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J Elion

Publications and source records attributed to J Elion.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Pharmacogenetics or "farm-ecogenetics"?].

Pharmacogenetics and ecogenetics constitute the study of the contribution of genetic factors in interindividual variations in drugs and xenobiotics metabolism respectively and also its physiopathology (toxicity, therapeutic failure and pejorative effect). However, the frontiers between these two fields are interpenetrant with no defined limits. Among the enzymes involved in transformation of drugs/xenobiotics, the cytochrome P450 superfamily plays a major role. Most of the "poor metabolisers" either homozygotes or compound heterozygotes for mutant cytochrome P450 alleles have no detectable enzyme activity. Although phenotyping using a marker drug is usefull, it suffers from several constraints and is influenced by several environmental factors and physiopathological state of the individual. To overcome not only these difficulties but also to improve the overall predictiveness of a drug biotransformation, genotype technology offers an advantage and pharmaco-economic technology further expands the horizon. These fast moving fields must, in near future, allow tailoring of drug prescription on a personalized basis and should, in principle, help in the design and development of novel drug molecules.

Biotransformation↗
PubMed2000

Identification of regions of the Escherichia coli chromosome specific for neonatal meningitis-associated strains.

Specific virulence factors associated with the pathogenesis of Escherichia coli strains causing neonatal meningitis (ECNM), such as the K1 capsular polysaccharide, the S fimbriae, and the Ibe10 protein, have been previously identified. However, some other yet unidentified factors are likely to be involved in the pathogenesis of ECNM. To identify specialized unique DNA regions associated with ECNM virulence, we used the representational difference analysis technique. The genomes of two strains belonging to nonpathogenic phylogenetic group A of the ECOR reference collection were subtracted from E. coli strain C5, isolated from a case of neonatal meningitis. Strain C5 belongs to the phylogenetic group B2 as do the majority of ECNM. We have isolated and mapped 64 DNA fragments which are specific for strain C5 and not found in nonpathogenic strains. Of these clones, 44 were clustered in six distinct regions on the chromosome. The sfa and ibe10 genes were located in regions 2 and 6, respectively. A group of genes (cnf1, hra, hly, and prs) known to be present in a pathogenicity island of the uropathogenic strain E. coli J96 colocalized with region 6. The occurrence of these DNA regions was tested in a set of meningitis-associated strains and in a control group composed of non-meningitis-associated strains belonging to the same B2 group. Regions 1, 3, and 4 were present in 91, 82, and 81%, respectively, of the meningitis strains and in 40, 13, and 47% of the control strains. Together, these data suggest that regions 1, 3, and 4 code for factors associated with the ability of E. coli to invade the meninges of neonates.

Blotting, Southern↗
PubMed2000

Ethnic heterogeneity of the factor XIII Val34Leu polymorphism.

A polymorphism in the coagulation factor XIII gene (FXIII Val34Leu) has been recently described to confer protection for arterial and venous thrombosis and to predispose to intracerebral hemorrhage. At present it is known that FXIII Val34Leu is prevalent in Caucasians, but information upon its distribution in different ethnic groups is scarce. We investigated the prevalence of FXIIIVal34Leu in 450 unrelated subjects of four ethnic groups: 97 Caucasians (Brazilians of European descent and Portuguese), 149 Blacks (Brazilians, and Africans from Cameroon, Zaire and Angola), 40 Asians (Japanese descendents) and 164 Amerindians from South America. PCR amplification of exon 2 of FXIII gene followed by MseI restriction-digestion was employed to define the genotypes. FXIIIVal34Leu was detected in 44.3% of the Caucasians, in 28.9% of the Blacks, in 2.5% of the Asians and in 51.2% of the Amerindians. These data confirm that FXIII Val34Leu is highly prevalent in Caucasians and indicate that it is rarer in populations of African origin. The very high frequency among Amerindians indicates that FXIII Val34Leu is not absent among Asians, and since it has a very low prevalence in Japanese, a heterogeneity in its distribution in Asia may be inferred. Taken together, our data showed that FXIII Val34Leu exhibits a significant ethnic heterogeneity, a finding that is relevant for studies relating this polymorphism with thrombotic and bleeding disorders.

