Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation.
Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation.
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DOI：
10.1073/pnas.92.3.880
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发表时间：
1995-01
影响因子：
11.1
通讯作者：
P. Sieving;JULiA E. RICHARDSt;Franklin NAARENDORPt;Eve L. BINGHAMt;Kathy SCOrrt;Mathew ALPERNt
中科院分区：
文献类型：
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作者：
P. Sieving;JULiA E. RICHARDSt;Franklin NAARENDORPt;Eve L. BINGHAMt;Kathy SCOrrt;Mathew ALPERNt
人类视紫红质突变，Gly-90-->；Asp(Gly90Asp)，在一个大型常染色体显性显性家系的22个高危成员中与先天性夜盲的不寻常特征共分离。尽管视紫红质突变通常与视网膜退化有关，但33岁以下受Gly90Asp影响的受试者没有表现出临床上的视网膜变化。在7名受试者(11岁至)中，视觉感知的绝对阈值提高了近3个对数单位，表明杆状阈值信号严重受损。然而，在体内视紫红质密度是正常的。尽管这位38岁的先证者无法感知昏暗的光线，但他的视杆递增阈值函数在较亮的背景下是正常的。暗淡但不明亮背景的视杆视力受损与热异构化导致的基础“暗光”增加的机制一致，相当于比野生型视紫红质增加了>；10(4)。第二个跨膜螺旋上的Gly90Asp突变在视蛋白口袋中放置了额外的负电荷；这可能导致视网膜Schiff碱基的部分去质子化，从而增加光感受器噪声。体外证据表明，在没有视网膜生色团和光的情况下，转导蛋白由Gly90Asp突变激活，这被称为“结构性活性”。在这个家族中，尽管存在广泛的终生夜盲，但功能视杆的明显保存与当前的一个假说不一致，该假说认为，构成活性突变视紫红质的慢性视紫红质视杆激活必然对人类视网膜营养不良的光感受器死亡起重要作用。
A human rhodopsin mutation, Gly-90-->Asp (Gly90Asp), cosegregated with an unusual trait of congenital nightblindness in 22 at-risk members of a large autosomal dominant kindred. Although rhodopsin mutations typically are associated with retinal degeneration, Gly90Asp-affected subjects up to age 33 did not show clinical retinal changes. Absolute threshold for visual perception was elevated nearly 3 logarithmic units in 7 individuals tested (ages 11-64), indicating greatly compromised rod threshold signaling. However, in vivo rhodopsin density was normal. Although the 38-year-old proband could not perceive dim lights, his rod increment threshold function was normal on brighter backgrounds. The impaired rod vision for dim but not bright backgrounds is consistent with a mechanism of increased basal "dark-light" from thermal isomerization equivalent to an increase of > 10(4) over that of wild-type rhodopsin. The Gly90Asp mutation on the second transmembrane helix places an extra negative charge in the opsin pocket; this could contribute to partial deprotonation of the retinal Schiff base and thereby increase photoreceptor noise. In vitro evidence had suggested that transducin is activated by the Gly90Asp mutation in the absence of both the retinal chromophore and light, termed "constitutive activity." The apparent preservation of functioning rods despite extensive and lifelong night-blindness in this kindred is inconsistent with one current hypothesis that chronic rod activation from constitutively active mutant rhodopsin necessarily contributes significantly to photoreceptor demise in human retinal dystrophies.