New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies
| Autor: | Patricia Ramos, María José Sánchez-Soler, Alison Stewart, Nicolas Chassaing, Jonathan Bruty, Patrick Calvas, Domingo Aguilera-Garcia, Helen Stewart, Dominic J. McMullan, Dorine Bax, Yvonne Wallis, Alan Fryer, Anand Saggar, Carmen Ayuso, Cristina Villaverde, Fabiola Ceroni, Marta Corton, Luciana Rodrigues Jacy da Silva, Lisa Cooper-Charles, Michael J. Griffiths, Victoria McKay, Jonathan Hoffman, Maria Tarilonte, David J. Bunyan, María Juliana Ballesta-Martínez, Nicola K. Ragge, Richard J. Holt, Katherine Lachlan, Fiona Blanco-Kelly, Joelle Roume, Pascal Dureau |
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| Přispěvatelé: | Oxford Brookes University, Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Oxford University Hospitals NHS Trust, University of Oxford, University College of London [London] (UCL), University Hospital Murcia, Partenaires INRAE, Birmingham Women's and Children's NHS Foundation Trust, Salisbury District Hospital, Sheffield Children's NHS Foundation Trust, University Hospital Southampton NHS Foundation Trust, University of Southampton, Liverpool Women's NHS Foundation Trust, CHI Poissy-Saint-Germain, Fondation Ophtalmologique Adolphe de Rothschild [Paris], St George's, University of London, The Wellcome Trust Sanger Institute [Cambridge], CP12/03256/Spanish Institute of Health Carlos III SAF2013-46943-R/Spanish Ministry of Economy and CompetitivenessHICF-1009-003/Health Innovation Challenge Fund, Pistre, Karine, Ceroni F., Aguilera-Garcia D., Chassaing N., Bax D.A., Blanco-Kelly F., Ramos P., Tarilonte M., Villaverde C., da Silva L.R.J., Ballesta-Martinez M.J., Sanchez-Soler M.J., Holt R.J., Cooper-Charles L., Bruty J., Wallis Y., McMullan D., Hoffman J., Bunyan D., Stewart A., Stewart H., Lachlan K., Fryer A., McKay V., Roume J., Dureau P., Saggar A., Griffiths M., Calvas P., Ayuso C., Corton M., Ragge N.K. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
MESH: Mutation Missense / genetics Human eye development genetic structures MESH: Lens Crystalline / pathology medicine.disease_cause Microphthalmia Connexins Cohort Studies Missense mutation Eye Abnormalities MESH: Cohort Studies Genetics (clinical) MESH: Heterozygote Genetics 0303 health sciences Coloboma Mutation 030305 genetics & heredity Gap Junctions MESH: Gap Junctions / genetics Pedigree GJA8 Phenotype MESH: Connexins / genetics [SDV.IMM]Life Sciences [q-bio]/Immunology Female Gap Junction Heterozygote [SDV.IMM] Life Sciences [q-bio]/Immunology MESH: Pedigree MESH: Eye Proteins / genetics Mutation Missense Biology Connexin [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics MESH: Phenotype Cataract 03 medical and health sciences Cataracts MESH: Genetic Association Studies / methods Lens Crystalline medicine Humans Sclerocornea Eye Proteins Genetic Association Studies 030304 developmental biology Anophthalmia MESH: Humans aphakia Len medicine.disease eye diseases MESH: Male MESH: Cataract / genetics microphthalmia [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics MESH: Eye Abnormalities / genetics Eye development sense organs MESH: Female |
| Zdroj: | Human Genetics Human Genetics, 2019, 138 (8-9), pp.1027-1042. ⟨10.1007/s00439-018-1875-2⟩ |
| ISSN: | 0340-6717 1432-1203 |
| DOI: | 10.1007/s00439-018-1875-2⟩ |
| Popis: | International audience; GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development. |
| Databáze: | OpenAIRE |
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