CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection

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.

Recent molecular insights into canonical pre-mRNA 3’-end processing

“…Defects and dysregulation of pre-mRNA 3′-end processing, both polyadenylation and APA, are linked to various diseases in humans [91][92][93]. Some of these diseases are caused by mutations in the PAS, indicating its functional importance.…”

Slc7a14 Is Indispensable in Zebrafish Retinas

“…The slc7a14 targeting MO was microinjected into the yolks of one-cell stage embryos with three different doses (2.0, 4.0, and 6.0 ng) (Leung et al, 2008;Rosen et al, 2009). Morphological analyses were performed at 3 or 5 dpf (Huang et al, 2018;Ouyang et al, 2019).…”

Cleavage and Polyadenylation Specific Factor 1 Promotes Tumor Progression via Alternative Polyadenylation and Splicing in Hepatocellular Carcinoma

“…CPSF1 expression decreases in diabetic retinopathy and mediates retinal vascular dysfunction via the MAPK/ERK pathway (Zhang et al, 2020). CPSF1 mutations are associated with early onset high myopia and involved in retinal ganglion cell axon projection (Ouyang et al, 2019).…”

“…CPSF1 expression decreases in diabetic retinopathy and mediates retinal vascular dysfunction via the MAPK/ERK pathway ( Zhang et al, 2020 ). CPSF1 mutations are associated with early onset high myopia and involved in retinal ganglion cell axon projection ( Ouyang et al, 2019 ). In tumors, CPSF1 plays an oncogenic role in head and neck squamous cell carcinoma ( Sakai et al, 2020 ), ovarian cancer ( Zhang et al, 2017 ), and prostate cancer growth ( Van Etten et al, 2017 ).…”