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

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... ass 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.