A leucine to arginine amino acid substitution at codon 46 of rhodopsin is responsible for a severe form of autosomal dominant retinitis pigmentosa.

To evaluate the extent to which rhodopsin mutations are involved in autosomal dominant forms of retinitis pigmentosa (adRP) we collected DNAs from patients with adRP and screened the rhodopsin coding sequence with single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. This screening revealed a thymidine to guanine transversion at nucleotide 431 (nucleotide sequence numbers as per Genebank) in affected members of one family (RFS04). The nucleotide substitution leads to a missense mutation at the 46th amino acid of rhodopsin. The mutation occurs at an amino acid conserved in mammals and changes the hydrophobic nature of the protein at a transmembrane-spanning region. The mutation causes the substitution of a non-polar hydrophobic amino acid, leucine, for the basic amino acid arginine (Leu46Arg). This nucleotide substitution is unique to the family studied and occurs in the affected individuals in the family. Full-field electroretinograms (ERGs) in four affected members of the family showed nondetectable rod responses at an early age, with markedly reduced cone responses, and a faster than average rate of progression of the phenotype as measured by yearly ERGs.