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Fluck C.E.,University of Bern | Mallet D.,Service dEndocrinologie Moleculaire et Maladies Rares | Hofer G.,University of Bern | Samara-Boustani D.,Hopital Necker Enfants malades | And 4 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399_E401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399_E401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17α-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399_E401 revealed reduced stability and flexibility of the mutant. In conclusion, P399_E401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399_E401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase. © 2011 Elsevier Inc.


Nguyen K.,Hopital denfants de la Timone | Putoux A.,Service de Genetique | Putoux A.,University Claude Bernard Lyon 1 | Busa T.,Hopital denfants de la Timone | And 17 more authors.
Clinical Genetics | Year: 2015

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique increases not only the diagnostic rate but also the possibility of finding unexpected variants unrelated to the indication of referral, namely incidental findings. The incidental finding of copy number variants (CNVs) located in X-linked genes in girls addresses the crucial question of genetic counseling in the family. We report here five cases of CNVs involving the dystrophin gene detected by aCGH in girls referred for developmental delay, without any family history of dystrophinopathy. The rearrangements included three in-frame deletions; one maternally and two paternally inherited, and two frameshift duplications: one de novo and one from undetermined inheritance. In two cases, the deletion identified in a girl was transmitted by the asymptomatic father. In the case of the maternally inherited deletion, prenatal diagnosis of dystrophinopathy was proposed for an ongoing pregnancy, whereas the cause of developmental delay in the index case remained unknown. Through these cases, we discussed the challenges of genetic counseling in the family, regarding the predictive issues for male individuals at risk for a muscular dystrophy without precise knowledge of the clinical consequences of some CNVs in the DMD gene. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Sediki F.Z.,Oran University of Science and Technology - Mohamed Boudiaf | Radoui A.,Etablissement Hospitalier Specialise EHS Canastel | Cabet F.,Service dEndocrinologie Moleculaire et Maladies Rares | Zemani-Fodil F.,Oran University of Science and Technology - Mohamed Boudiaf | And 2 more authors.
Annales de Biologie Clinique | Year: 2014

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians. Wrongly considered as a European disease, CF is found in Algeria; but the literature data on the clinical profile and the spectrum of CFTR gene mutations are poor. In this study we investigate twenty-four unrelated Algerian families, with at least one child with CF. DNA extracts from blood samples of patients and parents were screened for CFTR gene mutations using Elucigene CF30 Kit which is based on a PCR/ARMS technique. Only five different mutations were identified. On the 48 alleles studied, most common mutations were: c.1521-1523delCTT (F508del) 18.75%, c.579+1G>T (711+1G>T) 12.5%, c.1624G>T (G542X) 10.41%, c.3909C>G (N1303K) 4%, and c.1652G>A (G551D) 2%. The Elucigene CF30 kit highlights a portion of CFTR mutations in the Algerian population. It remains important for a first screening as it reveals the most common mutations. All this information is of interest for genetic testing and genetic counseling in Algeria and in European countries where immigration from the Maghreb is common. © 2014, John Libbey Eurotext. All rights reserved.


PubMed | Oran University of Science and Technology - Mohamed Boudiaf, Etablissement hospitalier specialise EHS Canastel and Service dendocrinologie moleculaire et maladies rares
Type: Journal Article | Journal: Annales de biologie clinique | Year: 2014

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians. Wrongly considered as a European disease, CF is found in Algeria; but the literature data on the clinical profile and the spectrum of CFTR gene mutations are poor. In this study we investigate twenty-four unrelated Algerian families, with at least one child with CF. DNA extracts from blood samples of patients and parents were screened for CFTR gene mutations using Elucigene CF30 Kit which is based on a PCR/ARMS technique. Only five different mutations were identified. On the 48 alleles studied, most common mutations were: c.1521_1523delCTT (F508del) 18.75%, c.579+1G>T (711+1G>T) 12.5%, c.1624G>T (G542X) 10.41%, c.3909C>G (N1303K) 4%, and c.1652G>A (G551D) 2%. The Elucigene CF30 kit highlights a portion of CFTR mutations in the Algerian population. It remains important for a first screening as it reveals the most common mutations. All this information is of interest for genetic testing and genetic counseling in Algeria and in European countries where immigration from the Maghreb is common.


Plotton I.,Service dEndocrinologie Moleculaire et Maladies Rares | Garby L.,Lyon University Hospital Center | Morel Y.,Service dEndocrinologie Moleculaire et Maladies Rares | Lejeune H.,Lyon University Hospital Center
Andrologia | Year: 2012

The aim of this study was to compare anti-Mullerian hormone (AMH) plasma levels in patients with azoospermia according to the physiopathology. In a prospective clinical study from April 2008 to March 2009 in University Hospital, we measured AMH levels in 49 consecutive patients with azoospermia. AMH plasma levels were correlated with FSH, inhibin B, bioavailable testosterone plasma levels and testicular volume and compared between nonobstructive azoospermia (NOA) and obstructive azoospermia (OA) and within four physiopathological subgroups of NOA: genetic, cryptorchidism, cytotoxic and unexplained. AMH, FSH, inhibin B, bioavailable testosterone plasma levels and testicular volumes were all related to each other. AMH plasma levels were lower in NOA relatively to OA. Lowest values were observed in cases of genetic NOA and on the other hand, the values observed in case of cytotoxic NOA were as high as the values observed in OA. FSH, inhibin B, bioavailable testosterone and testicular volume were not different between genetic and cytotoxic NOA. These results suggest that the decrease in AMH plasma levels is related to the origin of NOA, with low values in genetic NOA and values similar to OA in cytotoxic NOA. Further studies will be useful to understand the fine regulation of AMH production. © 2011 Blackwell Verlag GmbH.


Paris F.,Montpellier University Hospital Center | Tardy V.,Service dEndocrinologie Moleculaire et Maladies Rares | Chalancon A.,Montpellier University Hospital Center | Picot M.C.,Hopital Lapeyronie AIDER | And 2 more authors.
Gynecological Endocrinology | Year: 2010

Aim.This study investigated the prevalence and consequences of heterozygous CYP21A2 mutations in premature pubarche (PP) girls. Main finding.We investigated 36 French Mediterranean girls with isolated PP. We performed synacthen testing with 17OHP and 21-deoxycortisol evaluation, along with molecular analysis of the CYP21A2 gene in girls with abnormal elevation of one of these two adrenal steroids. Three girls (8.3) had nonclassical adrenal hyperplasia, secondary to compound heterozygosity that associated at least one severe mutation for the three girls. A heterozygous mutation of the CYP21A2 gene was confirmed by molecular biology in eight girls (22); a deletion of the CYP21A2 gene was found in one of them. Biological hyperandrogenism was found in the prepubertal CYP21A2 mutation carriers, whereas the four heterozygous girls who were followed long enough to have reached pubertal age presented biological and clinical hyperandrogenism. Conclusions.We underline the high prevalence of heterozygous CYP21A2 mutations in girls with PP and demonstrate the usefulness of systematic screening by synacthen testing, both to improve their future clinical management and to prevent the transmission of classical adrenal hyperplasia to future offspring. Because of the severe metabolic and cardiovascular consequences of hyperandrogenism, long-term follow-up of these heterozygous patients is mandatory. © 2010 Informa UK Ltd.

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