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N.W. Khan, B. Wissinger, S. Kohl, R. Singh, P.A. Sieving; CNGB3 Gene Mutations: Functional Deficits in Patients and Carriers Indicate More Than Simple Achromatopsia . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4893.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: CNGB3 encodes the ß-subunit of the cyclic nucleotide-gated channel on the cone photoreceptor plasma membrane. Mutations cause achromatopsia due to loss of cone function. We evaluated the CNGB3 phenotype in four affected subjects. Methods: Family A: three affected sisters (44-50 year old) and three carriers (5, 9, & 70 yr old). Family B: affected male (58 yr old). Examinations included acuity, color vision testing, Goldmann visual fields (GVF), dark-adapted (DA) absolute thresholds, ERG, and fundus ophthalmoscopy. Results: Family A: homozygous 1 bp-deletion 1148delC causing a frame shift after Thr383, introducing 12 novel amino acid sequence terminating with a premature stop codon yielding a 394 aa mutant protein (vs. 809 aa for WT). Family B: affected male is a compound heterozygote, with an 8bp-deletion (819-826del8bp) in exon 6 and a 1208G>A substitution (arg403gln) in exon 11. All four affected subjects have 20/200-20/400 acuity. GVF show slight constriction under standard mesopic background conditions. DA threshold sensitivity was normal, but ERG DA rod b-wave amplitude was abnormal in 2 affecteds (60% reduced in Family B). ERG photopic b-wave and flicker responses were extinguished, except in one affected in Family A with a 10 uV residual response who also had residual color discrimination on 24-plate Ishihara testing. Photo-transduction modeling of bright-flash DA a-waves gave rod sensitivity at the lowest of normals for all four affecteds. All four affecteds showed minimal to extensive bilateral macular atrophy and peripheral RPE disruption and heavy granularity. Family A carriers had acuity of 20/25-20/40 with normal rod and cone ERG amplitudes and color discrimination, but all three carriers had fundus changes of heavy RPE granularity and the 70 y/o showed considerable macular involvement that mirrored her affected daughters. Conclusions: CNGB3 causes more than simple achromatopsia and can have characteristics of very slowly progressive cone-rod dystrophy. Some CNGB3 affecteds retain minimal color discrimination. The middle-age macular atrophy in all four affecteds suggests progression. The abnormal rod b-waves and the lowest of normal phototransduction parameters suggest impaired rod function directly or indirectly from CNGB3. Macular changes in the Family A carriers suggest haplo-insufficiency of CNGB3 channels in the cone rich macula; the peripheral heavy RPE granularity indicates diffuse pathology.
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