Mouna Hadrami1, Crystel Bonnet2,3,4, Fatimetou Veten1, Christina Zeitz5, Christel Condroyer5, Panfeng Wang6, Mohamed Biya1, Med Ahmed Sidi Ahmed7, Qingjiong Zhang6, Sidi Cheikh8, Isabelle Audo5,9,10, Christine Petit2,3,4,11,12, Ahmed Houmeida1. 1. Unité de Recherche sur les Biomarqueurs dans la Population Mauritanienne, Université des Sciences de Technologies et de médecine (USTM), Nouakchott, Mauritanie. 2. Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, Paris, France. 3. UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France. 4. Complexité du Vivant, UPMC Université Paris 06, Sorbonne Universités, Paris, France. 5. Institut de la Vision, CNRS-INSERM, Sorbonne Université, Paris, France. 6. Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. 7. Programme national de lutte contre cécités, Nouakchott, Mauritanie. 8. Service Ophtalmologie, Centre Hospitalier National, Nouakchott, Mauritanie. 9. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, Paris, France. 10. Institute of Ophthalmology, University College of London, London, UK. 11. Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France. 12. Collège de France, Paris, France.
Abstract
OBJECTIVE OF THE STUDY: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations. METHODS: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband's DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software. RESULTS: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in GJA8, encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging. CONCLUSION: A new mutation (c.166A>C) in GJA8 underlying a nuclear congenital cataract was identified in this study. Its segregation with the phenotype might be useful as a predicting marker of the disease.
OBJECTIVE OF THE STUDY: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations. METHODS: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband's DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software. RESULTS: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in GJA8, encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging. CONCLUSION: A new mutation (c.166A>C) in GJA8 underlying a nuclear congenital cataract was identified in this study. Its segregation with the phenotype might be useful as a predicting marker of the disease.