Akiko Kubo

Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia

Congenital achromatopsia is a stationary retinal disorder with autosomal recessive inheritance that is characterized by loss of color discrimination, low visual acuity, photophobia, and nystagmus. This disorder has been shown to be associated with CNGA3, CNGB3, and GNAT2 mutations, and the frequency of mutations in the CNGA3 gene (encoding alpha subunit of the cone-specific cGMP-gated cation channel) was 23-33% in European populations. The aim of this study was to test the hypothesis that CNGA3 mutations are also responsible for congenital achromatopsia in Japanese patients. DNA from venous blood samples from a total of 14 patients from 13 Japanese pedigrees was prepared. Mutation screening of the CNGA3 gene was performed using direct sequencing and PCR-single-strand conformation polymorphism analysis. Compound heterozygous missense mutations (p.R436W and p.L633P, the latter of which was novel) were identified in one patient only, a 22-year-old female. Neither of these two mutations was found in 150 Japanese control individuals. The patients parents and sister carried one of these mutations each but were not affected. No mutations in the CNGB3 or GNAT2 genes were identified in the patient. Clinically, best-corrected visual acuity was 0.1 in both eyes. No specific findings were obtained in funduscopy. Optical coherence topography revealed a normal foveal thickness but a 20% decrease in parafoveal thickness. Ganzfeld full-field electroretinograms (ERGs) showed normal responses in rod and mixed rod-plus-cone ERGs but no response in cone or 30-Hz flicker ERGs. Spectral sensitivity on a white background revealed a curve with only one peak at around 500 nm, which fits the absorption spectrum of human rhodopsin. L633, conserved among vertebrate orthologs of human CNGA3, is a hydrophobic residue forming part of the carboxy-terminal leucine zipper (CLZ) domain, which is functionally important in the mediation of intracellular interactions. To our knowledge, this is the first report of a Japanese complete achromat with CNGA3 mutations, and of any patient with a missense mutation within the CLZ domain. The outcome suggests low frequency (7%, 1/14) of CNGA3 mutations in Japanese patients.

Clinical heterogeneity between two Japanese siblings with congenital achromatopsia.

Congenital achromatopsia is a stationary retinal disorder with autosomal recessive inheritance. It is characterized by significant attenuation of cone-photoreceptor function. Symptoms include photophobia, nystagmus, and poor visual acuity from birth. Unlike in cone or cone-rod dystrophies, the retinal fundus usually appears normal. Here we describe two siblings with congenital achromatopsia, who exhibit different ophthalmic phenotypes. History was taken, and ophthalmic examinations were performed in a 7-year-old girl and her 5-year-old brother, who were referred to our department because of poor visual acuity. Two of their grandparents were brother and sister, suggesting an autosomal recessive transmission in inheritance. They have been followed for more than 13 years since the initial evaluation. Symptoms, visual acuity, and kinetic visual field were very similar to each other, consistent with findings of typical congenital achromatopsia. However, color-vision tests suggested that the brother had residual color discrimination, but the sister did not. The siblings had different full-field electroretinographic and spectral-sensitivity findings: residual cone functions were detected in only the brother, in agreement with his residual color vision. They also had different findings of retinal fundi and ocular refractions: the sister had bilaterally atrophic-appearing macular lesions and myopic errors. In contrast, the brother remains hyperopia and has exhibited no specific retinal findings until age 18 years. The causes why both complete and incomplete achromats occur in the siblings are uncertain but might be caused by modifying effects of sex-related genes or by environmental factors influencing certain gene regulations in cone photoreceptors.

The necessary intensity of the white background when measuring the response of the S cone system

In order to investigate the necessary intensity of the white background when measuring the response of the S cone system, we measured the spectral sensitivities on various intensities of the white background at 15° from the fovea on two normal observers. The sensitivity curves on 10 and 31.4 photopic troland backgrounds for both observers have only one peak. However, from the sensitivity curve on 100 photopic troland background for both observers, the peak of the S cone response appears around the short wavelength range, then it becomes much clearer on the curve with a 1000 photopic troland background. From these results, it was suggested that the necessary intensity of the white background in order to measure the S cone system is at least 100 photopic trolands.

The spectral sensitivity characteristics of congenital red-green color vision deficiencies

The spectral sensitivity in congenital red-green color vision deficiencies was measured using intense 430 nm and 700 nm backgrounds. In protanopia and protanomaly, the spectral sensitivity curves in the middle and long wavelength regions on both backgrounds coincided with the spectral sensitivities of the middle-wavelength (M) cones. In deuteranopia and six out of the nine observes with deuteranomaly, the spectral sensitivity curves in the middle and long wavelength regions on both backgrounds coincided with the spectral sensitivities of the long-wavelength (L) cones. Three of the nine observers with deuteranomaly showed spectral sensitivity curves in the middle and long wavelength regions that showed slight but significant differences on the 430 nm background as compared to the 700 nm background.