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1. Screening of SLC26A4, FOXI1 and KCNJ10 genes in unilateral hearing impairment with ipsilateral enlarged vestibular aqueduct

Author

Natalie Loundon, Christine Francannet, Thierry Mom, Magali Niasme-Grare, Delphine Feldmann, Valérie Drouin-Garraud, Albert David, Marie-Françoise Thuillier-Obstoy, Hélène Dollfus, Françoise Duriez, Cyril Goizet, Hubert Journel, Hélène Catros, Catherine Calais, Catherine Gohler, Sandrine Marlin, Laurence Jonard, Marie Madeleine Eliot, Rémy Couderc, Françoise Denoyelle, Brigitte Gilbert-Dussardier, Erea Noel Garabedian, Crystel Bonnet, Isabelle Rouillon, and Florence Fellmann

Subjects
Adult, Male, medicine.medical_specialty, Vestibular aqueduct, Adolescent, Genetic Linkage, Hearing loss, KCNJ10, Audiology, Hearing Loss, Unilateral, Vestibular Aqueduct, Young Adult, otorhinolaryngologic diseases, medicine, Humans, Potassium Channels, Inwardly Rectifying, Child, Pendred syndrome, Polymorphism, Genetic, biology, business.industry, Infant, Newborn, Infant, Membrane Transport Proteins, Forkhead Transcription Factors, General Medicine, Anatomy, medicine.disease, Pedigree, medicine.anatomical_structure, Haplotypes, Otorhinolaryngology, FOXI1, Sulfate Transporters, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Mondini dysplasia, biology.protein, Female, sense organs, medicine.symptom, Unilateral hearing loss, business, Enlarged vestibular aqueduct
Abstract

Objective To investigate the implication of SLC26A4, FOXI and KCNJ10 genes in unilateral hearing impairment associated with ipsilateral inner ear malformation (Enlargement of the vestibular aqueduct and/or Mondini dysplasia). Methods We have gathered 25 patients presenting unilateral hearing impairment and ipsilateral enlarged vestibular aqueduct. For each of the patients, we have analyzed SLC26A4, FOXI1 and KCNJ10 genes sequences. Results The analysis of SLC26A4 revealed only eight heterozygous SLC26A4 sequence variants, three of them being novel (p.Met147Ile, p.Asn538Asn and p.Leu627Arg). None of the patients carried a second mutation on the other allele. Moreover, the SLC26A4 locus was excluded by segregation analysis in two families. No mutations were present in FOXI1 and KCNJ10 genes. Conclusions Together, these data suggest that SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct compared with their implication in Pendred syndrome and non-syndromic bilateral enlarged vestibular aqueduct.

Published
2010
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2. Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

Author

Didier Lacombe, Christine Francannet, Thierry Mom, Marianne Lévêque, Delphine Feldmann, Pascal Reynier, Vincent Procaccio, Marie-Madeleine Eliot, Patrizia Amati-Bonneau, Françoise Denoyelle, Hubert Journel, Denis Pierron, Sylvain Baulande, Laurence Jonard, Françoise Duriez, Christine Petit, Erea-Noel Garabedian, Hélène Catros, Valérie Drouin-Garraud, Sandrine Marlin, Rémy Couderc, Marie-Françoise Obstoy, Laurence Faivre, Hélène Dollfus, and Christian Duvillard

Subjects
Adult, Male, Mitochondrial DNA, Lineage (genetic), Hearing Loss, Sensorineural, Biology, medicine.disease_cause, DNA, Mitochondrial, Genome, Mice, Dogs, Genetics, medicine, Animals, Humans, Point Mutation, Electrophoresis, Gel, Two-Dimensional, Child, Gene, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Mutation, Point mutation, Sequence Analysis, DNA, Heteroplasmy, Mitochondria, Pedigree, Rats, Genome, Mitochondrial, Cattle, Female, DNA microarray
Abstract

Mitochondrial DNA (mtDNA) mutations have been implicated in non-syndromic hearing loss either as primary or as predisposing factors. As only a part of the mitochondrial genome is usually explored in deafness, its prevalence is probably under-estimated. Among 1350 families with non-syndromic sensorineural hearing loss collected through a French collaborative network, we selected 29 large families with a clear maternal lineage and screened them for known mtDNA mutations in 12S rRNA, tRNASer(UCN) and tRNALeu(UUR) genes. When no mutation could be identified, a whole mitochondrial genome screening was performed, using a microarray resequencing chip: the MitoChip version 2.0 developed by Affymetrix Inc. Known mtDNA mutations was found in nine of the 29 families, which are described in the article: five with A1555G, two with the T7511C, one with 7472insC and one with A3243G mutation. In the remaining 20 families, the resequencing Mitochip detected 258 mitochondrial homoplasmic variants and 107 potentially heteroplasmic variants. Controls were made by direct sequencing on selected fragments and showed a high sensibility of the MitoChip but a low specificity, especially for heteroplasmic variations. An original analysis on the basis of species conservation, frequency and phylogenetic investigation was performed to select the more probably pathogenic variants. The entire genome analysis allowed us to identify five additional families with a putatively pathogenic mitochondrial variant: T669C, C1537T, G8078A, G12236A and G15077A. These results indicate that the new MitoChip platform is a rapid and valuable tool for identification of new mtDNA mutations in deafness.

