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Hôpital-Camfrout, France

Dupuis N.,French Institute of Health and Medical Research | Dupuis N.,University Paris Diderot | Lebon S.,French Institute of Health and Medical Research | Lebon S.,University Paris Diderot | And 8 more authors.
Human Mutation | Year: 2013

Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi-metaphyseal dysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly. Although both syndromes were shown to result from mutations in the DYM gene, which encodes the Golgi protein DYMECLIN, a few SMC patients remained negative in DYM mutation screening. Recently, autozygosity mapping and exome sequencing in a large SMC family have allowed the identification of a missense mutation in RAB33B, another Golgi protein involved in retrograde transport of Golgi vesicles. Here, we report a novel RAB33B mutation in a second SMC case that leads to a marked reduction of the protein as shown by Western blot and immunofluorescence. These data confirm the genetic heterogeneity of SMC dysplasia and highlight the role of Golgi transport in the pathogenesis of SMC and DMC syndromes. © 2012 Wiley Periodicals, Inc. Source

Sabbagh A.,University of Paris Descartes | Pasmant E.,University of Paris Descartes | Imbard A.,Service de Biochimie Hormonologie | Luscan A.,University of Paris Descartes | And 10 more authors.
Human Mutation | Year: 2013

Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant-related patients. A genotype-phenotype study was performed in patients harboring a truncating (N = 368), in-frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity. © 2013 WILEY PERIODICALS, INC. Source

Pussard E.,Service de Genetique Moleculaire | Pussard E.,University Paris - Sud | Chaouch A.,Service de Genetique Moleculaire | Said T.,Service de Genetique Moleculaire
Clinical Chemistry and Laboratory Medicine | Year: 2014

Background: The determination of plasma metanephrines (MNs) provides a highly sensitive test for the diagnosis of catecholamine producing tumors. Chromatographic determinations with electrochemical or mass spectrometric detections are the methods of choice, but immunological assays have been developed. This study evaluated the clinical performances of a radioimmunoassay for free MNs in plasma. Methods: MNs, normetanephrine (NMN) and metanephrine (MN) and catecholamines, norepinephrine (NE) and epinephrine (E) were determined in plasma and urine of 533 patients suspected of catecholamine producing tumor. Urinary and plasma catecholamines and urinary MNs were determined by HPLC using amperometric detection. Plasma MNs were purified by solid phase chromatography and quantified by a specific radioimmunoassay. Results: Fifty-nine patients had tumors (13 paraganglioma and 46 pheochromocytoma) and the diagnosis was excluded in 474 patients. Receiver operator characteristic curves have identified optimal thresholds at 100 pg/mL for plasma NMN (sensitivity 96.6% and specificity 95.8%) and 70 pg/mL for plasma MN (sensitivity 61.0% and specificity 96.8%). These cut-off values were lower than those suggested by the manufacturer (170 and 100 pg/mL, respectively). The sensitivity of combined MNs was similar in plasma (100%) and urine (98%) but higher than that of urinary catecholamines (85%, p < 0.001). The specificity of combined MNs in plasma (95%) was higher than urinary MNs (85%, p < 0.001) and plasma catecholamines (75%, p < 0.001). Conclusions: Plasma-free and urinary-total MNs have a better discriminative power than catecholamines in the diagnosis of catecholamines producing tumors. Using these established cut-offs, measurement of plasma-free MN by radioimmunoassay represents an effective alternative to chromatographic methods. Source

Verstuyft C.,Service de Genetique Moleculaire | Verstuyft C.,University Paris - Sud | Delavenne X.,Jean Monnet University | Rousseau A.,Unite de Recherche Clinique Paris Est | And 7 more authors.
Clinical Pharmacokinetics | Year: 2012

Background and Objective: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. Methods: Fluindione concentrations, S-and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. Results:Atwo-compartmentmodelwith a first-order inputmodel was selected as the basemodel for the twodrugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamicmodel of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. Conclusion: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors. Source

Soisson V.,French Institute of Health and Medical Research | Soisson V.,University Paris - Sud | Brailly-Tabard S.,Service de Genetique Moleculaire | Brailly-Tabard S.,University Paris - Sud | And 8 more authors.
Maturitas | Year: 2013

Objectives Low plasma testosterone is associated with increased mortality in men. However, the relation between testosterone and cardiovascular disease is uncertain. We assessed the association of plasma sex hormones with the incidence of ischemic arterial disease (IAD) in elderly men. Methods We used data from the French Three-City prospective cohort study (3650 men aged >65 years). A case-cohort design was set up including a random sample of 495 men and 146 incident cases of first IAD event (112 coronary heart disease (CHD) and 34 strokes) after a 4-year follow-up. Plasma total and bioavailable testosterone, total estradiol and sex hormone-binding globulin (SHBG) were measured at baseline. Multivariate hazard ratios (HRs) and 95% confidence intervals for IAD were assessed using Cox model. Results After adjustment for cardiovascular risk factors, a J-shaped association between plasma total testosterone and IAD risk was found (p < 0.01). The HRs associated with the lowest and the highest total testosterone quintiles relative to the second quintile were 2.23 (95% CI: 1.02; 4.88) and 3.61 (95% CI: 1.55; 8.45) respectively. Additional analysis for CHD showed similar results (HR: 3.11, 95% CI: 1.27; 7.63 and HR: 4.75, 95% CI: 1.75; 12.92, respectively). Similar J-shaped association was observed between bioavailable testosterone and IAD risk (p = 0.01). No significant association of estradiol and SHBG with IAD was found. Conclusion High and low plasma testosterone levels are associated with an increased risk of IAD in elderly men. Optimal range of plasma testosterone may confer cardiovascular protection and these results may have clinical implications in the management of testosterone deficiency. © 2013 Elsevier Ireland Ltd. Source

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