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B Simon-Bouy

Publications and source records attributed to B Simon-Bouy.

At least 37 records · Page 2Linked to original sources
PubMed1999

Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).

Alkaline Phosphatase↗
PubMed1999

Correlations of genotype and phenotype in hypophosphatasia.

Hypophosphatasia, a rare inherited disorder characterized by defective bone mineralization, is highly variable in its clinical expression. The disease is due to various mutations in the tissue-non-specific alkaline phosphatase ( TNSALP ) gene. We report here the use of clinical data, site-directed mutagenesis and computer-assisted modelling to propose a classification of 32 TNSALP gene mutations found in 23 European patients, 17 affected with lethal hypophosphatasia and six with non-lethal hypophosphatasia. Transfection studies of the missense mutations found in non-lethal hypophosphatasia showed that six of them allowed significant residual in vitro enzymatic activity, suggesting that these mutations corresponded to moderate alleles. Each of the six patients with non-lethal hypophosphatasia carried at least one of these alleles. The three-dimensional model study showed that moderate mutations were not found in the active site, and that most of the severe missense mutations were localized in crucial domains such as the active site, the vicinity of the active site and homodimer interface. Some mutations appeared to be organized in clusters on the surface of the molecule that may represent possible candidates for regions interacting with the C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with other dimers to form tetramers. Finally, our results show a good correlation between clinical forms of the disease, mutagenesis experiments and the three-dimensional structure study, and allowed us to clearly distinguish moderate alleles from severe alleles. They also confirm that the extremely high phenotypic heterogeneity observed in patients with hypophosphatasia was due mainly to variable residual enzymatic activities allowed by missense mutations found in the human TNSALP gene.

Alkaline Phosphatase↗
PubMed1998

The intermediate alleles of the fragile X CGG repeat in patients with mental retardation.

We have analysed the size of the non-expanded FRAXA CGG repeat in 385 male patients affected by mental retardation and in 182 unrelated normal chromosomes as control. The results show that intermediate alleles with more than 40 repeats were not significantly more frequent in patients than in controls. These data do not corroborate previous findings supporting the idea that intermediate alleles may have a deleterious effect on mental retardation.

Fragile X Syndrome↗
PubMed1998

Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case.

BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the incidence of cystic fibrosis in 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. The diagnosis of cystic fibrosis was based on prenatal screening for the eight mutations most frequently observed in France (deltaF508, deltaI507, 1717-1G-->A, G542X, G551D, R553X, W1282X, N1303K) and at postnatal follow up. RESULTS: The overall incidence of cystic fibrosis was 7/209 (3.3%) which is 84 times the estimated risk of CF in the general population (112500). Of these seven cases, six were diagnosed prenatally based on DNA analysis (deltaF508/deltaF508, n=5; deltaF508/G542X, n=1). One case in which only one mutation had been recognised was diagnosed clinically after birth (deltaF508/unidentified mutation). Of the seven cases, none was diagnosed at 16-19 weeks, four at 16-24 weeks, and three after this. The incidence of heterozygous fetuses (15/209, 7%) was not significantly higher than the 5% expected in the general population. The mutations involved in these heterozygous cases were deltaF508 (n=13), G542X (n=1), and G551D (n=1). CONCLUSIONS: Screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. This underlines the need to review genetic counselling in this situation where the fetus is the index case for a genetic disease.

Cystic Fibrosis↗
PubMed1997

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD.

Anencephaly↗
PubMed1997

[Genetics of Fragile X syndrome and its prevention].

The fragile X syndrome is the most common inherited form of mental retardation. Its prevalence is estimated to be one in 1000-4000 males and one in 2000-6000 females, depending of the region. A large canadian population study in Quebec has shown a frequency of 1/260 carrier women. The fragile X syndrome was the first disease shown to be associated with "dynamic mutations", caused by an amplification of an unstable DNA sequence transmitted from generations to generations till a pathologic expression: mental retardation. The prevention is possible by a specific DNA analysis of patients and male and female carriers. It is possible to detect the mutation or the premutation in pregnant women and to propose a prenatal diagnosis by molecular study on chorionic villi samples or cultivated amniocytes.

Female↗
PubMed1996

Recurrent and unexpected segregation of the FMR1 CGG repeat in a family with fragile X syndrome.

