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

作者：Manes Gael^*; Cheguru Pallavi; Majumder Anurima; Bocquet Beatrice; Senechal Audrey; Artemyev Nikolai O; Hamel Christian P; Brabet Philippe

来源：PLos One, 2014, 9(4): e95768.

DOI：10.1371/journal.pone.0095768

Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin a-subunit (GNAT1), and cGMP phosphodiesterase type 6 beta-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 PDE6 beta 1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6 beta 1-313. We found that PDE6 beta 1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory c-subunit (Pc), and interferes with the inhibition of normal PDE6 alpha beta catalytic subunits by Pc. Moreover, both truncated forms of the PDE6 beta protein, PDE6 beta 1-313 and PDE6 beta 1-314fs* 50 expressed in rods of transgenic chi. 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 P gamma and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation.

• 出版日期2014-4-23