Published
2007
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3. Large deletion of theGJB6gene in deaf patients heterozygous for theGJB2gene mutation: Genotypic and phenotypic analysis

Author

Jacques Leman, Catherine Calais, Valérie Drouin-Garraud, Christine Petit, Cédric Le Maréchal, Bétina Montaut, Bruno Delobel, Pierre Chauvin, Patricia Lewin, Sandrine Marlin, Didier Bouccara, Hélène Catros, Marie-Françoise Obstoy, Marie-Madeleine Eliot, Sébastien Schmerber, Hélène Dollfus, Patrice Tran Ba Huy, Jacqueline Vigneron, Delphine Feldmann, Albert David, Erea-Noel Garabedian, Alain Joannard, Françoise Duriez, Rémy Couderc, Cyril Goizet, Olivier Sterkers, Françoise Denoyelle, J. P. Delaunoy, Hubert Journel, Sylvie Odent, Jocelyne Hélias, and Florence Fellmann

Subjects
Genetics, Mutation, biology, Hearing loss, Heterozygote advantage, medicine.disease_cause, Phenotype, Gjb2 gene, Genotype, otorhinolaryngologic diseases, medicine, biology.protein, medicine.symptom, Gene, Genetics (clinical), GJB6
Abstract

Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss.

Published
2004
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4. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome

Author

Elodie Sanchez, David Geneviève, Gudrun Nürnberg, Lionel Van Maldergem, Bérénice Doray, Dietmar R. Lohmann, Marie Vincent, Maria Rita Passos-Bueno, Chantal Bolender, Corinne Collet, Marie-Madeleine Eliot, Dagmar Wieczorek, and Elise Schaefer

Subjects
Adult, genetic structures, DNA Mutational Analysis, Medizin, Genes, Recessive, Biology, medicine, Humans, RNA, Messenger, Child, Genetics (clinical), Genetic Association Studies, Genetics, Messenger RNA, Homozygote, Facies, Nuclear Proteins, DNA-Directed RNA Polymerases, musculoskeletal system, medicine.disease, Phosphoproteins, eye diseases, Phenotype, Amino Acid Substitution, Gene Expression Regulation, Haplotypes, Genetic Loci, Child, Preschool, Mutation (genetic algorithm), Mutation, Female, sense organs, human activities, Treacher Collins syndrome, Mandibulofacial Dysostosis
Abstract

Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance.We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families.The four affected children shared the same homozygous mutation in POLR1D (c.163CG, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis.This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.

Published
2013

5. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Author

Jacques Dubin, Christine Francannet, Jacqueline Levilliers, Thierry Mom, Magali Niasme-Grare, J.-P. Hardelin, Françoise Denoyelle, Diana Zelenika, Valérie Drouin-Garraud, Didier Lacombe, Sandrine Marlin, Marc Delepine, Patrick Collignon, Alain Duvillard, Christel Thauvin, Sabine Sigaudy, Jacqueline Vigneron, Albert David, Anne Marie Frances, Christophe Vincent, Françoise Duriez, Dominique Weil, Catherine Calais, Marine Parodi, M'hamed Grati, Hélène Dollfus, Delphine Feldmann, Bruno Delobel, Laurence Jonard, Christine Petit, Marie Françoise Thuillier-Obstoy, Bettina Montaut-Verient, Crystel Bonnet, Jean Weissenbach, Aziz El-Amraoui, Georges Challe, Dominique Bonneau, Mark Lathrop, Marie Madeleine Eliot, José-Alain Sahel, Rémy Couderc, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), NIDCD, National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Génétique, Service ORL, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'ORL et chirurgie cervico-faciale, Service d'oto-rhino-laryngologie (ORL), Hôtel-Dieu, Maternité Régionale Adolphe Pinard [Nancy], Maternité Régionale Adolphe-Pinard, Centre de Référence des Maladies Neurogénétiques, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Oto-Rhino-Laryngologie [CHU de Dijon] (ORL [CHU de Dijon]), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ORL, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ophtalmologie [Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service ORL Pédiatrique, Normandie Université (NU)-Normandie Université (NU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale, Hôpital intercommunal de Font-Pré, CHU Pitié-Salpêtrière [AP-HP], Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), M.G. was supported by European Commission FP6 Integrated project, EuroHear (LSHG-CT-2004-512063) and C.B. by the French Foundation 'Voir et Entendre'. This work was supported by Fondation R & G Strittmatter (under the aegis of Fondation de France), FAUN Stiftung (Suchert Foundation), ECFP7 TREATRUSH (HEALTH-F2-2010-242013), Foundation Fighting Blindness, LHW-Stiftung, Fondation Orange, The Conny-Maeva Charitable Foundation, Genoscope-CNRG project AP2005, and S'entendre Foundation., Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chaire Génétique et physiologie cellulaire, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Hôpital St-Antoine, Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Normandie Université (NU)-Hôpital Charles-Nicolle, Hôpital Charles-Nicolle, Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and BMC, Ed.

