A point mutation in Semaphorin 4A associated with retinal degenerative diseases

Semaphorin 4A（Sema 4A）在光感受器存活中具有重要作用。在人类中，Sema 4A的突变被认为是导致视网膜退行性疾病的原因。在这里，我们产生了一系列在Sema 4A基因中具有相应突变（D345 H、F350 C或R713 Q）的敲入小鼠品系，并发现Sema 4A F350 C引起视网膜变性表型。F350 C突变导致Sema 4A蛋白的异常定位，导致感光细胞存活所必需的分子的内体分选受损。此外，蛋白质结构模型显示，第350个氨基酸的侧链对保持正确的蛋白质构象至关重要。此外，Sema 4A基因转移成功地防止了Sema 4A F350 C/F350 C和Sema 4A-/-小鼠的感光细胞变性。因此，我们的研究结果不仅表明Sema 4A蛋白构象在人类和小鼠视网膜稳态中的重要性，而且还确定了视网膜退行性疾病的新治疗靶点。

Semaphorin 4A(Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases. Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A F350C causes retinal degeneration phenotypes. The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A F350C/F350C and Sema4A-/- mice. Thus, our findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases.