Howard Hughes Medical Institute, Department of Pediatrics, University of California, San Diego, La Jolla, USA.
Nat Genet. 2010 Feb;42(2):175-80. doi: 10.1038/ng.519. Epub 2010 Jan 17.
Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration. We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary kidney disease nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in nephronophthisis.
光感受器变性是纤毛病的一个共同特征，这是由于这些细胞的特化纤毛结构的重要性。已经表明，编码一种定位于纤毛的蛋白的 AHI1 突变会导致一种高度穿透性的视网膜变性的杰特综合征。我们表明，Ahi1 基因敲除小鼠不能形成视网膜外节，并且视蛋白在其整个光感受器中的分布异常。在这些小鼠中，光感受器的凋亡性细胞死亡在 2 至 4 周龄时迅速发生，并且视蛋白的剂量减少显著（P=0.00175 和 0.00613）延迟。这种表型还与另一个纤毛病相关基因 Nphp1 表现出剂量敏感的遗传相互作用。虽然它不是人类视网膜盲的主要原因，但我们表明，在遗传性肾脏疾病肾单位肾病变的个体队列中，AHI1 的一个等位基因与视网膜变性的相对风险增加超过七倍相关。我们的数据支持 AHI1 在视网膜病变中的特定作用，并表明 AHI1 可能解释了在肾单位肾病变中观察到的视网膜表型的变异性的一部分。
