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S Lyonnet

Publications and source records attributed to S Lyonnet.

At least 181 records · Page 10Linked to original sources
PubMed1992

[Phenotypic expression of 12 mutations of the phenylalanine hydroxylase gene].

BACKGROUND: Several mutations in the human phenylalanine hydroxylase (PAH) gene have been described and it may be interesting to tentatively correlate mutant genotypes and clinical phenotypes of phenylketonuria (PKU). METHODS: Twelve mutations were searched for using classical techniques of molecular biology in a total of 126 patients. 3 phenotypes were arbitrarily defined: typical PKU, atypical PKU or Mediterranean form, and persistent mild hyperphenylalaninemia. The patients were classified according to the residual in vivo PAH activity. RESULTS: Mutations were found in 64 patients. One mutation was found in each of the 2 alleles in 20 children. Only one mutation could be identified in the other 44. Only 45 children could be assigned to a phenotype. Mutations leading to total loss of PAH activity were associated with typical PKU (in homozygotes or compound heterozygotes). Mutations leading to residual PAH activity were associated in homozygotes with atypical PKU; they were also associated in compounded heterozygotes with atypical PKU, irrespective of the fact that the other allele suppressed enzyme activity or was unknown. A mutation which changed the affinity of PAH for phenylalanine was associated with mild hyperphenylalaninemia. CONCLUSION: The clinical heterogeneity of PKU can be correlated with identified mutations of the human PAH gene. Molecular studies do not help to predict either the phenotype or the long-term outcome. However, description of the biochemical changes combined with identification of the mutation should lead to a better understanding of consequences of mutation for PAH activity.

Child↗
PubMed1992

[Molecular genetics and prenatal diagnosis].

Recombinant DNA techniques have provided new insight into genetic and prenatal diagnosis during the last 10 years. Human gene mapping data are increasing exponentially due to molecular biology advances. Most analyses are possible from chorionic villi biopsy specimens as early as the 10th week of fetal life. When the gene is known and cloned, the diagnosis is regularly made by using the polymerase chain reaction technique; when the gene is unknown but mapped, the restriction fragment length polymorphism technique is used. However, these methods for prenatal assessment require a reliable diagnosis of index case disease and a preliminary familial DNA study.

Female↗
PubMed1992

Time and space clusters of the French-Canadian M1V phenylketonuria mutation in France.

We performed mutation analysis and RFLP haplotype analysis of chromosomes associated with classical phenylketonuria (PKU) in contemporary French families. We also did genealogical reconstructions for seven obligate carriers in five contemporary French-Canadian families living in eastern Quebec, who carry the M1V mutation causing PKU. The M1V mutation, heretofore considered to be associated exclusively with French-Canadians, was found on 4 of 152 independent French chromosomes. The French and Quebec M1V mutations all occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistère Sud). Genealogical reconstructions of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The two clusters in France, one historical and the other contemporary, are not incompatible, if one assumes the possibilities that settlers returned from Nouvelle France or moved from Perche to southern Brittany. The M1V mutation is serving as a useful marker for historical demography.

Base Sequence↗
PubMed1991

A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive disease due to deficiency of a hepatic enzyme, phenylalanine hydroxylase (PAH). The absence of PAH activity results in typical PKU while persistence of a residual enzyme activity gives rise to variant forms of the disease. We report here a 3-base pair in-frame deletion of the PAH gene (delta 194) in a mild variant, with markedly reduced affinity of the enzyme for phenylalanine (Km = 160 nM), and we provide functional evidence for responsibility of the deletion in the mutant phenotype. Since the deletion was located in the third exon of the gene, which presents no homology with other hydroxylases, we suggest that exon 3 is involved in the specificity of the enzyme for phenylalanine. Finally, since none of the 98 PKU patients tested were found to carry this particular deletion, our study suggests that this molecular event probably occurred recently on the background of a haplotype 2 gene in Portugal.

Base Composition↗
PubMed1991

Splice-mediated insertion of an Alu sequence inactivates ornithine delta-aminotransferase: a role for Alu elements in human mutation.

In studies of mutations causing deficiency of ornithine delta-aminotransferase (EC 2.6.1.13), we found an allele whose mature mRNA has a 142-nucleotide insertion at the junction of sequences from exons 3 and 4. The insert derives from an Alu element in ornithine delta-aminotransferase intron 3 oriented in the direction opposite to transcription (an "antisense Alu"). A guanine----cytosine transversion creates a donor splice site in this Alu, activating a cryptic acceptor splice site at its 5' end and causing splice-mediated insertion of an Alu fragment into the mature ornithine-delta-aminotransferase mRNA. We note that the complement of the Alu consensus sequence has at least two cryptic acceptor sites and several potential donor sequences and predict that similar mutations will be found in other genes.

Amino Acid Sequence↗
PubMed1991

First-trimester prenatal diagnosis in quintuplets: a practical approach using step-by-step embryo reduction.

A multiple pregnancy of high rank may occur in a couple at risk for a Mendelian disorder. Prenatal diagnosis is hampered by the difficulty of (1) obtaining chorionic villi from each zygote and (2) unequivocally relating each sample to the corresponding embryo. The calculation of the genetic risk according to the number of zygotes led us to propose a diagnostic strategy based on embryo reduction, a technique initially designed to improve the perinatal outcome of multiple pregnancies with normal embryos. We report a case in which this approach allowed rational use of first-trimester chorionic villus sampling in a quintuplet pregnancy at risk for non-ketotic hyperglycinaemia, resulting in the selective birth of unaffected twins.

Abortion, Therapeutic↗
PubMed1991

Very large peroxisomes in distinct peroxisomal disorders (rhizomelic chondrodysplasia punctata and acyl-CoA oxidase deficiency): novel data.

