Badens C.,Laboratoire Of Genetique Moleculaire |
Agouti I.,Laboratoire Of Genetique Moleculaire |
Gonnet K.,Laboratoire Of Genetique Moleculaire |
Fattoum S.,Laboratoire Of Genetique Moleculaire |
And 4 more authors.
Haematologica | Year: 2011
A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) b-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia Intermedia phenotype associated with the different combinations of alleles. The presence or absence of the favorable alleles could accurately predict the type of thalassemia in 83.2% of the cases. The percentage of correct predictions made from the β-thalassemia mutations and the XmnI SNP alone were significantly improved by the adjustment with the 3 other modifiers; from 73.6% to 83.2% (P<0.001). In this study, we showed that predictions based on genetic modifiers can foresee the Major or Intermedia type of β-thalassemia, even in cohorts of patients with various β-globin genotypes. ©2011 Ferrata Storti Foundation.
Sacconi S.,Nice University Hospital Center |
Pecheux C.,Laboratoire Of Genetique Moleculaire |
Bernard R.,Laboratoire Of Genetique Moleculaire |
Casarin A.,University of Padua |
And 2 more authors.
Neuromuscular Disorders | Year: 2012
Mutations in the CRYAB gene, encoding alpha-B crystallin, cause distinct clinical phenotypes including isolated posterior polar cataract, myofibrillar myopathy, cardiomyopathy, or a multisystemic disorder combining all these features.Genotype/phenotype correlations are still unclear. To date, multisystemic involvement has been reported only in kindred harboring the R120G substitution. We report a novel CRYAB mutation, D109H, associated with posterior polar cataract, myofibrillar myopathy and cardiomyopathy in a two-generation family with five affected individuals. Age of onset, clinical presentation, and muscle abnormalities were very similar to those described in the R120G family. Alpha-B crystallin may form dimers and acts as a chaperone for a number of proteins. It has been suggested that the phenotypic diversity could be related to the various interactions between target proteins of individual mutant residues.Molecular modeling indicates that residues D109 and R120 interact with each other during dimerization of alpha-B crystallin; interestingly, the two substitutions affecting these residues (D109H and R120G) are associated with the same clinical phenotype, thus suggesting a similar pathogenic mechanism. We propose that impairment of alpha-B crystallin dimerization may also be relevant to the pathogenesis of these disorders. © 2011 Elsevier B.V.
Eckard S.C.,University of Washington |
Rice G.I.,University of Manchester |
Fabre A.,Aix - Marseille University |
Badens C.,Aix - Marseille University |
And 5 more authors.
Nature Immunology | Year: 2014
Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.
Langlais D.,Laboratoire Of Genetique Moleculaire |
Langlais D.,University of Montréal |
Couture C.,Laboratoire Of Genetique Moleculaire |
Kmita M.,Institute Of Recherches Cliniques Of Montreal Ircm |
And 3 more authors.
Molecular Endocrinology | Year: 2013
The identification of a stable pool of progenitor/stem cells in the adult pituitary has renewed the interest of identifying mechanisms for maintenance of pituitary cells throughout life. Whereas developmental studies have shown that progenitor expansion is the major source of new differentiated cells during pituitary organogenesis, the contribution of these progenitors for maintenance of the adult tissue is not clear although progenitors were clearly involved in cell expansion following end-organ ablation, notably after adrenalectomy and/or gonadectomy. We have used a genetic trick that eliminates dividing cells by apoptosis in order to assess the contribution of differentiated corticotropes and melanotropes for maintenance of their population in the adult pituitary. The system relies on chromosome instability created by the action of the Cre recombinase on inverted loxP sites. Expression of Cre recombinase in corticotropes and melanotropes led to progressive loss of corticotropes whereas melanotropes were unaffected. Because the Cre transgene is not expressed in progenitors, the data indicate that maintenance of the adult corticotrope pool is primarily due to self-duplication of differentiated cells. In contrast, melanotropes do not divide. Maintenance of corticotropes by self-duplication contrasts with the reported proliferative response of undifferentiated cells observed after adrenalectomy. If corticotrope reentry into cell cycle constitutes a normal mechanism to maintain the adult corticotrope pool, this same mechanism may also be perturbed during corticotrope adenoma development in Cushing's disease. © 2013 by The Endocrine Society.
Coupry I.,University of Bordeaux Segalen |
Sibon I.,University of Bordeaux Segalen |
Mortemousque B.,University of Bordeaux Segalen |
Rouanet F.,University of Bordeaux Segalen |
And 3 more authors.
