STRUCTURE AND FUNCTION IN RHODOPSIN .7. POINT MUTATIONS ASSOCIATED WITH AUTOSOMAL-DOMINANT RETINITIS-PIGMENTOSA
STRUCTURE AND FUNCTION IN RHODOPSIN .7. POINT MUTATIONS ASSOCIATED WITH AUTOSOMAL-DOMINANT RETINITIS-PIGMENTOSA
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DOI：
10.1021/bi00186a011
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发表时间：
1994-05-24
期刊：
影响因子：
2.9
通讯作者：
KHORANA, HG
中科院分区：
文献类型：
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作者：
KAUSHAL, S;KHORANA, HG
常染色体显性视网膜色素变性（ADRP）是视网膜色素变性的一种遗传形式，约占所有类型的后一种疾病的15%。最近，已在ADRP患者的视紫红质基因中鉴定出近50种突变，大多数是点突变。我们已经在合成的牛视紫红质基因中引入了这些突变，并在此报告了突变基因在COS-1细胞中的表达和体外表达的视蛋白的性质的研究。突变体表型分为三类：I类突变体在COS-1细胞中以野生型水平表达，与11-顺式-视黄醛形成正常的视紫红质发色团，并被转运到细胞表面。然而，在光照下，它们无效地激活转导素。II类突变体保留在内质网中，并且不结合11-顺式-视黄醛以形成发色团。III类突变体以低水平表达并且仅很差地形成视紫红质发色团。它们也保留在内质网中，并且如预期的那样显示高甘露糖基化。与野生型相比，几乎所有研究的突变体都表现出对光的异常敏感性，并且它们激活transducin的效率较低。我们的结论是，大多数的ADRP突变体有折叠缺陷。
Autosomal dominant retinitis pigmentosa (ADRP) is a hereditary form of retinitis pigmentosa which accounts for about 15% of all types of the latter disease. Recently, close to 50 mutations, mostly point mutations, have been identified in the rhodopsin gene in ADRP patients. We have introduced these mutations in the synthetic bovine rhodopsin gene and herein report on the expression of the mutant genes in COS-1 cells and studies in vitro of the properties of the expressed opsins. The mutant phenotypes fall into three classes: Class I mutants are expressed in COS-1 cells at wild-type levels, form the normal rhodopsin chromophore with 11-cis-retinal, and are transported to the cell surface. However, on illumination, they activate transducin inefficiently. Class II mutants remain in the endoplasmic reticulum and do not bind 11-cis-retinal to form the chromophore. Class III mutants are expressed at low levels and form rhodopsin chromophore only poorly. They also remain in the endoplasmic reticulum and, as expected, show high mannose glycosylation. Nearly all of the mutants studied show abnormal sensitivity to light compared to the wild type, and they activate transducin less efficiently. We conclude that the majority of the ADRP mutants have folding defects.