A novel DFNB1 deletion allele supports the existence of a distant cis-regulatory region that controls GJB2 and GJB6 expression
| Autor: | C Le Marechal, R Birkenhäger, Jill L. Elfenbein, Rachel Fisher, S M Da Silva-Costa, Arti Pandya, Edi Lúcia Sartorato, Karen H. Friderici, H Bolz, Eberhard Schneider, G. Van Camp, Richard J.H. Smith, Christian Kubisch, Hela Azaiez, Ellen Wilch, Hannie Kremer, Alessandra Murgia, Thomas Haaf, L. H. Hoefsloot, I del Castillo, Wim Wuyts |
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| Přispěvatelé: | Michigan State University [East Lansing], Michigan State University System, University of Iowa [Iowa City], University of Padua [Italy], Freiburg University Medical Center, Institute of Human Genetics [Cologne], University of Cologne-Universitätsklinikum Köln (Uniklinik Köln), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Radboud University Medical Center [Nijmegen], Institute of Human Genetics, Universität Ulm - Ulm University [Ulm, Allemagne], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université européenne de Bretagne - European University of Brittany (UEB), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Biomedical Sciences, Department of Medical genetics, University of Antwerp (UA), This work was supported by NIDCD grant DC004568 to K. H. F., an MSU Foundation grant to R. A. F. and a Families and Communities Together Coalition grant to J. E. R. J. H. S is the Sterba Hearing Research Professor at University of Iowa College of Medicine, who supported the project in part with National Institutes of Health (NIH)–National Institute on Deafness and Other Communication Disorders (NIDCD) grant DC02842., We are grateful to the many MSU‐DF5 family members for their participation. E. W. thanks Dr Patrick J. Venta for critical reading of the manuscript. |
| Rok vydání: | 2010 |
| Předmět: |
Male
Genetics and epigenetic pathways of disease [NCMLS 6] [SDV]Life Sciences [q-bio] Penetrance MESH: Base Sequence Regulatory Sequences Nucleic Acid sensorineural hearing loss Connexins MESH: Genotype MESH: Hearing Loss Sensorineural/diagnosis MESH: Penetrance Genotype Copy-number variation Genetics (clinical) Sequence Deletion Genetics Comparative Genomic Hybridization 0303 health sciences MESH: Genetic Testing MESH: Gene Expression Regulation 030305 genetics & heredity GJB2 Pedigree Connexin 26 MESH: Sequence Deletion MESH: Hearing Loss Sensorineural/genetics Female Chromosome Deletion Functional Neurogenomics [DCN 2] GJB6 MESH: Pedigree MESH: Chromosome Deletion Hearing Loss Sensorineural Molecular Sequence Data connexin 26 connexin 30 DFNB1 gene expression regulation GJB2 GJB6 sensorineural hearing loss sequence deletion Biology MESH: Connexin 30 MESH: Connexins/genetics MESH: Sequence Homology Nucleic Acid Article Genomic disorders and inherited multi-system disorders [IGMD 3] 03 medical and health sciences Monoallelic Mutation MESH: Connexin 26 Sequence Homology Nucleic Acid Connexin 30 otorhinolaryngologic diseases Humans Genetic Testing Allele Gene MESH: Regulatory Sequences Nucleic Acid/genetics Alleles DFNB1 030304 developmental biology Family Health MESH: Humans MESH: Molecular Sequence Data Base Sequence Chromosomes Human Pair 13 MESH: Alleles Breakpoint MESH: Male MESH: Comparative Genomic Hybridization Gene Expression Regulation MESH: Family Health biology.protein Human medicine MESH: Chromosomes Human Pair 13/genetics MESH: Female |
| Zdroj: | Clinical Genetics, 78, 267-74 Clinical Genetics, 78, 3, pp. 267-74 Clinical genetics Clinical Genetics Clinical Genetics, Wiley, 2010, 78 (3), pp.267-274. ⟨10.1111/j.1399-0004.2010.01387.x⟩ |
| ISSN: | 0009-9163 1399-0004 |
| DOI: | 10.1111/j.1399-0004.2010.01387.x |
| Popis: | Contains fulltext : 87760_1.pdf (author's version ) (Open Access) Contains fulltext : 87760_2.pdf (Publisher’s version ) (Closed access) Eleven affected members of a large German-American family segregating recessively inherited, congenital, non-syndromic sensorineural hearing loss (SNHL) were found to be homozygous for the common 35delG mutation of GJB2, the gene encoding the gap junction protein Connexin 26. Surprisingly, four additional family members with bilateral profound SNHL carried only a single 35delG mutation. Previously, we demonstrated reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons. Using array comparative genome hybridization (array CGH), we have now identified on this allele a deletion of 131.4 kb whose proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6. This deletion, del(chr13:19,837,344-19,968,698), segregates as a completely penetrant DFNB1 allele in this family. It is not present in 528 persons with SNHL and monoallelic mutation of GJB2 or GJB6, and we have not identified any other candidate pathogenic copy number variation by arrayCGH in a subset of 10 such persons. Characterization of distant GJB2/GJB6 cis-regulatory regions evidenced by this allele may be required to find the 'missing' DFNB1 mutations that are believed to exist. 01 september 2010 |
| Databáze: | OpenAIRE |
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