Factor XIII↗
PubMed1999

Genetic diversity of two African and sixteen South American populations determined on the basis of six hypervariable loci.

A total of 582 individuals (1,164 chromosomes) from two African, eight African-derived South American, five South American Amerindian, and three Brazilian urban populations were studied at four variable number of tandem repeat (VNTR) and two short tandem repeat (STR) hypervariable loci. These two sets of loci did not show distinct allele profiles, which might be expected if different processes promoted their molecular differentiation. The two African groups showed little difference between them, and their intrapopulational variation was similar to those obtained in the African-derived South American communities. The latter showed different degrees of interpopulation variability, despite the fact that they presented almost identical average degrees of non-African admixture. The F(ST) single locus estimates differed in the five sets of populations, probably due to genetic drift, indicating the need to consider population structure in the evaluation of their total variability. A high interpopulational diversity was found among Amerindian populations in relation to Brazilian African-derived isolated communities. This is probably a consequence of the differences in the patterns of gene flow and genetic drift that each of these semi-isolated groups experienced.

Alleles↗
PubMed1999

Compound SFTPB 1549C-->GAA (121ins2) and 457delC heterozygosity in severe congenital lung disease and surfactant protein B (SP-B) deficiency.

Several human respiratory disorders have been linked to an abnormality of pulmonary surfactant synthesis or turnover. Among those conditions, hereditary deficiency in the hydrophobic surfactant protein B (SP-B) has been recognized as a rare cause of respiratory failure in term newborn infants. Homozygosity for a common mutation (1549C-->GAA, or 121ins2) of the SP-B-encoding gene (SFTPB) results in rapidly fatal respiratory failure, with complete absence of the mRNA and protein observed in lung fluid or biopsy specimens. Hereditary SP-B deficiency is also associated with aberrant processing of proSP-C and deficiency of the active SP-C peptide. In the present study, we characterized the SFTPB gene in an infant with severe unexplained respiratory distress and identified a paternally derived 1549C-->GAA lesion, as well as a hitherto unreported mutation (457delC) inherited from the mother. Analysis of bronchoalveolar lavage fluid demonstrated the complete absence of SP-B. However, unlike previous infants with hereditary SP-B deficiency, proSP-C was processed to the active SP-C peptide, suggesting that the defect in SP-B, rather than SP-C, caused the respiratory distress in this infant. The present findings demonstrate the importance of SFTPB in pulmonary function and support the need for further genotype-phenotype correlations in patients with SP-B deficiency.

Base Sequence↗
PubMed1999

Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections.

Mannose-binding protein (MBP) is a serum lectin that participates in the innate immune response. MBP deficiency may constitute a risk factor in the development of infections. Three MBP structural variants have been identified with a dominant effect on MBP serum concentration. Similarly, polymorphisms in the promoter of the corresponding gene (HSMBP1B) have been related to variations of MBP concentration in serum. Children with sickle cell disease (SCD) have an increased susceptibility to infections with encapsulated organisms resulting in meningitis, septicaemia, and osteomyelitis. We have investigated the HSMBP1B genotype in 242 children with SCD living in Paris. Apart from the known variant alleles, we identified three novel ones and report their distribution in our sample population. In addition, we found rather unexpectedly an increased frequency of the variant alleles in patients who had not suffered severe infections.

Adolescent↗
PubMed1999

The erythrocyte effects of haemoglobin O(ARAB).

