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Biomedical subjects

D Labie

Publications and source records attributed to D Labie.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1985

The -158 site 5' to the G gamma gene and G gamma expression.

To test the hypothesis advanced by Gilman and Huisman that the -158 site 5' to the G gamma gene determines the G gamma expression after the first 4 months of life, we have examined DNA from sickle cell anemia (SS) patients from Africa and beta-thalassemic homozygotes from Algeria. We find that the Xmnl site is strongly linked to the Senegal haplotype among SS patients, to haplotype IX (most probably identical to the Senegal haplotype), and to haplotype III among the Algerian thalassemics. Thalassemics with haplotypes I/I and V/V have no Xmnl site and low G gamma expression. In contrast, beta-thalassemia-associated haplotype II (also characterized by high G gamma expression) fails to exhibit the Xmnl site. We conclude that, although highly correlated, the -158 C----T substitution does not perfectly predict the presence of high G gamma expression. These findings also exclude the possibility that the Xmnl site is solely involved in the determination of high G gamma expression and suggest that either several different site substitutions in the area 5' to the gamma gene might have the same effect or that, alternatively, the Xmnl site and its surrounding area is not involved in G gamma expression and may be only in linkage disequilibrium with a controlling sequence elsewhere.

Africa↗
PubMed1984

Covalent structures of beta and gamma autolytic derivatives of human alpha-thrombin.

Nonclotting beta- and gamma-thrombins have been prepared by autolysis of human alpha-thrombin at pH 8.6 in the presence of 0.4 M NaCl and purified on BioRex 70. Reduced and carbamidomethylated A and B chains fragments were separated by gel filtration and reverse phase high performance liquid chromatography. Structural characterization of these fragments demonstrated that alpha to beta conversion results from two cleavages at Arg 62 and Arg 73 in the B chain, releasing an intact 11-residue peptide. beta to gamma conversion corresponds to the additional loss of a fragment of the B chain stretching from Ile 124 to Lys 154. Autolysis is not accompanied by cleavages in the A chain. Loss of clotting activity is therefore related solely to the excision of residues 63 to 73 in the B chain. With the exception of cleavage at Arg 73, these results differ from a proposed model for alpha to gamma conversion of bovine thrombin.

Amino Acid Sequence↗
PubMed1984

Structure and function of Hb Saint-Jacques (alpha 2 beta 2 140 (H18) Ala----Thr): a new high-oxygen-affinity variant with altered bisphosphoglycerate binding.

A low P50 value in a fresh red blood cell suspension was discovered in a polycythemic patient (Hb 19 g X dl-1). Routine acid and alkaline electrophoreses of the hemolysate were identical to normal hemolysate. Isoelectrofocusing (pH gradient 6-8) did not reveal any abnormal band whether performed with the fully liganded or deoxygenated samples. Precise analyses of the oxygen dissociation curves of the propositus' red cells demonstrated a biphasic Hill plot, a normal Bohr effect and low interaction with 2,3-bisphosphoglycerate (2,3-DPG). Studies on the unfractionated hemolysate confirmed these observations and the inhibition of the effect of organic phosphates. Structural studies were carried out on the mixture of beta A + beta X chains and revealed the presence of two beta Tp14 peptides. Sequencing the abnormal beta Tp14 peptide showed the substitution Ala----Thr of the beta 140 (H18) residue. This new variant was named Hb Saint-Jacques. Examination of the three dimensional model of HbAo indicates that the substitution beta 140 (H18) Ala----Thr induces van der Waals interactions with the nearby lysine-82 (EF6) and leucine-81 (EF5) and a displacement of the EF corner of the beta chains. This is likely to change the normal position of the lysine-82 (EF6), a major anionic binding site in the central cavity between the two beta chains. Functional studies confirm the interpretation of a steric hindrance inhibiting the binding of large organic phosphates to Hb Saint-Jacques.

2,3-Diphosphoglycerate↗
PubMed1984

Immobilized pH gradients and reversed-phase high-performance liquid chromatography: a strategy for characterization of haemoglobin variants with electrophoretic mobility identical to that of Hb A. The case of Hb San Diego.

The preparative aspects of immobilized pH gradients applied to abnormal haemoglobins (Hb) is described. As shown with the example of Hb San Diego, this method is successful even with as small a difference in pHi as 0.01 pH unit. For characterization of such neutral variants, reversed-phase high-performance liquid chromatography is demonstrated to be a very efficient tool.

Amino Acids↗
PubMed1984

A leftward deletional alpha+ thalassemia found in East Sicily in conjunction with heterozygous beta-thalassemia.

Two types of alpha+ thalassemia (-alpha l) have been described, respectively termed leftward and rightward, which correspond to nonhomologous crossing-over in different homology zones X and Z within the alpha-globin gene cluster. Up to now the leftward type has been described only in Asiatic populations, whereas the rightward type is universally distributed. We report here a first case of leftward deletion observed in a Sicilian male. This raises the question of an identical or not crossing-over event.

Aged↗
PubMed1984

Hemoglobins S and C in Upper Volta.

We have studied the incidence of hemoglobinopathies in 1059 individuals in Upper Volta. We have found that this population has a high frequency of HbS and HbC and alpha-thalassemia. The gene frequency of HbS was high (0.1 for the beta s gene) in the arid Sahel portion of Upper Volta accompanied by a lower frequency for HbC (0.05 for the beta c gene). The reverse was true in the humid Savanna region of this country (0.03 for the beta s gene and 0.14 for the beta c gene). There was no age dependency of the HbS gene frequency, but alpha-thalassemia, detectable in HbS heterozygotes, showed a statistically significant decrease with age. No homozygote for HbS was detected after the age of 1 year, and SC and CC genotypes were found at a lower incidence than expected. The environmental and medical conditions in Upper Volta preclude the survival of SS individuals and decrease the survival of SC and CC genotypes.

