Variants in ASB10 are associated with open-angle glaucoma
Variants in ASB10 are associated with open-angle glaucoma
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DOI：
10.1093/hmg/ddr572
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发表时间：
2012-03-15
影响因子：
3.5
通讯作者：
Wirtz, Mary K.
中科院分区：
文献类型：
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作者：
Pasutto, Francesca;Keller, Kate E.;Wirtz, Mary K.
青光眼是世界范围内致盲的主要原因之一，但导致房水流出受阻和视网膜神经节细胞丧失的分子事件仍然知之甚少。我们在原发性开角型青光眼（POAG）大家族中发现了与GLC1F位点相关的锚蛋白重复序列和细胞因子信号传导盒蛋白10 （ASB10）抑制因子c.765CT （Thr255Thr）同属变异。这种变异影响外显子剪接增强子位点，并改变受影响家族成员淋巴细胞的mRNA剪接。对两组POAG患者（195例美国患者和977例德国患者）以及各自的对照组（85例和376例）进行系统序列分析，发现70例患者（1172例中有70例；6.0）中有26个氨基酸变化，而13例对照组（461例中有13例；2.8;P 0.008）中有9个氨基酸变化。分子模型表明，这些错义变体改变了ASB10的净电荷或破坏了锚蛋白重复序列的稳定性。发现ASB10 mRNA和蛋白在小梁网、视网膜神经节细胞和睫状体中强烈表达。在灌注的前节器官培养中，ASB10转录物的沉默与对照组感染的前节相比，减少了大约50%的流出设施（P < 0.02）。总之，遗传和分子分析为ASB10是青光眼的致病基因提供了证据。
The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765CT (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0) compared with 9 in 13 controls (13 of 461; 2.8; P 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by approximate to 50 compared with control-infected anterior segments (P 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.