State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China.
Hum Mol Genet. 2019 Jun 15;28(12):1959-1970. doi: 10.1093/hmg/ddz029.
High myopia is a severe form of nearsightedness, which can result in blindness due to its associated complications. While both genetic and environmental factors can cause high myopia, early-onset high myopia (eoHM), which is defined as high myopia that occurs before school age, is considered to be caused mainly by genetic variations, with minimal environmental involvement. Here we report six rare heterozygous loss-of-function (LoF) variants in CPSF1 that were identified in six of 623 probands with eoHM but none of 2657 probands with other forms of genetic eye diseases; this difference was statistically significant (P = 4.60 × 10-5, Fisher's exact test). The six variants, which were confirmed by Sanger sequencing, were c.3862_3871dup (p.F1291*), c.2823_2824del (p.V943Lfs65), c.1858C>T (p.Q620), c.15C>G (p.Y5*), c.3823G>T (p.D1275Y) and c.4146-2A>G. Five of these six variants were absent in existing databases, including gnomAD, 1000G and EVS. The remaining variant, c.4146-2A>G, was present in gnomAD with a frequency of 1/229918. Clinical data demonstrated eoHM in the six probands with these mutations. Knockdown of cpsf1 by morpholino oligonucleotide (MO) injection in zebrafish eggs resulted in small eye size in 84.38% of the injected larvae, and this phenotype was rescued in 61.39% of the zebrafish eggs when the cpsf1 MO and the cpsf1 mRNA were co-injected. The projection of retinal ganglion cell (RGC) towards the tectum was abnormal in cpsf1 morphants. Thus, we demonstrated that heterozygous LoF mutations in CPSF1 are associated with eoHM and that CPSF1 may play an important role in the development of RGC axon projection.
高度近视是一种严重的近视形式，由于其相关并发症，可能导致失明。虽然遗传和环境因素都可能导致高度近视，但发病年龄早于上学年龄的早发性高度近视（eoHM）被认为主要是由遗传变异引起的，环境因素的参与很小。在这里，我们报道了 6 个在 623 名 eoHM 先证者中发现的 CPSF1 杂合性失活（LoF）变异，而在 2657 名其他遗传性眼病先证者中均未发现；这种差异具有统计学意义（P=4.60×10-5，Fisher 精确检验）。这 6 个变异经 Sanger 测序证实，分别为 c.3862_3871dup(p.F1291*)、c.2823_2824del(p.V943Lfs65)、c.1858C>T(p.Q620)、c.15C>G(p.Y5*)、c.3823G>T(p.D1275Y)和 c.4146-2A>G。这 6 个变异中有 5 个在现有的数据库（包括 gnomAD、1000G 和 EVS）中均未发现。其余的变异 c.4146-2A>G 在 gnomAD 中存在，频率为 1/229918。临床数据显示，携带这些突变的 6 名先证者均患有 eoHM。用 CPSF1 构建体的 MO 注射到斑马鱼卵中导致 84.38%的注射幼虫的眼睛变小，而当共注射 CPSF1 MO 和 CPSF1 mRNA 时，61.39%的斑马鱼卵中的这种表型被挽救。cpsf1 突变体中视网膜神经节细胞（RGC）向顶盖的投射异常。因此，我们证明 CPSF1 中的杂合性 LoF 突变与 eoHM 相关，CPSF1 可能在 RGC 轴突投射发育中发挥重要作用。
