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Abstract
Mutations in the key rod phototransduction enzyme phosphodiesterase 6 (PDE6) are known
to cause recessive retinitis pigmentosa in humans. Mouse models of mutant PDE6 represent
a common approach to understanding the mechanisms of visual disorders related to PDE6
defects. Mutation N605S in the PDE6B subunit is linked to atypical retinal degeneration
3 (atrd3) in mice. We examined PDE6 in atrd3 mice and an atrd3 mutant counterpart
of human cone PDE6C expressed in rods of transgenic Xenopus laevis. These animal models
revealed remarkably different phenotypes. In contrast to dramatic downregulation of
the mutant rod PDE6 protein and activity levels in mice, expression and localization
of the cone PDE6C in X. laevis were essentially unaffected by this mutation. Examination
of the PDE6B mRNA in atrd3 retina showed that the mutation-carrying exon 14 was spliced-out
in the majority of the transcript. Thus, retinal degeneration in atrd3 mice is caused
by low levels of PDE6 protein due to defective processing of PDE6B pre-mRNA rather
than by deleterious effects of the N605S mutation on PDE6 folding, stability or function.