To identify genes responsible for cone dystrophies and determine the functiona l consequences of their underlying mutations. Case-control study. Two hundred f orty unrelated patients diagnosed with cone dystrophy, cone-rod dystrophy, macu lar dystrophy, macular degeneration, or Stargardt disease, 95 control individual s, and 2 unrelated families with a distinctive type of cone dystrophy. The DNAs of the 240 probands were screened for sequence variants in the PDE6H gene (that encodes the inhibitory γ-subunit of cone cyclic guanosine monophosphate [cGMP ] -phosphodiesterase [PDE]) by single-strand conformation polymorphism electro ph oresis. The effect of a nucleotide substitution in the DNA of a patient on gene expression efficiency was analyzed by in vitro transcrip-tion/translation. Cone -specific gene variants, fundus, visual field and electroretinogram (ERG) findi ngs, and protein synthesis efficiency. We found a heterozygous G to C substituti on in the 5′untranslated region (UTR) of the PDE6H gene in the DNA of a patient with a distinctive form of cone dystrophy, her sibling, and their father. This rare form of disease is very different in manifestation from other cone dystroph ies and has been described as “cone dystrophy with nyctalopia and supernormal r od responses,”“cone dystrophy with supernormal scotopic ERGs”and “supernorma l and delayed rod ERG syndrome.”Among the 240 patients that we studied, only 1 proband had the G to C variant. Furthermore, none of the 95 controls used in thi s study had this nucleotide change. We also determined that the PDE6H variant wa s not present in another family affected with this particular type of cone dystr ophy. Because the 5’UTR of mRNAs plays a critical role in the regulation of pro tein synthesis, we determined the effect of the G to C change in this process. B y use of in vitro transcription/translation experiments, we demonstrated that th is substitution could lead to an increase in PDE6H gene expression. Our results indicate that mutations in the PDE6H gene are not common, because only 1 of 240 patients with cone dystrophy showed a single nucleotide substitution in the 5′U TR of PDE6H mRNA that could be associated with the disease. If the effect of the G to C substitution we observed in vitro also occurs in vivo, it will lead to P DE6H overexpression in the photoreceptors. Excess of PDEγmay affect normal cone cGMP-PDE function by inhibiting the catalytic PDEα,βactivity and lead to pat hogenic elevation of cGMP and eventual degeneration of cone photoreceptors.
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