Adolescent↗
PubMed1984

alpha-Thalassemia among sickle cell anemia patients in various African populations.

We have studied the incidence of alpha-thalassemia in normal and SS individuals from Senegal, Benin, Upper Volta, and Central Republican Africa. The alpha thal gene frequency is not significantly different in the controls from the various populations and in the SS patients from Senegal. In contrast it is compatible with increased survival of SS patients in Benin, Upper Volta. The data suggest epistatic effects of other factors in the Senegalese population.

Adolescent↗
PubMed1984

Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa.

Previous studies of the Hpa I cleavage site-sickle cell hemoglobin gene linkage in various African populations suggested that the sickle gene arose independently more than once. In the present study we have performed restriction endonuclease haplotype analysis for the beta-globin-like gene cluster from four separate geographic areas in Africa, all of which possess the sickle gene. In Benin (Central West Africa) and Algeria (Arab North Africa) all chromosomes carrying the sickle gene possess an identical haplotype as defined by 11 different polymorphic restriction endonuclease sites within the 60-kilobase region of the beta-globin-like gene cluster. In the Central African Republic (Bantu-speaking Africa) and in Senegal (Atlantic West Africa) a very large proportion of the sickle gene chromosomes were associated with a haplotype specific for each country. Thus, three different haplotypes are shown to be associated with the sickle gene in Africa, and each is present at a very high frequency in geographically separate regions. Since the three haplotypes differ from each other by at least three sites residing both 5' and 3' to a putative hot spot for recombination, it is most likely that the sickle gene arose at least three times on separate preexisting chromosomal haplotypes. This may have implications for a better understanding of the variable nature of the expression of sickle cell anemia, because clinically relevant sequences (for example, gamma-globin gene regulatory sequences responsive to anemia) might be linked polymorphically to these haplotypes.

Africa↗
PubMed1984

Linkage between fetal A gamma globin chain polymorphism and DNA polymorphism of the human beta gene cluster in beta thalassaemia.

The association between the polymorphism of the A gamma chain of human fetal haemoglobin and the DNA polymorphism at the beta gene cluster has been investigated. The A gamma 75 threonine mutation was found in association with haplotypes II and VI described by Orkin et al. (1982), which share the HindIII cleavage site in the A gamma IVS 2 sequence. The distance between the two polymorphic sites is 868 base-pairs. In contrast, haplotypes I, III, V and IX which do not possess this HindIII cleavage site were associated with the normal A gamma 75 isoleucine allele. The simple detection of the gamma gene polymorphism at the protein level can be useful for identifying DNA haplotypes, and therefore beta thalassaemic mutations.

Chromosome Mapping↗
PubMed1984

[Erythrocytosis due to a high-affinity hemoglobulin: mutant hemoglobin Saint-Jacques beta 140 (H18) Ala----Thr with a change in the 2,3-diphosphoglycerate binding site].

All the high oxygen affinity variants have substitutions in regions that are crucial to hemoglobin function: mainly the alpha 1 beta 2 interface, the C-terminal end of the beta chain and the aminoacid residues involved in the 2,3 disphophoglycerate (2,3 DPG) binding site. In this report we describe a new variant with familial erythrocytosis: hemoglobin Saint-Jacques beta 140 (H18) Ala----Thr, whose main abnormality is a defect in organic phosphate binding in the central cavity between to two beta chains. This variant could not be separated from hemoglobin A by standard electrophoretic methods or by isoelectric focusing. The abnormal peptide was isolated by reverse-phase high performance liquid chromatography and the structural modification determined by manual sequencing micro-method. Functional studies on red blood cells as well as on stripped lysate showed increased oxygen affinity, normal Bohr effect, decreased heme-heme interaction and loss of the 2,3 DPG regulatory effect.

2,3-Diphosphoglycerate↗
PubMed1983

Monosaccharides bound to hemoglobins in normal and diabetic individuals. Evidence for glucose, mannose and galactose as sugars released by methanolysis of the different hemoglobin components.

Direct evidence is given for the presence of glucose, mannose and galactose as the products of hydrolysis of hemoglobins A1a1, A1a2, A1b, A1c and A0. The presence of galactose cannot be explained by the earlier hypothesis of Amadori rearrangement and suggests the existence of further complex rearrangements. Monosaccharide content of the different hemoglobin components varies from 0.2-2.0 mol/mol of alpha beta dimer with an increase of 1.5-2.0-times in diabetic components. This increase is not accompanied by net charge differences, suggesting that additionally bound sugars are not responsible for the pI modification of these hemoglobins. The pattern of glucose, mannose and galactose ratio in normal individuals divides these hemoglobins into two classes, hemoglobins A1b, A1c and A0 (ratio 0.60:0.25:0.15) on one hand and hemoglobins A1a1 and A1a2 (ratio 0.40:0.40: 0.20) on the other. These findings suggest that diverse mechanisms for sugar binding might exist between these two classes of glycosylated hemoglobins. This difference disappears in diabetic components suggesting that the non-NH2-terminal sites are glycosylated in all components by a common mechanism. Increase in glucose at the expense of mannose and galactose, as observed in diabetics, could be an indicator of recent glycosylation.

Blood Glucose↗