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.
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.
Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France.
Gaël
G
Manes
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America.
Pallavi
P
Cheguru
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States of America.
Anurima
A
Majumder
Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France.
Béatrice
B
Bocquet
Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France.
Audrey
A
Sénéchal
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.
Nikolai O
NO
Artemyev
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.
Christian P
CP
Hamel
Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France.
Philippe
P
Brabet
D000818:Animals; D030801:Animals, Genetically Modified; D020134:Catalytic Domain / Q000235:genetics / Q000502:physiology; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism*; D015785:Eye Diseases, Hereditary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D040181:Genetic Diseases, X-Linked / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055537:Light Signal Transduction / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009216:Myopia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D009755:Night Blindness / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D015293:Transducin; D014982:Xenopus laevis
C034809:GNAT1 protein, human; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D020962:Heterotrimeric GTP-Binding Proteins; D015293:Transducin