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E Mornet

Publications and source records attributed to E Mornet.

At least 19 recordsLinked to original sources
PubMed2000

Fifteen new mutations (-195C>T, L-12X, 298-2A>G, T117N, A159T, R229S, 997+2T>A, E274X, A331T, H364R, D389G, 1256delC, R433H, N461I, C472S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with hypophosphatasia.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and liver/bone/kidney-type alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 12 families affected by severe or mild hypophosphatasia. Twenty distinct mutations were found, 5 of which were previously reported. Nine of the 15 new mutations were missense mutations (T117N, A159T, R229S, A331T, H364R, D389G, R433H, N461I, and C472S). The others were 2 nonsense mutations (L-12X and E274X), one single nucleotide deletion (1256delC), 2 mutations affecting splicing (298-2A>G, 997+2T>A), and a mutation in the major transcription start site (-195C>T). Hum Mutat 15:293, 2000.

Alkaline Phosphatase↗
PubMed2000

Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene.

Hypophosphatasia is an inborn error of metabolism caused by a deficiency of liver-, bone- or kidney-type alkaline phosphatase due to mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Most of the 65 distinct mutations described to date are missense mutations, a result which must be correlated with the great variability of clinical expression ranging from stillbirth without mineralized bone to pathologic fractures developing only late in adulthood. Correlations of genotype and phenotype have been established on the basis of clinical data exhibited by the patients, transfection studies, computer-assisted modeling, and examination of biochemical properties of ALP in cultured fibroblasts of patients. Screening for mutations in the TNSALP gene allows genetic counseling and prenatal diagnosis of the disease in families with severe forms of hypophosphatasia, and screening may also be helpful in confirming diagnosis of hypophosphatasia when biochemical and clinical data are not clear. Screening is also the necessary first step in further studies to elucidate dominant transmission of the disease and of liver-, bone- and kidney-type alkaline phosphatase activity mechanism.

Alkaline Phosphatase↗
PubMed2000

A 3D model of human P450c21: study of the putative effects of steroid 21-hydroxylase gene mutations.

In order to better understand the disease-causing role of missense mutations found in the CYP21 gene from patients affected with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency, we built two three-dimensional (3D) models of human P450c21 using all known 3D structures of P450s. For each residue affected by a missense mutation, its location in the 3D structure and the putative changes in terms of biochemical properties brought about by the mutation were analyzed. Most of the severe alleles were found to affect residues located in functionally important regions of the molecule such as substrate recognition sites (SRS) or the heme region, whereas moderate mutations were mostly found in less crucial regions of the molecule. Thus, there is a good correlation between the 3D structure study and clinical data and mutagenesis experiments previously reported. In one case, however, the observed clinical severity of the mutation (E380D) did not match its expected severity deduced from the model, pointing to a potential functionally important region of the molecule. Our 3D human models provide a basic model for further studies of mutations responsible for 21-hydroxylase, and for identification of important residues involved in the specific activity of the enzyme.

Adrenal Hyperplasia, Congenital↗
PubMed2000

Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21.

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.

Adult↗
PubMed1999

Correlation of alkaline phosphatase (ALP) determination and analysis of the tissue non-specific ALP gene in prenatal diagnosis of severe hypophosphatasia.

Prenatal diagnosis of severe hypophosphatasia by mutation analysis of the tissue non-specific alkaline phosphatase (TNSALP) gene is reliable and mostly informative. However, alkaline phosphatase (ALP) assay of CVS may be a useful complementary and independent method, especially when a mutation is unidentified and DNA from the index case is unavailable, rendering impossible the use of DNA polymorphisms as genetic markers of the disease. We report here mutation analysis of the TNSALP gene and ALP assay in nine cases of prenatal diagnosis of severe hypophosphatasia. The results showed a good correlation between ALP assay and DNA analysis in all but one case, which suggested that in at least some cases low values of ALP may correspond to affected fetuses as well as to heterozygotes.

Alkaline Phosphatase↗
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

Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family.

