Purpose: To determine the molecular basis for phenotypic variability in a three-generation consanguineous family containing a single individual with complete achromatopsia and three individuals with progressive cone dystrophy.
Methods: Four affected individuals underwent ophthalmic examination, electrophysiological assessment, color fundus photography, and psychophysical testing. Blood samples were obtained for DNA extraction and mutation screening of the cone-specific cGMP-gated (CNG) channel protein gene CNGB3 was undertaken.
Results: The clinical findings in one family member were consistent with a diagnosis of complete achromatopsia, with nystagmus, photophobia, and poor visual acuity from early infancy and complete color-blindness, normal fundi, and absent cone responses with normal rod responses on electroretinography (ERG). Mutation analysis revealed her to be homozygous for the common CNGB3 achromatopsia mutation, 1148delC (Thr383fs). In contrast, the three other symptomatic individuals in the family had findings consistent with progressive cone dystrophy. Their visual problems began later in childhood (ranging from 3 to 14 years of age) and there was evidence of progressive deterioration in cone function. All three had a marked tritanopic color vision defect and fundoscopy revealed bilateral macular atrophy. Electrophysiological testing of these three subjects demonstrated clear evidence of progressive deterioration of cone responses over time; rod responses were normal. All three individuals with this progressive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3.
Conclusions: Mutations in CNGB3, which have been shown to cause achromatopsia, are now shown to be associated with autosomal recessive progressive cone dystrophy. In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the cone CNG cation channel beta-subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive cone dystrophy.