Journal Article

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

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

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animals / Animals, Genetically Modified / Biology and Life Sciences / Biophysics / Blindness / Catalysis / Catalytic Domain - genetics / Catalytic Domain - physiology / Catalytic subunits / Congenital diseases / Cyclic GMP / Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics / Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism / Deoxyribonucleic acid / Desensitization / DNA / Enzymes / Eye Diseases, Hereditary - etiology / Eye Diseases, Hereditary - genetics / Eye Diseases, Hereditary - metabolism / Genes / Genetic Diseases, X-Linked - etiology / Genetic Diseases, X-Linked - genetics / Genetic Diseases, X-Linked - metabolism / Genetic testing / Genomics / Heterotrimeric GTP-Binding Proteins - genetics / Heterotrimeric GTP-Binding Proteins - metabolism / Humans / Light Signal Transduction - genetics / Light Signal Transduction - physiology / Medicine and Health Sciences / Mutation / Myopia - etiology / Myopia - genetics / Myopia - metabolism / Neurosciences / Night / Night Blindness - etiology / Night Blindness - genetics / Night Blindness - metabolism / Nyctalopia / Pedigree / Phosphodiesterase / Photoreceptors / Phototransduction / Physiology / Plasmids / Research and Analysis Methods / Retina / Rhodopsin / Rodents / Rods / Stationary night blindness / Substitutes / Transducin / Transgenic / Tyrosine / Xenopus laevis