Subjects
Usher syndrome, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Genotype, Exon, 0302 clinical medicine, Genotype, Genetics(clinical), Pharmacology (medical), Genetics (clinical), Exome sequencing, Medicine(all), Genetics, 0303 health sciences, Mutation, Splice site mutation, MESH: Genomics, Exons, Genomics, General Medicine, MESH: Case-Control Studies, Pedigree, 3. Good health, France, Usher Syndromes, MESH: Mutation, MESH: Pedigree, Molecular Sequence Data, Biology, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, Humans, Amino Acid Sequence, MESH: Usher Syndromes, Gene, Genotyping, MESH: Genome, Human, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Genome, Human, Research, lcsh:R, medicine.disease, MESH: France, Case-Control Studies, MESH: Exons, 030217 neurology & neurosurgery
Abstract

Background Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Results Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Conclusions Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

Published
2011
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6. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations

Author

Sebastien Albert, Pierre Bitoun, Christine Francannet, Françoise Denoyelle, Bruno Delobel, Didier Lacombe, Marie-Madeleine Eliot, Annie Sergent-Allaoui, Hélène Dollfus, Sébastien Schmerber, Alain Joannard, Pierre Chauvin, Muriel Houang, Valérie Drouin-Garraud, N. Loundon, Albert David, Erea-Noel Garabedian, Catherine Calais, Françoise Duriez, Rémy Couderc, Hélène Blons, Delphine Feldmann, Laurence Jonard, Christine Petit, Marie-Françoise Obstoy, Hélène Catros, Sandrine Marlin, Patrice Tran Ba Huy, Jacques Leman, Hubert Journel, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins (DS3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Service d'ORL et de chirurgie cervicale, CHU Grenoble, CHU Saint-Antoine [AP-HP], Centre Rochin, Unité de Génétique Médicale, CHR Vannes, Centre Gabriel Deshayes, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'ORL et chirurgie cervico-faciale, Service d'oto-rhino-laryngologie (ORL), Hôtel-Dieu, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'ORL, chirurgie cervico-faciale [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service d'oto-rhino-laryngologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ORL, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôtel-Dieu-CHU Clermont-Ferrand, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Chaire Génétique et physiologie cellulaire, Service de génétique et embryologie médicales [CHU Trousseau], Chauvin, Pierre, Neurobiologie des réseaux sensorimoteurs (NRS (U7060)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des réseaux sensorimoteurs ( NRS (U7060) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), and Magnani, Christophe

Subjects
Male, Pediatrics, Vestibular aqueduct, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Deafness, Connexins, MESH: Membrane Transport Proteins, Cohort Studies, 0302 clinical medicine, MESH: Child, Prevalence, Medicine, Nonsyndromic deafness, Child, 030223 otorhinolaryngology, MESH: Cohort Studies, Genetics (clinical), Pendred syndrome, Genetics, Goiter, Homozygote, Syndrome, MESH: European Continental Ancestry Group, MESH: Infant, Connexin 26, medicine.anatomical_structure, Sulfate Transporters, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Sensorineural hearing loss, medicine.symptom, MESH: Homozygote, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, Hearing loss, Hearing Loss, Sensorineural, MESH: Deafness, MESH: Goiter, White People, Vestibular Aqueduct, 03 medical and health sciences, otorhinolaryngologic diseases, Humans, Alleles, MESH: Prevalence, MESH: Adolescent, MESH: Humans, business.industry, MESH: Alleles, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Infant, Membrane Transport Proteins, Congenital sensorineural hearing impairment, MESH: Adult, medicine.disease, MESH: Male, MESH: Connexins, FOXI1, MESH: Hearing Loss, Sensorineural, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, business, MESH: Female, Enlarged vestibular aqueduct
Abstract

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Published
2006
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7. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates

Author

Masazumi Tada, J. Paul Chapple, Andrew J. Copp, Andrew Forge, James R. Lupski, Philip L. Beales, Nicholas Katsanis, Marie-Madeleine Eliot, Masatake Kai, Perciliz L. Tan, Hélène Dollfus, Josephine Hill, Peter M. G. Munro, Michel R. Leroux, Deborah J. Henderson, Helen May-Simera, Jennifer N. Murdoch, Erica R. Eichers, David T. Kemp, Alison Ross, Shannon Fisher, Daniel J. Jagger, Carmen C. Leitch, and Helen M. Phillips