We report very large hepatic peroxisomes (d-circle greater than 1 micron) in a patient with rhizomelic chondrodysplasia punctata and a patient with acyl-CoA oxidase deficiency. The effects of peroxisomal enlargement on the enzymatic activity are discussed. As increase in peroxisomal size is also reported in at least 12 other patients with peroxisomal disorders, we propose a relationship between the enlargement of the organelles and their functional deficiency.

Acyl-CoA Oxidase↗
PubMed1991

Two distinct mutations at a single BamHI site in phenylketonuria.

Classical phenylketonuria is an autosomal recessive disease caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively). Both mutations were detected in north eastern France or Belgium and occurred on the background of RFLP haplotype 7 alleles. The present study supports the view that the clinical heterogeneity in PKU is accounted for by the large variety of mutant genotypes associated with PAH deficiencies.

Base Sequence↗
PubMed1991

Single-strand conformation polymorphism for detection of mutations and base substitutions in phenylketonuria.

In the past few years, more than 20 different mutations have been reported in hyperphenylalaninemias. In southwestern Europe and Mediterranean countries, however, the mutant genotypes reported account for only a fraction (27%) of all mutant alleles at the phenylalanine hydroxylase (PAH) locus, and most of the mutations causing the disease remain unknown. In order to develop a strategy for rapid detection of mutation-containing exons, we applied the single-strand conformation-polymorphism (SSCP) technique to exons 3, 5, 7, and 12 of the PAH gene. We observed five abnormal patterns of migration in mutant PAH genes, and we consistently found base substitutions in the corresponding exons, with no false-positive results. By this procedure, two novel putative mutations were detected in the seventh exon of the PAH gene, (A259V and Y277D) and we were able to demonstrate that the delta I94, R158Q, R408W, and E280K mutations were easily detectable by the SSCP technique. This procedure is therefore of particular interest for rapid detection of mutation-containing exons and for determination of further genotype-phenotype correlations in hyperphenylalaninemias.

Base Sequence↗
PubMed1990

Response of discoid and subacute cutaneous lupus erythematosus to recombinant interferon alpha 2a.

Ten patients suffering from discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) were treated with interferon alpha 2a. A marked improvement or clearing of cutaneous lupus erythematosus lesions was observed in eight of them. However, the response to interferon was of short duration and within a few weeks after interferon withdrawal all patients who were improved or cleared relapsed. This study suggests that interferon alpha 2a represents a new interesting approach in the treatment of DLE and SCLE. Ongoing trials will define the optimal treatment schedule for the maintenance of interferon-induced improvement of cutaneous lupus erythematosus.

Dose-Response Relationship, Drug↗
PubMed1990

Recombinant interferon alpha 2a is effective in the treatment of discoid and subacute cutaneous lupus erythematosus.

Ten patients suffering from either discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) were treated with interferon alpha 2a. Eight received low or intermediate doses (18-45 x 10(6) U/week) for a short period of time (4-8 weeks), with marked improvement of skin lesions in six, an exacerbation in one patient and no change in the other. Two patients with SCLE received high doses (100-120 x 10(6) U/week) over 12 weeks, with complete clearing of the lesions in one and a marked improvement in the other. The responses were of short duration and within a few weeks of stopping treatment all who had improved or cleared relapsed. The side-effects in all the patients were fever and a flu-like syndrome which necessitated a reduction of the dose in one case. In two patients there were increases in the liver enzyme levels, but no haematological toxicity was noted.

Adult↗
PubMed1989

Apolipoprotein-E-gene expression in rat liver during development in relation to insulin and glucagon.

An apolipoprotein-E (apo-E) cDNA probe, cloned by immunoscreening of a lambda GT11 rat liver cDNA library, was used to further characterize the expression of the apo-E gene in rat liver during development, in relation to plasma insulin and glucagon levels. The apo-E mRNA level was low in fetus liver, then abruptly increased at birth and rose further during the suckling period. It returned to the level at birth in 10-week-old adults. These variations were paralleled with dramatic changes in plasma glucagon, which rose at birth and remained high during suckling. At the same time, the insulin/glucagon molar ratio fell. Administration of N6,O2-dibutyryl cAMP to 5-day-old rats resulted in a significant induction of liver apo-E mRNA. Moreover, liver apo-E mRNA rose in 10-h-fasted suckling rats as compared to controls, while plasma glucagon increased and the insulin/glucagon ratio decreased. Conversely, glucose feeding of suckling rats did not induce any increase in liver apo-E mRNA, the insulin/glucagon ratio was 10-fold higher than in fasted animals. Our results are consistent with liver apo-E gene expression being under the control of plasma glucagon and of the glucagon/insulin balance.

Animals↗
PubMed1989

CpG dinucleotides are mutation hot spots in phenylketonuria.

The coding region of the phenylalanine hydroxylase (PAH) gene contains 22 CpG dinucleotides, including five doublets in the seventh exon of the gene. We hypothesized that CpG doublets could represent mutation hot spots in PAH deficiencies and we carried out the systematic sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of two novel missense mutations whose location and nature (CG to CA and CG to TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet (codon 261arg----gln and codon 252arg----trp). Moreover, the codon 261 mutation was found to be associated with mutant restriction fragment length polymorphism (RFLP) haplotype 1, the most frequent mutant RFLP haplotype at the PAH locus in the studies reported thus far. However, since the mutation was detected in only 36% of haplotype 1 mutant alleles, it appears that this haplotype at the PAH locus is genotypically heterogeneous in Mediterranean countries.

Amino Acid Sequence↗