title: Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.
abstract: Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Ophthalmology, University of Toronto, 340 College Street, Toronto, ON M5T 3A9, Canada.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Vincent
authors.affiliation: INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France; INSERM-DHOS CIC1423, Centre Hospitalier National d'Ophtalmologie (CHNO) des Quinze-Vingts, DHU Sight Restore, 28 Rue de Charenton, 75012 Paris, France; Institute of Ophthalmology, University College of London, London EC1V 9EL, UK.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Tavares
authors.affiliation: Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Maynes
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Anupreet
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wright
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Shuning
authors.initials: S
authors.lastname: Li
authors.affiliation: INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Michiels
authors.affiliation: INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Condroyer
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: MacDonald
authors.affiliation: Eye Center, 3 Rue Rigoberta Menchu, 84000 Avignon, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Verdet
authors.affiliation: INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France; INSERM-DHOS CIC1423, Centre Hospitalier National d'Ophtalmologie (CHNO) des Quinze-Vingts, DHU Sight Restore, 28 Rue de Charenton, 75012 Paris, France; Institute of Ophthalmology, University College of London, London EC1V 9EL, UK; Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France; Academie des Sciences, Institut de France, 75006 Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM U 1051, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, 34295 Montpellier Cedex 05, France; Affections Sensorielles Génétiques, CHU de Montpellier, 191 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex, France; Université Montpellier, 163 Avenue Auguste Broussonnet, 34090 Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.affiliation: Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Ophthalmology, University of Toronto, 340 College Street, Toronto, ON M5T 3A9, Canada. Electronic address: elise.heon@sickkids.ca.
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D004596:Electroretinography; D015785:Eye Diseases, Hereditary / Q000209:etiology* / Q000473:pathology; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000209:etiology* / Q000473:pathology; D005838:Genotype; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009216:Myopia / Q000209:etiology* / Q000473:pathology; D009755:Night Blindness / Q000209:etiology* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D014792:Visual Acuity / Q000235:genetics
chemical_list: C000595803:GNB3 protein, human; D020962:Heterotrimeric GTP-Binding Proteins
keywords: G-protein beta 3 subunit; congenital stationary; exome; human GNB3; light signal transduction; night blindness; retinal dystrophies