Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness

Audo, Isabelle; Bujakowska, Kinga; Orhan, Elise; Poloschek, Charlotte M.; Defoort‐Dhellemmes, Sabine; Drumare, Isabelle; Kohl, Susanne; Luu, Tien D.; Lecompte, Odile; Zrenner, Eberhart; Lancelot, Marie-Elise; Arnaiz‐Villena, Antonio; Germain, Aurore; Michiels, Christelle; Audier, Claire; Letexier, Mélanie; Saraiva, Jean-Paul; Leroy, Bart P.; Munier, Francis L.; Mohand‐Saïd, Saddek; Lorenz, Birgit; Friedburg, Christoph; Preising, Markus N.; Kellner, Ulrich; Renner, Agnes B.; Moskova-Doumanova, Veselina; Berger, Wolfgang; Wissinger, Bernd; Hamel, Christian; Schorderet, Daniel F.; Baere, Elfride De; Sharon, Dror; Banin, Eyal; Jacobson, Samuel G.; Bonneau, Dominique; Zanlonghi, Xavier; Meur, Guylène Le; Casteels, Ingele; Koenekoop, Robert K.; Long, Vernon; Meire, Françoise; Prescott, Katrina; Ravel, Thomy de; Simmons, Ian; Nguyen, Hoan; Dollfus, Hélène; Poch, Olivier; Léveillard, Thierry; Nguyen-Ba-Charvet, Kim T.; Sahel, José‐Alain; Bhattacharya, Siladitya; Zeitz, Christina

doi:10.1016/j.ajhg.2011.12.007

Cited by 115 publications

(70 citation statements)

References 42 publications

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“…Prior to genetic testing, written informed consent, which had been previously approved by the CPP, was obtained from each study participant. Targeted next generation sequencing (NGS) and whole exome sequencing (WES) were performed in collaboration with a company (IntegraGen, Evry, France) [14,15]. A panel of 123 genes known to be associated with retinal dystrophies was used for targeted NGS as previously described [11].…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

et al. 2016

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GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321*) in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321*) is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.

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Section: Methodsmentioning

confidence: 99%

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

et al. 2016

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“…Such a possibility seems plausible considering recent findings on GPR179, a close homolog of GPR158. GPR179 is selectively expressed by retina ON-bipolar neurons, and its loss results in synaptic transmission deficits leading to night blindness (39,40). Just like GPR158, GPR179 associates with R7 RGS proteins and was shown to play an essential role for their synaptic targeting (38).…”

Section: Discussionmentioning

confidence: 99%

Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain

Orlandi

Xie

Masuho

et al. 2015

Journal of Biological Chemistry

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Background: RGS7 plays an essential role in regulating neuronal G protein signaling. Results: Elimination of GPR158 in mice reduces RGS7 expression and membrane localization. Unique domains in GPR158 control RGS7 catalytic activity. Conclusion:The function of RGS7 in the brain is critically regulated by binding to GPR158. Significance: This introduces a new player and its mechanism for regulating RGS activity in the nervous system.

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“…This could make GPR158 a uniquely effective drug target for ocular hypertension and glaucoma. One caveat for pharmaceutical targeting is that mutations in GPR179 have been demonstrated to cause night blindness (Audo et al, 2012; Peachey et al, 2012). It seems unlikely that GPR158 is also involved in visual transduction, as it does not appear to be expressed in the retina or optic nerve (Orlandi et al, 2012).…”

Section: Pharmacogenomicsmentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

105

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness

Cited by 115 publications

References 42 publications

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy

Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

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