Archives of Ophthalmology | Year: 2010
Objective: To investigate the wide variability of ocular manifestations associated with mutations in the COL4A1 gene that encodes collagen IVα1. Methods: We clinically evaluated 7 patients from 2 unrelated families in whom ocular features segregated with COL4A1 mutations that were identified by direct sequencing. Results: The G2159A transition (c.2159G>A) that leads tothemissensemutationp.Gly720Aspwasidentified infamily A.Anocularphenotypeof variable severitywasobserved in all affected relatives.Themissensemutationc. 2263G>A, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Conclusions: The COL4A1 mutations may be associated with various ophthalmologic developmental anomalies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cerebrovascular disorders should be added to the list of signs potentially associated with ARA. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in the clinical treatment of patients with apparently isolated ARA, even when neurological symptoms or signs are lacking. ©2010 American Medical Association. All rights reserved.
Castiglioni C.,Unit of Neurology |
Lopez I.,Unit of Neurology |
Riant F.,Laboratoire Of Genetique Moleculaire |
Bertini E.,Bambino Gesu Childrens Research Hospital IRCCS |
Terracciano A.,Bambino Gesu Childrens Research Hospital IRCCS
European Journal of Paediatric Neurology | Year: 2013
PRRT2 gene mutations have recently been identified as a causative gene of Paroxysmal kinesigenic dyskinesia (PKD), a rare movement disorder characterised by the occurrence of chorea, dystonia or athetosis triggered by sudden action. Some patients have additional intermittent neurologic disorders like infantile convulsions. The association with migraine has been rarely reported in this condition. Here we report the coexistence of PKD and hemiplegic migraine in twins harbouring a heterozygous mutation in PRRT2. Two monozygotic twins manifesting PKD together with repeated episodes of migraine with some severe attacks of hemiplegic migraine have been followed and treated for more than 10 years. Molecular genetic analysis disclosed the c.649-650insC, p.R217Pfs*8 heterozygous mutation in both twins. This mutation was segregating from the mother who likewise harboured the same mutation c.649dupC although she had never manifested PKD but complained of rare common migraine attacks in her past history. The association of PKD and hemiplegic migraine has been previously reported in one large family, associated to febrile convulsions and afebrile seizures in some individuals, but our report relates this association of symptoms to a mutation in PRRT2. The co-occurrence of both hemiplegic migraine and PKD in monozygotic twins expands the phenotypic spectrum of intermittent manifestations related to PRRT2 and perhaps suggests an additional causing gene for hemiplegic migraine. © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Petit F.M.,Laboratoire Of Genetique Moleculaire |
Serres C.,University of Paris Descartes |
Bourgeon F.,French Institute of Health and Medical Research |
Pineau C.,French Institute of Health and Medical Research |
Auer J.,University of Paris Descartes
Human Reproduction | Year: 2013
STUDY QUESTION: Which human sperm proteins interact with zona pellucida (ZP) glycoproteins, ZPA/2, ZPB/4 and ZPC/3?SUMMARY ANSWERCo-precipitation experiments with recombinant human ZP (rhZP) coated beads demonstrated interactions with various proteins, including glutathione S-transferase M3 (GSTM) with ZPB/4 and voltage-dependent anion channel 2 (VDAC2) with ZPA/2 and ZPC/3.WHAT IS KNOWN ALREADYRegarding sperm-ZP binding, several target spot/proteins have been detected in several species, but not all have been characterized. The limit of these studies was that a mixture of the different ZP glycoproteins was used and did not allow the identification of the specific ZP glycoprotein (ZPA/2, ZPC/3 or ZPB/4) involved in the interaction with the sperm proteins.STUDY DESIGN, SIZE, DURATIONTo identify the human sperm proteins interacting with the oocyte ZP, we combined two approaches: immunoblot of human spermatozoa targeted by antisperm antibodies (ASAs) from infertile men and far western blot of human sperm proteins overlayd by each of the rhZP proteins.MATERIALS, SETTING, METHODSWe used rhZP expressed in Chinese hamster ovary (CHO) cells and ASA eluted from infertile patients undergoing IVF failure. Sperm proteins separated by two-dimensional (2D) electrophoresis recognized by both sperm-eluted ASAs from infertile patients and rhZP were identified by mass spectrometry (MALDI-MS/MS). Some of these proteins were further validated by co-precipitation experiments with rhZP and functional zona binding tests. MAIN RESULTS AND THE ROLE OF CHANCE: We identified proteins that are glycolytic enzymes such as pyruvate kinase 3, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, aldolase A, triosephosphate isomerase, detoxification enzymes such as GSTM or phospholipid hydroperoxide glutathione peroxidase, ion channels such as VDAC2 and structural proteins such as outer dense fibre 2. Several of the proteins were localized on the sperm head. However, these proteins have also been described to exert other functions in the flagellum. Co-precipitation experiments with rhZP-coated beads confirmed the direct interaction of GSTM with ZP4 and of VDAC2 with ZP2 and ZP3. LIMITATIONS, REASONS FOR CAUTION: We used recombinant ZP in place of native ZP. Thus, the post-translational modifications of the proteins, such as glycosylations, can be different and can influence their function. However, CHO cell-expressed rhZP are functional, e.g. can bind human spermatozoa and induce the acrosome reaction. Moreover, the identification of relevant proteins was limited by the need for sufficient amounts of proteins on the preparative 2D-gel to be subsequently analysed in MALDI-TOF MS/MS. WIDER IMPLICATIONS OF THE FINDINGS: Our results bring new insights on the ability of sperm proteins to exert several functions depending on their sub-cellular localization, either the head or flagellum. Their multiple roles suggest that these sperm proteins are multifaceted or moonlighting proteins. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the grant ReproRio (CNRS, INRA, INSERM and CEA) and the Société d'Andrologie de Langue Française.Trial registration numberNot applicable. © 2013 The Author.
