Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina
Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina
复制标题
DOI：
10.1093/hmg/ddu573
复制
发表时间：
2015-03-15
影响因子：
3.5
通讯作者：
Chen, Rui
中科院分区：
文献类型：
--
作者：
Eblimit, Aiden;Nguyen, Thanh-Minh T.;Chen, Rui
利伯先天性黑蒙（LCA）和青少年视网膜色素变性（RP）是严重的遗传性疾病，导致视力障碍的婴儿和儿童。SPATA 7最近被鉴定为人类的LCA 3和青少年RP基因，其在视网膜中的功能仍然是难以捉摸的。在这里，我们发现，SPATA 7定位在初级纤毛的细胞和感光细胞的连接纤毛（CC），表明SPATA 7是一种纤毛蛋白。此外，SPATA 7直接与视网膜色素变性GTP酶调节因子相互作用蛋白1（RPGRIP 1）相互作用，这是一种关键的连接纤毛蛋白，也与LCA相关。在Spata 7无效突变小鼠的视网膜中，观察到感光细胞CC处的RPGRIP 1水平显著降低，表明SPATA 7是睫状体RPGRIP 1蛋白复合物稳定组装和定位所需的。此外，我们的结果还确定了该复合物在蛋白质穿过CC运输到外节中的作用，因为我们发现视紫红质积聚在光感受器的内节和细胞核周围。然后，这种积累可能触发所观察到的视杆细胞光感受器的凋亡。Spata 7功能的丧失确实导致了小鼠的幼年RP样表型，其特征在于感光细胞的进行性变性和强烈降低的光反应。总之，这些结果表明，SPATA 7作为视网膜睫状体病相关蛋白复合物的关键成员发挥作用，并且由蛋白质错误定位引发的视杆细胞凋亡可能是LCA 3/青少年RP患者疾病进展的机制。
Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are severe hereditary diseases that causes visual impairment in infants and children. SPATA7 has recently been identified as the LCA3 and juvenile RP gene in humans, whose function in the retina remains elusive. Here, we show that SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, indicating that SPATA7 is a ciliary protein. In addition, SPATA7 directly interacts with the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a key connecting cilium protein that has also been linked to LCA. In the retina of Spata7 null mutant mice, a substantial reduction of RPGRIP1 levels at the CC of photoreceptor cells is observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. Furthermore, our results pinpoint a role of this complex in protein trafficking across the CC to the outer segments, as we identified that rhodopsin accumulates in the inner segments and around the nucleus of photoreceptors. This accumulation then likely triggers the apoptosis of rod photoreceptors that was observed. Loss of Spata7 function in mice indeed results in a juvenile RP-like phenotype, characterized by progressive degeneration of photoreceptor cells and a strongly decreased light response. Together, these results indicate that SPATA7 functions as a key member of a retinal ciliopathy-associated protein complex, and that apoptosis of rod photoreceptor cells triggered by protein mislocalization is likely the mechanism of disease progression in LCA3/juvenile RP patients.