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Brief Report |

Recessive Retinopathy Consequent on Mutant G-Protein β Subunit 3 (GNB3)

Gavin Arno, PhD1,2; Graham E. Holder, MSc, PhD1,2; Christina Chakarova, PhD1,2; Susanne Kohl, PhD3; Nikolas Pontikos, PhD4; Alessia Fiorentino, PhD1,2; Vincent Plagnol, MSc, PhD4; Michael E. Cheetham, PhD1,2; Alison J. Hardcastle, PhD1,2; Andrew R. Webster, MD(Res), FRCOphth1,2; Michel Michaelides, MD(Res), FRCOphth1,2 ; for the UK Inherited Retinal Disease Consortium
[+] Author Affiliations
1University College London Institute of Ophthalmology, London, England
2Moorfields Eye Hospital, London, England
3Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany
4University College London Genetics Institute, London, England
JAMA Ophthalmol. 2016;134(8):924-927. doi:10.1001/jamaophthalmol.2016.1543.
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Importance  Mutations in phototransduction and retinal signaling genes are implicated in many retinopathies. To our knowledge, GNB3 encoding the G-protein β subunit 3 (Gβ3) has not previously been implicated in human disease.

Observations  In this brief report, whole-exome sequencing was conducted on a patient with distinct inherited retinal disease presenting in childhood, with a phenotype characterized by nystagmus, normal retinal examination, and mild disturbance of the central macula on detailed retinal imaging. This sequencing revealed a homozygous GNB3 nonsense mutation (c.124C>T; p.Arg42Ter). Whole-exome sequencing was conducted from April 2015 to July 2015.

Conclusions and Relevance  Expressed in cone photoreceptors and ON-bipolar cells, Gβ3 is essential in phototransduction and ON-bipolar cell signaling. Knockout of Gnb3 in mice results in dysfunction of cone photoreceptors and ON-bipolar cells and a naturally occurring chicken mutation leads to retinal degeneration. Identification of further affected patients may allow description of the phenotypic and genotypic spectrum of disease associated with GNB3 retinopathy.

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Figure 1.
Retinal Examinations

A and C, Color fundus imaging showing normal central and peripheral retinal appearance. B, Spectral-domain optical coherence tomography showing mild central inner segment ellipsoid interruption and reduced foveal cone outer segment lengthening. D, Fundus autofluorescence imaging showing less reduction than expected of the central macular hypoautofluorescent area. E, Goldmann visual fields reveal relatively intact isopters to the larger, brighter targets, with mild constriction to smaller, dimmer targets to a greater extent in the right eye than the left.

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Figure 2.
Full-Field Electroretinography (ERG) and Pattern ERG (PERG)

The numbers refer to the stimulus strength in cd.s.m-2 as recommended by the International Society for Clinical Electrophysiology of Vision. See the Results section for full details. DA indicates dark adapted; LA, light adapted.

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