Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases

Abstract

Unrelated patients with achromatopsia, macular degeneration with onset under age 50 years, cone degeneration or dysfunction, cone-rod degeneration, or macular malfunction were screened for mutations in the three genes known to be associated with achromatopsia: the GNAT2 gene encoding the alpha subunit of cone transducin and the CNGA3 and CNGB3 genes encoding the alpha and beta subunits of the cone cGMP-gated cation channel. We found no examples of patients with GNAT2 mutations. Out of 36 achromats, 12 (33%) had mutations in CNGA3 (13 different mutations including five novel mutations) and 12 (33%) had mutations in CNGB3 (six different mutations including four novel mutations). All achromats with CNG mutations had residual, presumably cone function as determined by computer-averaged 30-Hz electroretinograms (ERGs). There was considerable variability in acuity and color vision, with most patients having acuities of 20/200-20/400 and complete absence of color perception, and others having acuities of 20/25-20/40 and some color vision. Two pseudodominant achromatopsia cases were uncovered, both with CNGA3 mutations, including one family in which some compound heterozygotes with achromatopsia mutations were clinically unaffected. We found two novel CNGB3 changes in three patients with juvenile macular degeneration, a phenotype not previously associated with mutations in the cone channel subunits. These patients had subnormal acuity (20/30-20/60), normal to subnormal color vision, and normal to subnormal full-field cone ERG amplitudes. Our results indicate that some patients with channel protein mutations retain residual foveal cone function. Based on our findings, CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration.

An extended 15 Hz ERG protocol (2): data of normal subjects and patients with achromatopsia, CSNB1, and CSNB2

“…Therefore, we argue that there is no difference between the 15 Hz ERGs of an achromat and normal subjects for low flash strengths and that the primary and secondary rod pathways function normally. In the literature, the functioning of the rods in achromatic patients is generally described as normal [32][33][34][35][36], although recently, abnormalities in rod driven ERGs have also been reported [37,38]. Therefore, it would be interesting to measure 15 Hz ERGs in more patients with achromatopsia.…”

Retinal Morphology of Patients With Achromatopsia During Early Childhood

“…[13][14][15] In preparation for translation to human clinical trials, it will be important to be able to identify the best candidates who still have intact retinal architecture and may best benefit from genetic therapy as well as to develop objective tools for monitoring safety and efficacy. Initial studies using lower-resolution time-domain optical coherence tomography (OCT) have shown some general changes in macular thickness, 16,17 but subsequent higherresolution spectral-domain (SD) OCT devices have revealed changes in foveal architecture that suggest achromatopsia is a progressive disease that worsens with age. [18][19][20][21] Additional studies are required to determine whether retinal architecture is indeed more preserved at an earlier age, but only cooperative adults and older children are able to be imaged on conventional SD-OCT systems.…”

Endoplasmic Reticulum Stress-associated Cone Photoreceptor Degeneration in Cyclic Nucleotide-gated Channel Deficiency

“…Naturally occurring mutations in genes encoding CNGA3 and CNGB3 are highly associated with human cone diseases, including achromatopsia, progressive cone dystrophy, and early-onset macular degeneration (7)(8)(9). Indeed, Ͼ70 disease-associated mutations have been identified in CNGA3 and CNGB3 (8,9), and these mutations account for Ͼ70% of achromatopsia patients (7,8).…”

“…Indeed, Ͼ70 disease-associated mutations have been identified in CNGA3 and CNGB3 (8,9), and these mutations account for Ͼ70% of achromatopsia patients (7,8). Achromatopsia is a devastating hereditary visual disorder, characterized by deficient cone-mediated electroretinographic (ERG) responses, color blindness, visual acuity loss, pendular nystagmus, extreme light sensitivity, and daytime blindness.…”