导致常染色体显性遗传性视网膜色素变性的突变视紫红质的功能异质性

Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa.

作者信息

Sung C H, Schneider B G, Agarwal N, Papermaster D S, Nathans J

机构信息

Howard Hughes Medical Institute, Department of Molecular Biology, Johns Hopkins University School of Medicine, Baltimore 21205.

出版信息

Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8840-4. doi: 10.1073/pnas.88.19.8840.

Thirteen mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa (ADRP) have been produced by transfection of cloned cDNA into tissue culture cells. Three mutants [class I: Phe-45----Leu, Gln-344----termination (deletion of C-terminal positions 344-348), and Pro-347----Leu] resemble wild-type rhodopsin in yield, regenerability with 11-cis-retinal, and plasma membrane localization. Ten mutants [class II: Thr-17----Met, Pro-23----His, Thr-58----Arg, Val-87----Asp, Gly-89----Asp, Gly-106----Trp, Arg-135----Leu, Arg-135----Trp, Tyr-178----Cys, and Asp-190----Gly] accumulate to significantly lower levels, regenerate with 11-cis-retinal variably or not at all, and are transported inefficiently to the plasma membrane, remaining primarily in the endoplasmic reticulum. These data suggest that there are at least two distinct biochemical defects associated with different rhodopsin mutants in ADRP.

通过将克隆的互补DNA（cDNA）转染到组织培养细胞中，已产生了13种导致常染色体显性遗传性视网膜色素变性（ADRP）的视紫红质突变体。三种突变体[I类：苯丙氨酸-45→亮氨酸、谷氨酰胺-344→终止（C末端第344 - 348位缺失）和脯氨酸-347→亮氨酸]在产量、与11-顺式视黄醛的再生能力以及质膜定位方面与野生型视紫红质相似。十种突变体[II类：苏氨酸-17→甲硫氨酸、脯氨酸-23→组氨酸、苏氨酸-58→精氨酸、缬氨酸-87→天冬氨酸、甘氨酸-89→天冬氨酸、甘氨酸-106→色氨酸、精氨酸-135→亮氨酸、精氨酸-135→色氨酸、酪氨酸-178→半胱氨酸和天冬氨酸-190→甘氨酸]积累到显著较低的水平，与11-顺式视黄醛的再生能力各不相同或根本无法再生，并且向质膜的转运效率低下，主要保留在内质网中。这些数据表明，ADRP中不同的视紫红质突变体至少存在两种不同的生化缺陷。