Novel mutations in the gene for α-subunit of retinal cone cyclic nucleotide-gated channels in a Japanese patient with congenital achromatopsia
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To present the characteristics and pathology of a patient with congenital achromatopsia.
Patient and methods
The patient was a 22-year-old Japanese woman who was 8 years old when she first visited our clinic. Comprehensive ophthalmic examinations including visual acuity measurements, perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, electroretinography (ERG), and color vision tests were performed. Her genomic DNA was used as the template for the amplification of exons of five candidate genes for achromatopsia; CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H, and the amplified products were sequenced. A missense mutation, found in the CNGA3, was studied both electrophysiologically and biochemically.
Her phenotype was typical of congenital complete achromatopsia. She was followed for 14 years, and her vision and fundus findings were stable. However, the scotopic ERG b-waves at age 22 were smaller than those at age 8, and her FAF images showed increased autofluorescence in both maculae. Genetic examinations revealed combined heterozygous mutations of c.997_998delGA and p.M424V in the CNGA3 gene. The homomeric channel consisting of the CNGA3 subunit with the p.M424V mutation had a weak cGMP-activated current in patch-clamp recordings. In heterologous expression analyses, the expression at the cell surface of the mutant CNGA3 subunit was about 28 % of the wild type.
The two novel mutations found in the CNGA3 gene, c.997_998delGA and p.M424V, can cause complete achromatopsia. The vision of the patient was stationary until the third decade of life although the FAF was altered at the age of 22 years.
KeywordsAchromatopsia CNGA3 gene Optical coherence tomography Fundus autofluorescence Electroretinogram
We thank Ms. Yukiko Koyama in Central Research Laboratory, Shiga University of Medical Science for her technical assistance (sequencing). The authors thank Professor Duco I. Hamasaki of the Bascom Palmer Eye Institute of the University of Miami for critical discussion and final manuscript editing. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (25462712, 25462711 and 26462654). This work was also supported by the Ministry of Health, Labour and Welfare, Japan (13803661 and 23164001), and by the Japan Agency for Medical Research and Development (Practical Research Project for Rare/Intractable Diseases, 15ek0109072h0002).
Conflicts of interest
K. Kuniyoshi, None; S. Muraki-Oda, None; H. Ueyama, None; F. Toyoda, None; H. Sakuramoto, None; H. Ogita, None; M. Irifune, None; S. Yamamoto, None; A. Nakao, None; K. Tsunoda, None; T. Iwata, None; M. Ohji, None; Y. Shimomura, None.
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