Subjects
Axoneme, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Group II Chaperonins, Nerve Tissue Proteins, Biology, Mice, Bardet–Biedl syndrome, Internal medicine, Cell polarity, Genetics, medicine, Basal body, Animals, Cilia, Neural Tube Defects, Zebrafish, Bardet-Biedl Syndrome, Convergent extension, Cilium, Wnt signaling pathway, Cell Polarity, Eyelids, Epithelial Cells, medicine.disease, biology.organism_classification, Mice, Mutant Strains, Cell biology, Cochlea, Endocrinology, Mutation, Microtubule-Associated Proteins, Molecular Chaperones
Abstract

The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation1. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation2. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction3, 4, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes.

Published
2005

8. Two large French pedigrees with non syndromic sensorineural deafness and the mitochondrial DNA T7511C mutation: evidence for a modulatory factor

Author

Damien Sternberg, Elise Chapiro, Christine Petit, Didier Bouccara, Dominique Weil, Marie-Madeleine Eliot, Françoise Denoyelle, Delphine Feldmann, Claude Jardel, Rémy Couderc, Sandrine Marlin, and Erea-Noel Garabedian

Subjects
Adult, Male, Mitochondrial DNA, Adolescent, Offspring, Hearing Loss, Sensorineural, DNA Mutational Analysis, Pedigree chart, Biology, DNA, Mitochondrial, Polymerase Chain Reaction, otorhinolaryngologic diseases, Genetics, medicine, Humans, Gene, Genetics (clinical), Aged, Point mutation, Middle Aged, medicine.disease, Heteroplasmy, Pedigree, Mutation (genetic algorithm), Mutation, Sensorineural hearing loss, Female, France, Polymorphism, Restriction Fragment Length
Abstract

Hearing impairment is the most frequent sensory defect in children, with a genetic basis in about 50% of cases. Several point mutations and deletions in mitochondrial DNA (mtDNA) have been identified in non-syndromic sensorineural hearing loss (NSSNHL). Beside the frequent A1555G mutation, a number of mutations in tRNAs have been reported recently, but their incidence remains unknown. We identified the T7511C mutation in the tRNASer(UCN) gene in two French families with isolated deafness. Maternal transmission was obvious in both. The 15 patients with hearing impairment exhibited a variable disease phenotype in terms of onset, severity, and progression. T7511C was present in all the patients screened. Homoplasmic and heteroplasmic levels were observed and did not correlate with the severity of the disease. T7511C was also present in 12 hearing offspring of the oldest deaf mothers, confirming the existence of modulatory factors. Our data suggest that this mtDNA mutation should be screened for in all cases of familial NSSNHL compatible with maternal transmission.

Published
2002

9. GJB2 and GJB6 Mutations

Author

Hubert Journel, Jean-Louis Delaunoy, Sebastien Albert, Valérie Drouin-Garraud, Delphine Feldmann, Sylvie Odent, Hélène Dollfus, Natalie Loundon, Jacqueline Vigneron, Catherine Calais, Clarisse Baumann, Françoise Denoyelle, Marie-Madeleine Eliot, Alain Joannard, Christine Petit, Laurence Faivre, Albert David, Erea-Noel Garabedian, Marie-Françoise Obstoy, Bruno Delobel, Rémy Couderc, Cyril Goizet, Sébastien Schmerber, Jocelyne Hélias, Bettina Montaut, Françoise Duriez, Hélène Catros, Hélène Blons, Cédric Lemarechal, Isabelle Rouillon, Florence Fellmann, Sandrine Marlin, Pierre Chauvin, Patricia Lewin, Jacques Leman, and Dominique Matin-Coignard

Subjects
Mild hearing impairment, medicine.medical_specialty, Genotype, Hearing loss, DNA Mutational Analysis, Compound heterozygosity, medicine.disease_cause, Connexins, Internal medicine, Connexin 30, otorhinolaryngologic diseases, medicine, Humans, Prospective Studies, Hearing Disorders, Allele frequency, Genetics, Mutation, biology, medicine.diagnostic_test, business.industry, General Medicine, Connexin 26, Phenotype, Otorhinolaryngology, biology.protein, Surgery, Chromosome Deletion, medicine.symptom, Audiometry, business, GJB6
Abstract

Objectives To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1. Design Case series. Setting Collaborative study in referral centers, institutional practice. Patients A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion ( GJB6 -D13S1830)del. Main Outcome Measures The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes. Results Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6 , ( GJB6 -D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%). Conclusion Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.

Published
2005
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