A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.
A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.
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DOI：
10.1038/s42003-021-01662-9
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发表时间：
2021-01-29
影响因子：
5.9
通讯作者：
Nakazawa T
中科院分区：
文献类型：
--
作者：
Nishiguchi KM;Miya F;Mori Y;Fujita K;Akiyama M;Kamatani T;Koyanagi Y;Sato K;Takigawa T;Ueno S;Tsugita M;Kunikata H;Cisarova K;Nishino J;Murakami A;Abe T;Momozawa Y;Terasaki H;Wada Y;Sonoda KH;Rivolta C;Tsunoda T;Tsujikawa M;Ikeda Y;Nakazawa T
日本常染色体隐性遗传色素性视网膜炎（ARRP）的遗传基础仍然很大程度上未知。在此，我们对 640 名日本患者应用了两步全基因组关联研究 (GWAS)。 Meta-GWAS 在 P < 5.0 × 10−8 处识别出三个独立峰，均位于主要 ARRP 基因 EYS 内。三者中的两个各自与不同的低频变异处于连锁不平衡（等位基因频率 < 0.05）；已知的创始人孟德尔突变（c.4957dupA，p.S1653Kfs*2）和意义未知的非同义变异（c.2528 G > A，p.G843E）。含有 c.2528 G > A 的 mRNA 未能恢复斑马鱼中由吗啡啉介导的 eys 敲低引起的视紫红质错误定位，这与该变异的致病性一致。 c.2528 G > A 解决了另外 7.0% 的日本 ARRP 案例。第三个峰与常见的非同义变异（c.7666 A > T，p.S2556C）连锁不平衡，可能代表未报告的疾病易感性信号。 GWAS 成功地揭示了一种罕见的单基因疾病的遗传原因，并确定了可能与局部基因组疗法的开发相关的高频变异。西口浩二等人。通过全基因组关联研究，确定了 EYS 基因内与色素性视网膜炎相关的三种遗传变异。他们证明这些变异之一 (G843E) 会导致斑马鱼视网膜功能障碍，这表明 EYS 在视网膜色素变性中具有因果作用。
The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10−8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics. Koji Nishiguchi et al. identify three genetic variants within the EYS gene that are associated with retinitis pigmentosa using a genome-wide association study. They demonstrate that one of these variants (G843E) causes retinal dysfunction in zebrafish, suggesting a causal role for EYS in retinitis pigmentosa.
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影响因子：
15.9
作者：
Frio, Thomas Rio;Wade, Nicholas M.;Rivolta, Carlo
通讯作者：
Rivolta, Carlo
影响因子：
4.8
作者：
Malicki, J;Jo, HY;Pujic, Z
通讯作者：
Pujic, Z
影响因子：
3.7
作者：
Hosono K;Ishigami C;Takahashi M;Park DH;Hirami Y;Nakanishi H;Ueno S;Yokoi T;Hikoya A;Fujita T;Zhao Y;Nishina S;Shin JP;Kim IT;Yamamoto S;Azuma N;Terasaki H;Sato M;Kondo M;Minoshima S;Hotta Y
通讯作者：
Hotta Y
斑马鱼 EYS 的消融导致外节蛋白错误定位、F-肌动蛋白破坏和锥杆营养不良
影响因子：
4.6
作者：
Lu Z;Hu X;Liu F;Soares DC;Liu X;Yu S;Gao M;Han S;Qin Y;Li C;Jiang T;Luo D;Guo AY;Tang Z;Liu M
通讯作者：
Liu M
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian