Alternative titles; symbols
HGNC Approved Gene Symbol: CPSF1
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:144,393,231-144,409,335 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Myopia 27 | 618827 | Autosomal dominant | 3 |
Cleavage and polyadenylation specificity factor (CPSF) is a multisubunit complex that plays a central role in 3-prime processing of pre-mRNAs. CPSF recognizes the AAUAAA signal in the pre-mRNA and interacts with other proteins to facilitate both RNA cleavage and poly(A) synthesis. CPSF1 is the largest subunit of the CPSF complex (Murthy and Manley, 1995).
By biochemical purification, micropeptide sequence analysis, and screening a HeLa cell cDNA library, Murthy and Manley (1995) obtained a cDNA encoding CPSF1. The 1,442-amino acid protein contains a bipartite nuclear localization signal and an RNA-binding domain. Northern blot analysis revealed expression of a 5.0-kb transcript. Immunofluorescence microscopy and Western blot analysis showed expression of an exclusively nuclear 160-kD protein.
By RT-qPCR in various human tissues, Ouyang et al. (2019) showed that CPSF1 is highly expressed in human eye structures, including the retina, ciliary body, choroid, optic nerve, sclera, and lens. The highest expression was observed in the testis.
Samiotaki et al. (2000) mapped the CPSF1 gene to 8q24.23 by radiation hybrid analysis.
Functional analysis by Murthy and Manley (1995) showed that anti-CPSF1 blocks polyadenylation reactions and has a preference for AAUAAA-containing RNAs. Binding analysis indicated that CPSF1 interacts with CSTF3 (600367) and with PAPOLA (605553).
Transcription, 5-prime capping, 3-prime polyadenylation, and splicing of pre-mRNA are coupled in vivo. Kyburz et al. (2006) found that proteins of the U2 snRNP (see 180690) were associated with CPSF. CPSF was necessary for efficient splicing activity in coupled assays, and mutations in the pre-mRNA binding site of the U2 snRNP resulted in impaired splicing and reduced cleavage efficiency. Efficient cleavage required the presence of U2 snRNA in coupled assays. Kyburz et al. (2006) concluded that interaction between CPSF and U2 snRNP contributes to the coupling of splicing and 3-prime end formation.
In 6 probands with early-onset high myopia (MYP27; 618827), Ouyang et al. (2019) identified heterozygous mutations in the CPSF1 gene (see, e.g., 606027.0001-606027.0004).
Ouyang et al. (2019) designed an oligonucleotide morpholino (MO) to disrupt cpsf1 in zebrafish. At a lower dose, the zebrafish morphants showed small eyes at 3 days post-fertilization (dpf), and exhibited a reduced number of retinal ganglion cell axons projecting to the tectum at 5 dpf. The small-eye phenotype could be rescued by wildtype cpsf1-mRNA. At a higher dose, additional toxic effects were produced, including cardiac edema, severely curved tail and body, and abnormal pigmentation.
In a male proband (family HM949) with early-onset high myopia (MYP27; 618827), Ouyang et al. (2019) identified heterozygosity for a splicing mutation (c.4146-2A-G, NM_013291.3) in intron 35 of the CPSF1 gene. Minigene analysis showed that the mutation results in inclusion of the 76-bp intron 35. The mutation was inherited from his mother, who had moderate myopia with unknown age of onset, and was not found in 2,657 probands with other eye diseases; however, it was present in the gnomAD database with a frequency of 1/229,918 alleles.
In an affected mother and son (family HM943) with early-onset high myopia (MYP27; 618827), Ouyang et al. (2019) identified heterozygosity for a c.3823G-T transversion (c.3823G-T, NM_013291.3) in exon 33 of the CPSF1 gene, resulting in an asp1275-to-tyr (D1275Y) substitution at a highly conserved residue. Minigene analysis showed that both the mutant allele (T) and the wildtype allele (G) at c.3823 caused retention of intron 32. The mutation was not found in 2,657 probands with other eye diseases, or in the EVS, 1000 Genomes Project, or gnomAD databases.
In a male proband (HM337) with early-onset high myopia (MYP27; 618827), Ouyang et al. (2019) identified heterozygosity for a c.1858C-T transition (c.1858C-T, NM_013291.3) in exon 18 of the CPSF1 gene, resulting in a gln620-to-ter (Q620X) substitution. DNA was unavailable from his unaffected parents for segregation analysis; however, the mutation was not found in 2,657 probands with other eye diseases, or in the EVS, 1000 Genomes Project, or gnomAD databases.
In a female proband (HM653) with early-onset high myopia (MYP27; 618827), Ouyang et al. (2019) identified heterozygosity for a 2-bp deletion (c.2823_2824del, NM_013291.3) in exon 24 of the CPSF1 gene, causing a frameshift predicted to result in a premature termination codon (Val943LeufsTer65). DNA was unavailable from her unaffected parents for segregation analysis; however, the mutation was not found in 2,657 probands with other eye diseases, or in the EVS, 1000 Genomes Project, or gnomAD databases.
Kyburz, A., Friedlein, A., Langen, H., Keller, W. Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of pre-mRNA 3-prime end processing and splicing. Molec. Cell 23: 195-205, 2006. [PubMed: 16857586] [Full Text: https://doi.org/10.1016/j.molcel.2006.05.037]
Murthy, K. G. K., Manley, J. L. The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3-prime-end formation. Genes Dev. 9: 2672-2683, 1995. [PubMed: 7590244] [Full Text: https://doi.org/10.1101/gad.9.21.2672]
Ouyang, J., Sun, W., Xiao, X., Li, S., Jia, X., Zhou, L., Wang, P., Zhang, Q. CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection. Hum. Molec. Genet. 28: 1959-1970, 2019. [PubMed: 30689892] [Full Text: https://doi.org/10.1093/hmg/ddz029]
Samiotaki, M., Balatsos, N. A. A., Courtis, N., Tsiapalis, C. M. Assignment of the 160-kDa subunit of cleavage and polyadenylation specificity factor (CPSF1) to human chromosome 8q24.23 by radiation hybrid mapping. Cytogenet. Cell Genet. 90: 234-235, 2000. [PubMed: 11124521] [Full Text: https://doi.org/10.1159/000056776]