To test the hypothesis that HbOARAB induces an increase in red cell mean corpuscular haemoglobin concentration (MCHC), we studied members of four Tunisian families who were either homo- or heterozygous for HbOARAB or were double heterozygotes for HbS and HbOARAB. The alpha-gene status was also tested. The findings included: (1) Distinctive variation in red cell density (MCHC) as determined by separation of red cells on isopycnic gradients: (a) All red cells from patients homozygous for HbOARAB were denser than normal red cells, as is observed for homozygous HbC patients. (b) In patients heterozygous for HbOARAB, red cell density was strongly influenced by the presence of alpha-thalassaemia. The coexistence of -alpha/alphaalpha resulted in an average red cell density slightly greater than normal (AA) red cells. Patients heterozygous for HbOARAB with a normal complement of four alpha genes had denser red cells similar to sickle cell disease with some cells of normal density but with most cells very dense. (c) Finally, the double heterozygotes for HbS and HbOARAB had significant haemolytic anaemia and red cells denser than normal with some as dense as the densest cells found in sickle cell anaemia. (2) Reticulocytes in patients homozygous for HbOARAB were found in the densest density fraction of whole blood. (3) Cation transport in patients homozygous for HbOARAB was abnormal, with K:Cl cotransport activity similar to that of HbS-Oman and only somewhat lower than in sickle cell anaemia red cells. The activity of the Gardos channel was indistinguishable from that found in HbS, HbC and HbS-Oman cells. We conclude that the erythrocytic pathogenesis of HbOARAB involves the dehydration of red cells due, at least in part, to the K:Cl cotransport system. The similarity of the charge and consequences of the presence of both HbC and HbOARAB, which are the products of mutations at opposite ends of the beta-chain, raises the possibility that this pathology is the result of a charge-dependent interaction of these haemoglobins with the red cell membrane and/or its cytoskeleton and that this abnormality is present early in red cell development.

Adolescent↗
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

The link between phylogeny and virulence in Escherichia coli extraintestinal infection.

Previous studies suggesting a link between Escherichia coli phylogenetic groups and extraintestinal virulence have been hampered by the difficulty in establishing the intrinsic virulence of a bacterial strain. Indeed, unidentified virulence factors do exist, and the susceptibility of the host to infection is highly variable. To overcome these difficulties, we have developed a mouse model of extraintestinal virulence to test the virulence of the strains under normalized conditions. We then assessed the phylogenetic relationships compared to the E. coli reference (ECOR) collection, the presence of several known virulence determinants, and the lethality to mice of 82 human adult E. coli strains isolated from normal feces and during the course of extraintestinal infections. Commensal strains belong mainly to phylogenetic groups A and B1, are devoid of virulence determinants, and do not kill the mice. Strains exhibiting the same characteristics as the commensal strains can be isolated under pathogenic conditions, thus indicating the role of host-dependent factors, such as susceptibility linked to underlying disease, in the development of infection. Some strains of phylogenetic groups A, B1, and D are able to kill the mice, their virulence being most often correlated with the presence of virulence determinants. Lastly, strains of the B2 phylogenetic group represent a divergent lineage of highly virulent strains which kill the mice at high frequency and possess the highest level of virulence determinants. The observed link between virulence and phylogeny could correspond to the necessity of virulence determinants in a genetic background that is adequate for the emergence of a virulent clone, an expression of the interdependency of pathogenicity and metabolic activities in pathogenic bacteria.

Adult↗
PubMed1999

Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases.

Mutations in the Wilms' tumor suppressor gene (WT1) are linked with Denys-Drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with Frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of Frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228+5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 +KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal +KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in Frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for Frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.

Adult↗
PubMed1999

Characterization of a new polymorphism, IVS-I-108 (T-->C), and a new beta-thalassemia mutation, -27 (A-->T), discovered in the course of a prenatal diagnosis.

We report two new substitutions, IVS-I-108 (T-->C) and -27 (A-->T), identified in a couple at risk for beta-thalassemia. One is of Iranian origin and presents with two mutations: a new substitution of T-->C at nucleotide IVS-I-108, which is a silent polymorphism, and a previously described beta-thalassemia mutation at nucleotide -28 (A-->C). The other is from the island of Corsica, the only place in France where beta-thalassemia is endemic. He presents a new substitution of A-->T at nucleotide -27 in the TATA box, which was also found in several members of his family with the beta-thalassemia trait. The fetus was found to have inherited both these novel mutations.

Female↗
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

CFTR regions containing duodenum specific DNase I hypersensitive sites drive expression in intestinal crypt cells but not in fibroblasts.