We report on two families in which one or two children had a severe disorder of skeletal development detected by prenatal ultrasonography. The children died postnatally and showed typical radiological and biochemical findings of perinatal hypophosphatasia. Biochemical analysis revealed a low activity of alkaline phosphatase (AP) and a high value of pyridoxal-5-phosphate (PLP), one of its natural substrates. The screening for mutations of the tissue nonspecific alkaline phosphatase (TNSALP) gene showed homozygosity for a point mutation (G 317 --> D) in the two affected children of the first family. The affected child of the second family was homozygous for a nonsense mutation (R 411 --> X). Family screening revealed that the determination of AP and PLP is helpful for detection of heterozygotes. However, heterozygote children had values of AP in the lower normal range during phases of rapid growth. The determination of PLP proved to be more sensitive in these cases. It should be kept in mind that during the last trimester of gestation there is an increase in maternal AP activity and a normalization of PLP due to placental AP, which is not affected. Therefore, in the course of a prenatal diagnosis in an index case, paternal blood should be analyzed in parallel. For detailed genetic counseling and early prenatal diagnosis in following pregnancies, the possibility of mutation analysis should be used.

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↗
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

Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women.

21-hydroxylase (21-OH) deficiency accounts for the vast majority of nonclassic (NC) forms of congenital adrenal hyperplasia (CAH), and is associated with symptoms detectable either in childhood (precocious puberty) or sometimes only later in adulthood (hirsutism, acne, amenorrhea). While the severe forms of the disease responsible for salt wasting or simple virilization have been extensively studied, the NC 21-OH deficiency is less well characterized, especially in adults. We studied the 21-OH gene (CYP21) in a population of 69 unrelated hyperandrogenic subjects suspected to be homozygous or heterozygous for NC 21-OH deficiency, based on basal and adrenocorticotrophin (ACTH)-stimulated plasma 17-hydroxyprogesterone (17-OHP, 17-OHPSI) and 21-desoxycortisol (21-DOF, 21-DOFSI) levels. To identify all mutations involved, determination of the whole gene sequence, including exons, exon-intron junctions, and promoter region, was performed, followed by a study of large rearrangements and identification of compound heterozygotes. Alterations were identified in at least one allele of 55 hyperandrogenic subjects. Two NC alterations, Val282Leu and Pro454Ser, were detected in 68% and 7% of the affected alleles, respectively, whereas mutations involved in severe forms were identified in 21% of them. These results document the utility of a molecular diagnosis in hyperandrogenic women suspected of being either heterozygous or homozygous for NC 21-OH deficiency and clearly indicate the importance of genetic counseling in such a population.

17-alpha-Hydroxyprogesterone↗
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

Analysis of germline variation at the FMR1 CGG repeat shows variation in the normal-premutated borderline range.

In order to characterize the dynamics of CGG repeat instability at the fragile X syndrome locus (FMR1 gene), we have used small pool PCR to estimate the mutation rate within germline (sperm) and somatic tissue (leukocytes) of two normal males, one carrying the most common 29 CGG repeats allele, the other carrying a borderline normal-premutated allele of 55 repeats. Large contractions and moderate expansions of the repeat were found in sperm and blood for the 55 repeat allele while almost no variation was found in sperm or blood with the 29 repeat allele. Somatic blood DNA exhibited fewer expansions and contractions than sperm. Contractions were more frequent than expansions, and all the expansions were found in the +4 to +10 repeats range, while most of the contractions were found in the -10 to -30 range, suggesting that a subset of contractions results from a distinct mechanism. These results also suggest that the dynamics of the CGG repeat could be partly due to germline instability within the high normal or premutated ranges.

Fragile X Messenger Ribonucleoprotein 1↗
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↗
PubMed1994

Identification by molecular diagnosis of mosaic Turner's syndrome in an obligate carrier female for fragile X syndrome.

A case of mosaic Turner's syndrome with a 45,X/46,XX/47,XXX karyotype, who was also a fragile X obligate carrier as the mother of an affected boy, was identified by molecular diagnosis. Complete haplotyping and direct DNA analysis showed that the X chromosome in all metaphases was the normal X. At the age of 57, she is mentally normal. Her external appearance was typical of Turner's syndrome. This report shows that molecular studies in conjunction with cytogenetic analysis can help in the clinical diagnosis of a rare case and can show the uniqueness of a case such as the one here described.

Female↗