Fragile X syndrome, the most common cause of hereditary mental retardation, results from amplification of a CGG trinucleotide repeat in the FMR1 gene. The transmission of the CGG repeat from premutated individuals to their premutated descendants is usually unstable, showing an increase in the size of the repeat. We report here a family which exhibits recurrent and unexpected transmission of the maternal premutation to three daughters. The first daughter exhibited mosaicism with two premutated alleles, one contracted and the other expanded. The second daughter showed a reversion from the maternal premutation to the normal range, and the third carried an expanded premutated allele associated with an expanded paternal allele within the normal range. These variations in the size of the CGG repeat may result from many different mechanisms such as DNA polymerase slippage on the leading or lagging strand during replication, large contractions of repeats on the parental strand during replication, or recombination through unequal crossover between sister chromatids. Our results suggest that the variation of the CGG premutated alleles in this family may be the result of intrinsic instability associated with a trans-acting factor such as a mismatch repair gene product.

Female↗
PubMed1996

[Molecular biology of fragile X syndrome: recent data and diagnostic applications].

Fragile X syndrome is the most common cause of inherited mental retardation. Since the identification of the mutation, a Cytosine-Guanine-Guanine repeat in the Fragile X Mental Retardation (FMR1) gene, the genetic counselling and the diagnosis of the disease have been dramatically improved. The nature of the mutation and its size must be integrated in the calculation of the risk of transmission of mental retardation and in the genetic counselling in the family. Out of 245 patients affected with mental retardation referred to our laboratory, we found 37 (15%) fragile X patients, allowing to screen for the mutation in the family and to propose prenatal diagnosis in carrier females.

Adult↗
PubMed1996

Parental origin and mechanisms of formation of three cases of 12p tetrasomy.

Pallister-Killian syndrome is a clinically recognizable syndrome characterized by tissue-limited mosaicism for an extra 12p isochromosome. Very little is known about the underlying mechanism of this rare rearrangement. Microsatellite markers were studied from three fetuses with Pallister-Killian syndrome and their parents to determine the parent of origin and the cell division yielding the additional isochromosome. In two cases the isochromosome contained the same allele(s) as a normal transmitted chromosome 12, one paternal and one maternal in origin. A third case showed inheritance of two different maternal alleles, indicating that at least one meiotic error was involved in the ultimate formation of the extra isochromosome.

Abnormalities, Multiple↗
PubMed1995

Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency.

The frequency of 12 different mutations of the steroid 21-hydroxylase gene (CYP21) was investigated in 129 French patients affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. Eighty-nine percent of the CAH chromosomes were characterized. The most frequent mutations were a C-G substitution in intron 2, the deletion of the CYP21 gene and a T-A substitution in exon 4 in the severe form of the disease, and a G-T substitution in exon 7 in the nonclassic form. The correlation between the genotypes and the clinical forms of the disease showed marked variation in the phenotype from a single genotype, suggesting that individual variation and undetected additional mutations on the same CAH chromosome accounted for the phenotype. In 65 informative meioses of CAH families, no de novo mutation was found.

Adrenal Hyperplasia, Congenital↗
PubMed1995

Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome.

OBJECTIVE: Fetal hyperchogenic bowel is associated with a variety of conditions, the incidence of which has yet to be studied. STUDY DESIGN: The outcomes of 182 cases of fetal hyperechogenic bowel were reviewed. Screening for maternal toxoplasmosis, fetal karyotyping, and amniotic fluid digestive enzyme assays were performed in all cases. Eight mutations associated with cystic fibrosis were analyzed in 116 cases. RESULTS: Of 135 newborns, 121 were normal, but nine underwent surgery for gastrointestinal obstruction, three had cytomegalovirus or parvovirus infection, one had a triple X chromosome, and one died from sudden infant death syndrome. In utero fetal death was observed in 24 cases. Elective termination of pregnancy was performed in 23 cases for associated anomalies. CONCLUSIONS: Hyperechogenic fetal bowel was associated with increased risk for adverse outcome. Prenatal management should include ultrasonographic surveillance, fetal karyotyping, amniotic digestive enzyme assays, and screening for cystic fibrosis and infectious disease.

Amniocentesis↗
PubMed1994

Transition from normal to premutated alleles in fragile X syndrome results from a multistep process.

