Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness

Ajoy Vincent; Isabelle Audo; Erika Tavares; Jason T Maynes; Anupreet Tumber; Thomas Wright; Shuning Li; Christelle Michiels; GNB3 Consortium; Christel Condroyer; Heather MacDonald; Robert Verdet; José-Alain Sahel; Christian P Hamel; Christina Zeitz; Elise Héon

doi:10.1016/j.ajhg.2016.03.021

Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness

Am J Hum Genet. 2016 May 5;98(5):1011-1019. doi: 10.1016/j.ajhg.2016.03.021. Epub 2016 Apr 7.

Authors

Affiliations

¹ 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.
² 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.
³ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ 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.
⁵ Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶ INSERM, CNRS, Université Pierre et Marie Curie (Paris 6), Sorbornne Universités, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
⁷ 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.
⁸ Eye Center, 3 Rue Rigoberta Menchu, 84000 Avignon, France.
⁹ 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.
¹⁰ 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.
¹¹ 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.

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.

Keywords: G-protein beta 3 subunit; congenital stationary; exome; human GNB3; light signal transduction; night blindness; retinal dystrophies.

MeSH terms

Alleles
Amino Acid Sequence
Animals
Case-Control Studies
Electroretinography
Eye Diseases, Hereditary / etiology*
Eye Diseases, Hereditary / pathology
Female
Genes, Recessive / genetics*
Genetic Diseases, X-Linked / etiology*
Genetic Diseases, X-Linked / pathology
Genotype
Heterotrimeric GTP-Binding Proteins / chemistry
Heterotrimeric GTP-Binding Proteins / genetics*
Homozygote
Humans
Male
Mice
Middle Aged
Mutation / genetics*
Myopia / etiology*
Myopia / pathology
Night Blindness / etiology*
Night Blindness / pathology
Pedigree
Phenotype
Protein Conformation
Sequence Homology, Amino Acid
Visual Acuity / genetics

Substances

GNB3 protein, human
Heterotrimeric GTP-Binding Proteins

Supplementary concepts

Night blindness, congenital stationary