Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice
Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice
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DOI：
10.1371/journal.pgen.1008130
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发表时间：
2019-05-01
期刊：
影响因子：
4.5
通讯作者：
Prasovid, Lev
中科院分区：
文献类型：
--
作者：
Garnai, Sarah J.;Brinkmeier, Michelle L.;Prasovid, Lev
纳米眼球是一种罕见的、具有潜在破坏性的眼部疾病，其特征是眼睛较小、解剖结构相对正常、高度远视屈光不正，并且经常与闭角型青光眼和视力丧失相关。这种情况构成了极端的远视或远视，这是一种与儿童斜视和弱视相关的常见屈光不正。 NNO1 是第一个绘制的纳米眼基因座。我们使用合并的外显子组测序和大家族中的强连锁数据来绘制该基因座，以确定编码髓鞘质调节因子（MYRF c.3376-1G>A）的基因最后一个外显子上游的典型剪接位点改变，髓磷脂调节因子是一种膜结合转录因子，经过自蛋白水解切割以进行核定位。该变体产生稳定的 RNA 转录本，导致蛋白质 C 末端出现移码突变 p.Gly1126Valfs*31。此外，我们在一名患有极度轴性远视和综合征特征的患者中发现了早期截短的 MYRF 移码突变 c.769dupC (p.S264QfsX74)。 Myrf 条件性基因敲除小鼠 (CKO) 出现视网膜色素上皮 (RPE) 脱色和视网膜变性，支持该基因在视网膜和 RPE 发育中的作用。此外，我们还证明了 Myrf CKO 小鼠中另一种已知的纳米眼基因 Tmem98 的表达降低，以及 MYRF 与 TMEM98 的物理相互作用。我们的研究将 MYRF 确定为纳米眼球基因，并揭示了眼睛生长和发育的新途径。
Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.