A Truncated Form of Rod Photoreceptor PDE6 β-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the γ-Subunit

Gaël Manes; Pallavi Cheguru; Anurima Majumder; Béatrice Bocquet; Audrey Sénéchal; Nikolai O Artemyev; Christian P Hamel; Philippe Brabet

doi:10.1371/journal.pone.0095768

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A Truncated Form of Rod Photoreceptor PDE6 β-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the γ-Subunit

Journal article

Open access

Peer reviewed

A Truncated Form of Rod Photoreceptor PDE6 β-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the γ-Subunit

Gaël Manes, Pallavi Cheguru, Anurima Majumder, Béatrice Bocquet, Audrey Sénéchal, Nikolai O Artemyev, Christian P Hamel and Philippe Brabet

PloS one, Vol.9(4), pp.e95768-e95768

2014

DOI: 10.1371/journal.pone.0095768

PMCID: PMC3997432

PMID: 24760071

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Abstract

Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin α-subunit (GNAT1), and cGMP phosphodiesterase type 6 β-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6β1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6β1-313. We found that PDE6β1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory γ-subunit (Pγ), and interferes with the inhibition of normal PDE6αβ catalytic subunits by Pγ. Moreover, both truncated forms of the PDE6β protein, PDE6β1-313 and PDE6β1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation

Mutation

Night Blindness - metabolism

Humans

Night Blindness - etiology

Transducin

Heterotrimeric GTP-Binding Proteins - metabolism

Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics

Light Signal Transduction - genetics

Genetic Diseases, X-Linked - etiology

Heterotrimeric GTP-Binding Proteins - genetics

Myopia - metabolism

Genetic Diseases, X-Linked - genetics

Light Signal Transduction - physiology

Night Blindness - genetics

Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism

Animals, Genetically Modified

Xenopus laevis

Catalytic Domain - genetics

Genetic Diseases, X-Linked - metabolism

Myopia - etiology

Catalytic Domain - physiology

Eye Diseases, Hereditary - genetics

Myopia - genetics

Animals

Eye Diseases, Hereditary - etiology

Eye Diseases, Hereditary - metabolism

Details

Title: Subtitle: A Truncated Form of Rod Photoreceptor PDE6 β-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the γ-Subunit
Creators: Gaël Manes - Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France
Pallavi Cheguru - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America
Anurima Majumder - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America
Béatrice Bocquet - Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France
Audrey Sénéchal - Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France
Nikolai O Artemyev - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States of America
Christian P Hamel - Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France; CHRU, Genetics of Sensory Diseases, Montpellier, France
Philippe Brabet - Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France
Resource Type: Journal article
Publication Details: PloS one, Vol.9(4), pp.e95768-e95768
DOI: 10.1371/journal.pone.0095768
PMID: 24760071
PMCID: PMC3997432
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: EY-12682 / NEI NIH HHS R01 EY010843 / NEI NIH HHS R01 EY012682 / NEI NIH HHS EY-10843 / NEI NIH HHS
Language: English
Date published: 2014
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9984025367902771

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