We have investigated CFTR specific intestinal expression by transfection assays in mouse cultured fibroblasts and transimmortalized intestinal crypt m-ICc12 cells using the beta-galactosidase gene linked to rat CFTR non-coding regions. Two constructs were studied, one encompassing a 5.3 kb region 5' to the gene where numerous duodenum-specific DNase I hypersensitive sites (DHSs) were previously mapped and the other including a 1.3 kb 3' region in which novel DHSs had been identified. In transient transfection assays, transgenes were expressed in m-ICc12 cells but not in fibroblasts. In m-ICc12 cells, the pattern of expression of the chromosomally integrated transgenes paralleled the endogenous expression of CFTR and beta-galactosidase activity was detected in cells containing villin and forming domes. Thus, a 6.6 kb region encompassing 5' and 3' non-coding parts of rat CFTR is able to drive specific expression of a reporter gene in cultured mouse intestinal cells having kept a crypt phenotype.

3T3 Cells↗
PubMed1998

Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease.

We have studied the cellular and molecular responses to long-term hydroxyurea (HU) treatment in 29 severely affected young patients with sickle cell disease (mean age, 10.9 +/- 4.1 years). Patients received HU at 20 mg/kg/d on 4 consecutive days per week initially, with a monthly escalated dose avoiding marrow-toxicity (mean steady-state dose, 34.2 +/- 4.6 mg/kg/d) for 12 to 36 months (mean duration, 22 months). The studied parameters were hemoglobin F (HbF), F reticulocytes (F retics), F cells, the amount of HbF per F cell (F/F cell), polymer tendency at 40% and 70% oxygen saturation, and hemolysis. Initial HbF (Fi) was dispersed (from 0.85% to 13.9%). HbF increased in all patients but 1. HbF at maximal response (Fmax) reached a sustained level varying from a 1.5-fold to a 16-fold Fi after a variable delay (6 to 24 months). Fmax was not related to HU dosage, but triangle upF (Fmax - Fi) was strongly correlated to triangle upMCV (MCVmax - MCVi). HbF increase resulted from the increase of both F cells and F/F cell. In this rather short series, Fi and Fmax were not significantly associated with age, gender, or beta-globin haplotype. Neither Fmax nor triangle upF was related to bone marrow reserve, as measured by baseline reticulocyte or neutrophil counts. However, Fmax was highly dependent on Fi. When patients are individualized into three groups according to Fmax (group 1, Fmax >20% [12 patients]; group 2, 10% < Fmax < 20% [11 patients]; group 3, Fmax <10% [5 patients]), Fi is significantly different between groups, being the highest in group 1. In addition, the best responders (group 1) were significantly different from patients in the two other groups with higher levels of total hemoglobin, decreased bilirubin, and decreased polymer tendency.

Adolescent↗
PubMed1998

Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.

Amino Acid Sequence↗
PubMed1998

Phylogenetic analysis of Escherichia coli strains causing neonatal meningitis suggests horizontal gene transfer from a predominant pool of highly virulent B2 group strains.

Phylogenetic relationships of 69 neonatal meningitis Escherichia coli strains isolated worldwide were studied. Restriction fragment length polymorphism of rrn operons (rrn RFLP) in these isolates was compared with that of the 72 strains of the ECOR reference collection. Distributions of K1 antigen, of polymerase chain reaction-detected ibe10 gene, pap, afa, sfa/foc, hly, and aer operons, and of a 14.9-kb rrn-containing HindIII fragment previously associated with neonatal meningitis were compared. Oligoclonality was observed for the meningitis strains. Factorial analysis of correspondence on the rrn RFLP data showed a frequency gradient of meningitis strains from the phylogenetic B2 group (68%) to the A group (6%), via the D and B1 groups (26%). The distribution of the virulence determinants argues for their horizontal transfer during the evolution of E. coli. Analysis of the status of some neonates further suggests that neonatal meningitis results from a balance between bacterial genes of virulence and host factors.

Bacterial Typing Techniques↗