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.
Highlights
Congenital stationary night blindness (CSNB; MIM 163500) is a clinically and genetically heterogeneous group of non-progressive hereditary retinal disorders characterized by night blindness and decreased visual acuity [1]
We show that the addition of the truncated phosphodiesterase-6 bsubunit (PDE6b) to normal PDE6ab catalytic subunits interferes with the enzyme inhibition by Pc, supporting the hypothesis that the mutant protein causes constitutive activation of the phototransduction, and rod desensitization
Clinical findings The three-generation French family MTP1481 presented typical congenital stationary night blindness (CSNB) symptoms segregating as an autosomal dominant trait (Figure 1A)
Summary
Congenital stationary night blindness (CSNB; MIM 163500) is a clinically and genetically heterogeneous group of non-progressive hereditary retinal disorders characterized by night blindness and decreased visual acuity [1]. Mutations in rhodopsin (RHO), rod cGMP phosphodiesterase type 6 bsubunit (PDE6B), and rod transducin a-subunit (GNAT1), three genes of the rod phototransduction cascade, have been associated with the autosomal dominant CSNB (adCSNB) [2,3,4]. PDE6 mediates the phototransduction cascade from rhodopsin to cGMP-gated cation channels in the rod plasma membrane. Rhodopsin activates its downstream target, transducin, which in turn binds the effector enzyme PDE6, resulting in the relief of the inhibition of the PDE6ab catalytic subunits by the Pc [8,9,10]. The activated PDE6ab hydrolyzes intracellular cGMP thereby lowering its concentration and producing a closure of cGMP-gated channels and the hyperpolarization of the rod outer segment plasma membrane [8,10,11]
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