编码光感受器特异性蛋白PRPH2(也称为外周蛋白2或rds)的PRPH2基因突变会引起广泛的常染色体显性视网膜疾病。这些突变大多影响光敏感光体外段的结构,它由一堆被质膜包围的扁平“圆盘”膜组成。在一个过程中每天更新外段,由此在外段基部处添加新的盘并且在外段尖端处脱落旧的盘。新的圆盘形成为连续的膜逃避,最终通过复杂的膜重塑过程(完全在杆中,部分在锥体中)封闭。随着盘柜的进行,PRPH2定位于封闭圆盘的边缘,在那里它形成低聚物,这些低聚物强化了这些边缘的高度弯曲的膜结构。在这项研究中,我们分析了携带单拷贝C150S或Y141CPRPH2突变的两种性别小鼠的外节表型,该突变已知可防止或增加PRPH2寡聚化程度,分别。引人注目的是,两种突变都增加了新形成的数量,尚未封闭的光盘,表明光盘外壳的精度受PRPH2低聚调节。没有严格控制的外壳,盘偶尔过度拉长,形成大的膜状\“螺纹\”,而不是盘堆叠。这些数据表明,由异常的PRPH2低聚引起的外段结构缺陷在圆盘封闭阶段表现出来。重要声明光敏感光体外段包含一堆扁平的“圆盘”膜,这些膜被包围,或随函附上,“由外段膜。圆盘外壳是通过促进第二信使沿外段轴的扩散来增加感光器光敏度的适应性。然而,光感受器盘包裹在外段膜内的分子机制仍然知之甚少。我们现在证明,光感受器特异性蛋白外周蛋白2或PRPH2的寡聚物在此过程中起积极作用。我们进一步提出,由于异常的PRPH2寡聚化导致外段的主要结构异常,最终导致PRPH2突变模型和人类患者的视觉功能丧失和细胞变性。
Mutations in the PRPH2 gene encoding the photoreceptor-specific protein PRPH2 (also known as peripherin-2 or rds) cause a broad range of autosomal dominant retinal diseases. Most of these mutations affect the structure of the light-sensitive photoreceptor outer segment, which is composed of a stack of flattened \"disc\" membranes surrounded by the plasma membrane. The outer segment is renewed on a daily basis in a process whereby new discs are added at the outer segment base and old discs are shed at the outer segment tip. New discs are formed as serial membrane evaginations, which eventually enclose through a complex process of membrane remodeling (completely in rods and partially in cones). As disc enclosure proceeds, PRPH2 localizes to the rims of enclosed discs where it forms oligomers which fortify the highly curved membrane structure of these rims. In this study, we analyzed the outer segment phenotypes of mice of both sexes bearing a single copy of either the C150S or the Y141C PRPH2 mutation known to prevent or increase the degree of PRPH2 oligomerization, respectively. Strikingly, both mutations increased the number of newly forming, not-yet-enclosed discs, indicating that the precision of disc enclosure is regulated by PRPH2 oligomerization. Without tightly controlled enclosure, discs occasionally over-elongate and form large membranous \"whorls\" instead of disc stacks. These data show that the defects in outer segment structure arising from abnormal PRPH2 oligomerization are manifested at the stage of disc enclosure.SIGNIFICANCE STATEMENT The light-sensitive photoreceptor outer segment contains a stack of flattened \"disc\" membranes that are surrounded, or \"enclosed,\" by the outer segment membrane. Disc enclosure is an adaptation increasing photoreceptor light sensitivity by facilitating the diffusion of the second messenger along the outer segment axes. However, the molecular mechanisms by which photoreceptor discs enclose within the outer segment membrane remain poorly understood. We now demonstrate that oligomers of the photoreceptor-specific protein peripherin-2, or PRPH2, play an active role in this process. We further propose that defects in disc enclosure because of abnormal PRPH2 oligomerization result in major structural abnormalities of the outer segment, ultimately leading to loss of visual function and cell degeneration in PRPH2 mutant models and human patients.