Novel compound heterozygous mutation associated with retinal cone dystrophy.

Retinal cone dystrophy (COD) is an inherited retinal disease characterized by reduced central vision, color vision defects and photophobia, resulting from the degeneration of photoreceptors in cone cells, and commonly occurs due to mutations in cyclic nucleotide-gated channel subunit α 3 (). mutations are associated exclusively with autosomal recessive retinal disorders, requiring homozygous or compound heterozygous mutations for pathogenicity. In the present study, whole-exome sequencing was performed on a 9-year-old girl diagnosed with COD and her parents, which identified a compound heterozygous mutation in the proband. The previously reported c.C1001T:p.S334F variant was inherited from her mother and a novel frameshift mutation, c.566_567insT:p.R189fs, was inherited from her father. Further analysis identified that the p.S334F mutation affects a conserved residue in the ion-transport (ion-trans) structural domain, while the frameshift mutation p.R189fs introduces a premature stop codon at position 194, resulting in a truncated protein that retains only the ion-trans structural domain and lacks the cysteine-rich CAP domain-extended domain and cyclic nucleotide-gated ligand-binding zinc finger-like domain. Through ectopic expression in 293T cells and western blotting, p.S334F mutated was observed to increase CNGA3 protein levels, while the p.R189fs mutation produced a truncated protein. These findings suggest that both mutations compromise normal CNGA3 channel function and are likely to contribute to the disease pathogenesis.