CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection
CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection
复制标题
CPSF1突变与早发性高度近视相关并参与视网膜神经节细胞轴突投射
DOI：
10.1093/hmg/ddz029
复制
发表时间：
2019-06-15
影响因子：
3.5
通讯作者：
Zhang, Qingjiong
中科院分区：
文献类型：
--
作者：
Ouyang, Jiamin;Sun, Wenmin;Zhang, Qingjiong
摘要高度近视是一种严重的近视，其并发症可导致失明。虽然遗传和环境因素都可以引起高度近视，但早发性高度近视（eoHM）被定义为学龄前发生的高度近视，被认为主要由遗传变异引起，与环境的参与最小。在这里，我们报告了CPSF 1中6种罕见的杂合性功能丧失（LoF）变异，在623例eoHM先证者中发现了6种，但在2657例其他形式遗传性眼病先证者中没有发现;这种差异具有统计学显著性（P = 4.60 × 10−5，Fisher精确检验）。经桑格测序证实，6个变异体分别为c.3862_3871dup（p.F1291*）、c.2823_2824del（p.V943Lfs*65）、c.1858C>T（p.Q620*）、c.15C>G（p.Y5*）、c.3823G>T（p.D1275Y）和c.4146-2A>G。这六个变体中有五个在现有数据库中不存在，包括gnomAD，1000 G和EVS。剩下的变异体c.4146-2A>G存在于gnomAD中，频率为1/229918。临床数据表明，eoHM在六个先证者与这些突变。通过注射morpholino oligonucleotide（MO）敲低斑马鱼卵中的cpsf 1导致84.38%的注射的幼体的小眼睛大小，并且当cpsf 1 MO和cpsf 1 mRNA共注射时，61.39%的斑马鱼卵中的这种表型被拯救。cpsf 1吗啡突变体视网膜神经节细胞（RGC）向顶盖的投射异常。因此，我们证明了CPSF 1的杂合LoF突变与eoHM相关，并且CPSF 1可能在RGC轴突投射的发展中发挥重要作用。
Abstract 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.V943Lfs*65), 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.