PURPOSE. CNGB3 encodes the β-subunits of cyclic nucleotide-gated channels in the photoreceptor plasma membrane. CNGB3 mutations cause a channelopathy that results in impaired cone function manifesting achromatopsia. The clinical physiology and phenotype of three affected sisters and three carriers were evaluated in a family with a homozygous CNGB3 mutation and an unrelated male harboring both CNGB3 and CNGA3 mutations. METHODS. Index patients were screened for mutations in CNGA3 and CNGB3 by DNA sequencing. Visual examination included acuity, color vision, Goldmann visual fields (GVF), dark-adapted absolute thresholds (DAT), electroretinography, and fundus photography. RESULTS. The three affected sisters were homozygous for a 1-bp deletion (c.1148delC) in CNGB3 that induces a frame shift after Thr383, whereas the carriers were heterozygous for this mutation. The unrelated male carried a heterozygous 8-bp deletion (c.819_826del8bp) in exon 6, as well as a heterozygous base substitution (c.l208G→A) in exon 11 that causes an Arg403Gln exchange. All affected subjects had acuity ranging between 20/200 and 20/400, moderately constricted GVFs, normal DATs, reduced rod b-wave amplitudes, and extinguished photopic b-wave and flicker responses. Rod photoreceptor sensitivity and amplitude, calculated by fitting the rod a-waves by a model of activation of phototransduction were below normal mean. Carriers had mildly decreased acuity (20/25-20/40), normal rod and cone ERGs, and normal color vision. The fundi of the affected subjects showed macular atrophy by middle age, while the carriers showed peripheral RPE granularity in childhood and macular atrophy in late middle age. CONCLUSIONS. Foveomacular atrophy can occur in CNGB3-affected subjects, and even heterozygous carriers can exhibit maculopathy. Cone ERG responses in affected subjects are nearly extinguished, but some retain residual function into middle age and then progressively lose even this remnant. Rod responses are impaired in some CNGB3-affected subjects.
ASJC Scopus subject areas
- Sensory Systems
- Cellular and Molecular Neuroscience