Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain.

Over 40 mutations in the rhodopsin gene have been identified in patients with autosomal dominant retinitis pigmentosa. Twenty-one of these mutations have been introduced into a human rhodopsin cDNA by site-directed mutagenesis, and the encoded proteins have been produced by transfection of a human embryonic kidney cell line (293S). Three of the mutant proteins (G51V, V345M, and P347S) resemble the wild type in yield, regenerability with 11-cis-retinal, and accumulation in the plasma membrane (class I). The remaining 18 mutant proteins are produced at lower levels, regenerate variably or not at all with 11-cis-retinal, and accumulate partially or predominantly in the endoplasmic reticulum (class II). Together with an earlier analysis of 13 mutant rhodopsins (Sung, C.-H., Schneider, B., Agarwal, N., Papermaster, D.S., and Nathans, J. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 8840-8844), these experiments define distinct classes of biochemical defects in human rhodopsin and further show that amino acid substitutions in class II reside within the transmembrane and extracellular domains, whereas class I mutants cluster in the first transmembrane domain and at the extreme carboxyl terminus.