Alternative titles; symbols
HGNC Approved Gene Symbol: CPSF3
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38) : 2:9,423,654-9,473,101 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p25.1 | Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures | 619876 | Autosomal recessive | 3 |
Most eukaryotic mRNA precursors (pre-mRNAs) undergo extensive maturational processing, including cleavage and polyadenylation at the 3-prime end. CPSF3 encodes the 73-kD subunit of the cleavage and polyadenylation specificity factor and is the pre-mRNA 3-prime-end-processing endonuclease (Mandel et al., 2006).
Jenny et al. (1996) cloned a cDNA encoding bovine Cpsf3. Scott (2001) determined that the human sequence is nearly identical to the bovine sequence.
Crystal Structure
Mandel et al. (2006) reported the crystal structures of human CPSF73 at 2.1-angstrom resolution, complexed with zinc ions and a sulfate that might mimic the phosphate group of substrate, and the related yeast protein CPSF100 (CPSF2; 606028) at 2.5-angstrom resolution. Both CPSF73 and CPSF100 contain 2 domains, a metallo-beta-lactamase domain and a novel beta-CASP (named for metallo-beta-lactamase, CPSF, Artemis, Snm1, Pso2) domain. The active site of CPSF73, with 2 zinc ions, is located at the interface of the 2 domains. Purified recombinant CPSF73 possesses RNA endonuclease activity, and mutations that disrupt zinc binding in the active site abolish this activity. Mandel et al. (2006) concluded that their studies provided the first direct experimental evidence that CPSF73 is the pre-mRNA 3-prime end-processing endonuclease.
Using yeast 2-hybrid analysis, coimmunoprecipitation studies, and protein pull-down assays, Zhu et al. (2009) showed that CSR1, a putative tumor suppressor in prostate cancer (176807), interacted with CPSF3. Deletion analysis showed that the C terminus of CSR1 mediated the interaction. CSR1 directed CPSF3 from its nuclear localization to a patchy cytosolic distribution in prostate cancer cell lines. Induction of CSR1 expression significantly decreased RNA polyadenylation activity in nuclear cell fractions and generally reduced the cellular level of mRNA. Knockdown of CSR1 rendered cells resistant to tetracycline-induced apoptosis, whereas knockdown of CPSF3 induced cell death in tetracycline-treated cells in a manner similar to CSR1 expression. Cell lines expressing mutant CSR1 that could not interact with CPSF3 did not die when exposed to tetracycline, implying that CSR1-induced cell death requires interaction of CSR1 with CPSF3. Zhu et al. (2009) concluded that CSR1 induces cell death by sequestering CPSF3, a critical RNA-processing enzyme.
Stumpf (2022) mapped the CPSF3 gene to chromosome 2p25.1 based on an alignment of the CPSF3 sequence (GenBank BC011654) with the genomic sequence (GRCh38).
In 4 patients (patients A-D) from 2 Icelandic families with neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS; 619876), Arnadottir et al. (2022) identified a homozygous missense mutation in the CPSF3 gene (G468E; 606029.0001). The mutation was initially found by analyzing whole-genome data from a large cohort of over 153,054 adult Icelandic individuals for a deficit of carriers of homozygous missense variants in different genes. The affected individuals with NEDMHS were then identified from a clinical cohort of Icelandic patients with various disorders who had undergone whole-genome sequencing. Samples from 2 additional deceased affected children of Icelandic descent (patients E and F) were not available, but the phenotype was similar to the other patients and the unaffected parents were heterozygous carriers. Western blot analysis of cells derived from patient B confirmed that the mutant protein is produced at normal levels, suggesting that the mutation causes a functional defect. The variant had a frequency of 0.41% in Iceland. Two further patients (G and H) from a large Mexican family with a homozygous missense mutation in the CPSF3 gene (I354T; 606029.0002) were identified through the GeneMatcher program. Functional studies of the variants were not performed, but they were both predicted to disrupt the pre-mRNA cleavage mechanism, resulting in the accumulation of unprocessed pre-mRNA in cells, which would in turn activate a cellular stress response.
In 4 patients (patients A-D) from 2 Icelandic families with neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS; 619876), Arnadottir et al. (2022) identified a homozygous c.1403G-A transition (c.1403G-A, NM_016207.3) in exon 12 of the CPSF3 gene, resulting in a gly468-to-glu (G468E) substitution at a highly conserved residue. The mutation was found by analyzing whole-genome data from a large cohort of over 153,054 adult Icelandic individuals for a lack of carriers of homozygous missense variants in different genes. Two homozygous carriers of the CPSF3 G468E mutation (patients A and B) were then identified from a clinical cohort of patients with various disorders who had undergone whole-genome sequencing. Three additional couples of Icelandic descent were found to be heterozygous carriers of the variant, which had a frequency of 0.41% in Iceland. Combined, the 3 couples had 10 offspring, 4 of whom died before 8 years of age and had a phenotype similar to patients A and B. Sanger sequencing of paraffin-embedded tissue from 2 of the deceased affected children who were sibs (patients C and D) confirmed that they carried the homozygous G468E mutation. These sibs were part of the same extended family as patient A. Samples from the other 2 deceased affected children of Icelandic descent (patients E and F) were not available, but the phenotype was similar to the other patients and the unaffected parents were heterozygous carriers. Western blot analysis of cells derived from patient B confirmed that the mutant protein is produced at normal levels, suggesting that the mutation causes a functional defect. Functional studies of the variant were not performed.
In 2 patients (patients G and H) from a large consanguineous Mexican family with neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS; 619876), Arnadottir et al. (2022) identified a homozygous c.1061T-C transition (c.1061T-C, NM_016207.3) in exon 9 of the CPSF3 gene, resulting in an ile354-to-thr (I354T) substitution at a highly conserved residue in the beta-CASP domain. The mutation, which was found by whole-exome sequencing, was present at a low frequency among Latinos and admixed Americans in the gnomAD database (6 x 10(-3)). Functional studies of the variant and studies of patient cells were not performed.
Arnadottir, G. A., Oddsson, A., Jensson, B. L., Gisladottir, S., Simon, M. T., Arnthorsson, A. O., Katrinardottir, H., Fridriksdottir, R., Ivarsdottir, E. V., Jonasdottir, A., Jonasdottir, A., Barrick, R., 21 others. Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene. Nature Commun. 13: 705, 2022. [PubMed: 35121750] [Full Text: https://doi.org/10.1038/s41467-022-28330-8]
Jenny, A., Minvielle-Sebastia, L., Preker, P. J., Keller, W. Sequence similarity between the 73-kilodalton protein of mammalian CPSF and a subunit of yeast polyadenylation factor I. Science 274: 1514-1517, 1996. [PubMed: 8929409] [Full Text: https://doi.org/10.1126/science.274.5292.1514]
Mandel, C. R., Kaneko, S., Zhang, H., Gebauer, D., Vethantham, V., Manley, J. L., Tong, L. Polyadenylation factor CPSF-73 is the pre-mRNA 3-prime-end-processing endonuclease. Nature 444: 953-956, 2006. [PubMed: 17128255] [Full Text: https://doi.org/10.1038/nature05363]
Scott, A. F. Personal Communication. Baltimore, Md. 6/18/2001.
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/19/2022.
Zhu, Z.-H., Yu, Y. P., Shi, Y.-K., Nelson, J. B., Luo, J.-H. CSR1 induces cell death through inactivation of CPSF3. Oncogene 28: 41-51, 2009. [PubMed: 18806823] [Full Text: https://doi.org/10.1038/onc.2008.359]