In fragile X syndrome, the most common cause of inherited mental retardation, phenotypic expression has been linked to a region containing a repetitive sequence, (CGG)n, that appears to lengthen dramatically in fragile X patients and to show length variation in normal individuals. In order to investigate possible mechanisms responsible for further expansion of CGG in the normal population, we selected 31 normal unrelated X chromosomes carrying either the high-risk DX204-AC155 or DX196-AC151 haplotypes, as defined by the flanking microsatellites, DXS548 and FRAXAC2. Nearly 100% of CGGs with more than 35 repeats were found on DX204-AC155 haplotypes, with a mean length significantly higher and much more variable than in normal individuals carrying other haplotypes including the high-risk haplotype DX196-AC151. These findings suggest that the transition from the normal to the abnormal range occurs by a multistep process, a primary event, such as unequal crossing-over, leading to increased size and moderate instability of the repeat, and from which DNA polymerase slippage could lead to recurrent premutations. Our results also suggest that the upper limit of the normal range is roughly 35 repeats in the fragile X gene. The 36-54 repeats range would define an intermediate allele only observed, up to now, in DX204-AC155 fragile X chromosomes.

Analysis of Variance↗
PubMed1993

Molecular analysis of a ring chromosome X in a family with fragile X syndrome.

The phenotypically normal sister of a patient affected by fragile X syndrome was referred for genetic counselling and was found to carry a mosaic karyotype 46,X,r(X)/45,X. Because the probability of the simultaneous chance occurrence of fragile X syndrome and a ring chromosome X in the same family is very low, we postulated that the breakpoint of the ring chromosome X originated in the cytogenetic break in Xq27.3 responsible for fragile X syndrome. In order to determine the relative positions of the breakpoint on the ring chromosome X and the (CGG)n unstable sequence responsible for the fragile X mutation, we used molecular markers to analyse the telomeric regions of chromosome X in this family. The results showed that the ring chromosome X was the maternal fragile X chromosome and that the telomeric deletion on the long arm encompassed the (CGG)n sequence. This suggests that the cytogenetic break in Xq27.3 is distinct from the unstable (CGG)n sequence, or that the break followed by the end-to-end fusion creating the ring chromosome was not completely conservative. Analysis of DNA markers on the short arm of chromosome X evidenced a deletion of a large part of the pseudoautosomal region, allowing us to position the genes involved in stature and in some syndromes associated with telomeric deletions of Xp on the proximal side of the pseudoautosomal region.

Adult↗
PubMed1993

Oncogene-mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT-1 and CFT-2 cells in culture.

Primary tracheal epithelial cells obtained from two fetuses with cystic fibrosis (CF) were successfully transfected with a plasmid vector recombined with the large T oncogene of SV40. The resulting tracheal cells were propagated in culture for up to 25 passages and retained the mutations of the CF genes carried by the two fetuses, one heterozygous for the S549N and N1303K substitutions (CFT-1 cells), and the other homozygous for the most common deletion delta F508 (CFT-2 cells). The transfected cells: (a) expressed the SV40 large T oncogene, as determined by immunofluorescence and Northern blot analysis; (b) retained typical epithelial morphology, as assessed by the presence of microvilli, desmosomes, gap junctions, and cytokeratin expression; (c) were fully responsive to the cAMP-stimulating agents isoproterenol, forskolin and vasoactive intestinal peptide for cAMP production and PKA activation; (d) do not produce any tumour in the athymic nude mice; (e) were diploid and tetraploid with a normal chromosomal complement at early passages, and (f) exhibited the abnormal regulation of chloride conductance characteristic of CF. These results indicate that CFT-1 and CFT-2 cells constitute a suitable model for: (a) comparison of the maturation and function of the CFTR protein mutated in the two nucleotide-binding domains; (2) analysis of the biochemical defect in CF epithelial airway cells, (c) development of new therapeutic agents, and correction of the CF defect by gene replacement therapy in vitro.

Animals↗
PubMed1993

General cystic fibrosis mutations are usually missense mutations affecting two specific protein domains and associated with a specific RFLP marker haplotype.

Some 250 different mutations have so far been screened in the cystic fibrosis (CF) gene. The 50 nonsense, 33 splicing and 60 frameshift mutations are randomly distributed within the gene, unlike the 107 missense mutations or amino acid deletions. A large excess of missense mutations affects the exons encoding the first transmembrane (MS1) and first ATP-binding fold (NBF1) domains. Sixty-four of the 107 missense mutations may be classified as private, demic, local and general mutations on the basis of their geographic distribution in Europe. Private and demic mutations are randomly distributed within the gene; local and general mutations are not. It is well known that some RFLP markers are in linkage disequilibrium with some mutations. Private, demic and local mutations are randomly associated with each class of RFLP haplotypes. In contrast, general mutations, frequent and infrequent, are not randomly associated with RFLP markers. General mutations usually affect a specific part of the gene and are more likely to be associated with a specific RFLP marker. This suggests the existence of selective factors favoring these mutations, a hypothesis formerly postulated as a possible cause of the high frequency of the disease.

Cystic Fibrosis↗