Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 12, Pages 1959-1970Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz029
Keywords
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Funding
- National Natural Science Foundation of China [81770965]
- Science and Technology Planning Projects of Guangzhou [201607020013]
- Fundamental Research Funds of the State Key Laboratory of Ophthalmology
- National Science Fund for Distinguished Young Scholars
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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 x 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.
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