythrocyte shape changes and vasoocclusion. Still unexplained is the wide variability in clinical expression of SCD, whose spectrum ranges from severely incapacitating forms to virtually silent forms. Recent research has focused on genetic or environmental factors that may interfere with one or more steps of the basic pathophysiologic mechanisms. These factors can be roughly classified in three groups: i) factors that modify HbS levels within erythrocytes, thereby impacting the propensity of HbS for polymerization; ii) other normal or abnormal hemoglobins present in the erythrocyte that may modify side contacts of the hemoglobin molecule within the polymer, thus either stopping or enhancing polymerization; iii) molecules other than hemoglobin expressed at the surface of the SCD reticulocytes that may adhere to the vascular endothelium, thus slowing flow in the microcirculation and delaying HbS reoxygenation. Whatever the starting point, the same vicious circle is set in motion. These mechanisms have generally been studied separately, in vitro, under artificial conditions. An important goal is to understand how they interact in vivo in a given patient.

Anemia, Sickle Cell↗
PubMed1998

Diversity of sequence haplotypes associated with beta-thalassaemia mutations in Algeria: implications for their origin.

We report the allelic sequence polymorphism associated with seven beta-thalassaemia mutations. Thirty-two DNAs originating from Algeria and 12 DNAs from Sardinia and Sicily were investigated. Their analysis revealed an association with a unique haplotype for three beta-thalassaemia mutations (-29, IVS-I-2 and IVS-I-1). It seems clear that these mutations have a unicentric origin. The presence of the -29 mutation could be explained by migration and founding effect. However, the local origin of IVS-I-2 seems clear. The four other mutations, FS6, IVS-I-6, IVS-I-110 and stop39 were found to be associated with at least two different sequence haplotypes. The likelihood of so many recurrent nucleotide dimorphisms in different lineages as a consequence of random mutation is very low; it is supported neither by the analysis of equivalent regions in other primates, nor by the presence of highly mutable sites such as CpG dinucleotides. The fact that these mutations are found exclusively in the Mediterranean area is not in favour of a recurrent origin of the mutation. The diversity is far more important for the preponderant thalassaemia mutations of the Mediterranean area and is higher in the 5' part of the beta-globin gene. Hence, the IVS-I-110, the preponderant beta-thalassaemia in the Eastern Mediterranean, probably emerged in the extension of the fertile crescent. For the stop39, all the data support the hypothesis of a West-Mediterranean origin. The diversity of haplotypes would then be generated by recombination events (crossing-over or gene conversions) between the original beta-thalassaemia chromosome and the other chomosomal structures present in the normal population.

Algeria↗
PubMed1997

Dissection of the association status of two polymorphisms in the beta-globin gene cluster with variations in F-cell number in non-anemic individuals.

Expression of fetal hemoglobin (Hb F) is under polygenic control involving determinants both linked and unlinked to the beta-globin gene cluster on chromosome 11. Variations in the DNase I-hypersensitive site 2 of the locus control region (LCR-HS2) and a C --> T change at position -158 from the Ggamma-gene (detected as an XmnI polymorphism) correlate with the high level of Hb F expression in patients with sickle-cell anemia and beta-thalassemia. Interpretation of data under these conditions of anemic stress is difficult because the preferential survival of Hb F-containing erythrocytes (F-cells) may not reflect the true status of Hb F expression. We investigated the relationship between these markers and Hb F expression in terms of F-cell levels in 48 unrelated non-anemic AS heterozygotes from Sicily. The betaS-chromosome of all these individuals was of the Benin haplotype and they differed only by their betaA chromosomes. We demonstrate that F-cell expression is more strongly associated with LCR-HS2 polymorphism than with XmnI polymorphism. The observed association between XmnI polymorphism and Hb F expression is very likely to be due to linkage disequilibrium with LCR-HS2 sequences.

Adult↗
PubMed1997

Molecular basis of alpha-thalassemia in Sicily.

To evaluate the allelic frequency and genetic diversity of alpha-thalassemia defects in Sicily, both epidemiological and patient-oriented studies were carried out. For the epidemiological study, phenotypic data were collected on more than 1000 Sicilian individuals. Among them, 427 were explored at the molecular level for nine alpha-thalassemic variants known to be common in the Mediterranean region. Our data reveal an allele frequency of 4.1% for alpha(+)-thalassemia matching that of beta-thalassemia in this region. The presence of alpha0-thalassemia (--MEDI and --CAL) was observed only in the group of referred patients. Newly acquired nucleotide sequence data on the deletional breakpoint of --CAL allowed us to design a simple PCR-based procedure for exploring this allele. The data also provide additional information concerning the genetic mechanisms involved in such large deletions.

Adolescent↗
PubMed1996

Sequence polymorphisms of potential functional relevance in the beta-globin gene locus.

The purpose of this review is to give a general up-date of the most recent developments concerning polymorphisms within the beta-globin gene cluster. The first polymorphisms to be identified were mostly restriction fragment length polymorphisms. They were important markers both for their use as diagnostic tools and for anthropological investigations. Although they have been associated with specific patterns of globin gene expression in the hemoglobinopathies, none have been demonstrated to have any intrinsic functional significance. More recently, additional single nucleotide variations and microsatellite-like polymorphic simple sequence repeats have been identified which are frequently located in trans-acting protein binding segments and hence might affect regulatory processes.

Anemia, Sickle Cell↗
PubMed1994

Fetal haemoglobin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease.

Haematological features of 64 patients suffering from non operable cyanotic congenital heart disease (CCHD) treated with hydroxyurea (HU) were compared with those of 43 patients suffering from the same disorder who had not yet received this drug. Patients with subclinical renal dysfunction were excluded by measuring plasma creatinine levels. MCV and HbF were higher among patients receiving HU, the increase in MCV being cumulative with HU dosage but the rise in HbF dose independent. HbF response to HU was found to be due to the coordinated increase in F-cell and F-reticulocyte production rather than to a selective survival of F-cells. Absence of a relationship between plasma erythropoietin and HbF levels excluded a dominant role of the former in increasing F-cell production and results determined after doubling the HU dosage or immediately after initiating therapy suggested genetic differences to be responsible for the individual variations in Hb F response. No irreversible toxic effects or malignancies were noted in this series of patients. HU was administered for a relatively long period of time, the mean duration of treatment exceeding 5 years, while the study also included patients below the age of 10 years.

Adolescent↗
PubMed1994

Anthropological approach to the heterogeneity of beta-thalassemia mutations in northern Africa.

Results of an epidemiological survey for beta-thalassemic defects involving 239 chromosomes in Algeria are analyzed in relation to the geographic and historical background of the country and are compared with published series for the Tunisian population. Four common mutations account for 81% of the chromosomes, but 13 other defects have been found, illustrating the highly heterogeneous nature of the disease in the northern African countries of the Maghreb. The high frequency of homozygous cases reflects the endogamous social structure of these populations. Distribution of the mutations and linkage to specific RFLP haplotypes provide information concerning their origin and date of introduction in good correlation with the anthropological history of Algeria.

Algeria↗