Al-Aama J.Y.,King Abdulaziz University |
Al-Ghamdi S.,Prince Sultan Cardiac Center |
Bdier A.Y.,King Abdulaziz University |
Wilde A.A.M.,King Abdulaziz University |
And 2 more authors.
Clinical Genetics | Year: 2014
Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive disorder, clinically characterized by severe cardiac arrhythmias [due to prolonged QTc interval in electrocardiogram (ECG)] and bilateral sensory neural deafness. Molecular defects causal to JLNS are either homozygous or compound heterozygous mutations, predominantly in the KCNQ1 gene and occasionally in the KCNE1 gene. As the molecular defect is bi-allelic, JLNS patients inherit one pathogenic mutation causal to the disorder from each parent. In this report, we show for the first time that such a disorder could also occur due to a spontaneous de novo mutation in the affected individual, not inherited from the parent, which makes this case unique unlike the previously reported JLNS cases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Soufir J.-C.,Groupe Hospitalier Cochin |
Meduri G.,Laboratoire Of Genetique Moleculaire |
Ziyyat A.,Groupe Hospitalier Cochin |
Ziyyat A.,University of Paris Descartes
Human Reproduction | Year: 2011
Background: We previously demonstrated in a small pilot study that oral medroxyprogesterone acetate and percutaneous testosterone (OMP/PT) induce reversible spermatogenesis suppression. The aims of this study were to determine the rate of spermatogenetic inhibition and recovery and to obtain preliminary data on efficacy for a larger population under OMP/PT. Methods: A total of 35 healthy men with normal spermiograms requesting male hormonal contraception were treated with OMP (20 mg/day) and PT (50125 mg/day) for periods up to 18 months. Couples were included in a contraceptive efficacy phase after a value of ≤1 million/ml spermatozoa was reached between 1 and 3 months of treatment. Results: Sperm counts decreased by 47 at 1 month, reaching 90 at 2 months and 98100 between 4 and 8 months. At 3 months, 80 of men had ≤1 million/ml spermatozoa. Follicle-stimulating hormone and luteinizing hormone decreased to 35 of pretreatment levels after 1 month of treatment and to 7580 at 2 and 6 months, respectively. Plasma testosterone and estradiol levels were in the eugonadal range at 3, 6, 9 and 12 months of treatment. Dihydrotestosterone concentrations were 24 times higher than pretreatment values. The rate of spermatogenetic recovery was rapid (73 ± 29.5 days). During the efficacy phase (211 months for 25 couples), one pregnancy attributable to poor compliance of the male partner was observed. Conclusions: OMP/PT efficiently inhibits spermatogenesis in 80 of men, maintains testosterone at physiological levels and avoids the need for parenteral administration, which is poorly accepted by French men. These Results: justify larger studies to define a more adequate dosage of OMP/PT and to confirm its efficacy and safety. © 2011 The Author.
Institute Of Recherche Pour Le Development Ird and Laboratoire Of Genetique Moleculaire | Date: 2013-07-18
The present invention relates to molecular markers and to the use thereof for distinguishing male date palm plants from female date palm plants. The invention also relates to a method for identifying the sex of date palm plants using these molecular markers, and to a kit for carrying out the method.