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HGNC Approved Gene Symbol: SFPQ
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38): 1:35,176,380-35,193,145 (from NCBI)
The RNA-binding protein PSF is a pre-mRNA splicing factor that also acts as a transcriptional corepressor, and is a constituent of the PERIOD (PER) complex involved in the generation of circadian rhythms (summary by Duong et al., 2011).
Patton et al. (1993) identified a 100-kD protein that copurified and associated with polypyrimidine tract-binding protein (PTB; 600693). By microsequence analysis and PCR, followed by screening a fetal brain cDNA library, Patton et al. (1993) isolated cDNAs encoding alternatively spliced isoforms of this protein, which they called PSF (PTB-associated splicing factor). The deduced 669- and 707-amino acid PSF isoforms contain 2 consensus RNA-binding domains and an unusual N terminus rich in proline and glutamine residues. PSF is highly basic and has a predicted molecular mass of 76 kD, which is much lower than the experimentally determined molecular mass of 100 kD. Northern blot analysis detected PSF transcripts of 2.5 and 3.0 kb, consistent with the alternative splicing. The authors found that the RNA-binding properties of PSF are identical to those of PTB and that both proteins, together and independently, bind the polypyrimidine tract of mammalian introns. Biochemical complementation, antibody inhibition, and immunodepletion experiments demonstrated that PSF is an essential pre-mRNA splicing factor required early in spliceosome formation. Bacterially synthesized PSF was able to complement immunodepleted extracts and restore splicing activity. Despite its association with PSF, complementary experiments with antibodies against PTB did not suggest an essential role for PTB in pre-mRNA splicing.
Duong et al. (2011) analyzed protein constituents of PERIOD (PER) complexes purified from mouse tissues and identified PSF. Within the complex, PSF functions to recruit SIN3A (607776), a scaffold for assembly transcriptional inhibitory complexes; the PER complex thereby rhythmically delivers histone deacetylases to the PER1 (602260) promoter, which repress PER1 transcription. Duong et al. (2011) concluded that their findings provided a function for the PER complex and a molecular mechanism for circadian clock negative feedback.
Clark et al. (1997) identified cases of papillary renal cell carcinoma (RCCX1; 300854) in which the splicing factor gene PSF was partnered with the TFE3 gene as a result of a translocation, t(X;1)(p11.2;p34).
Thomas-Jinu et al. (2017) performed whole-exome sequencing in 151 patients with familial amyotrophic lateral sclerosis (ALS; see 105400) and identified 2 patients with heterozygous mutations in the SFPQ gene, a c.1597A-C transversion (NM_005066) resulting in an asn533-to-his (N533H) substitution, and a c.1600C-A transversion (NM_005066) resulting in a leu534-to-ile (L534I) substitution. Neither mutation was present in the dbSNP (build 142), 1000 Genomes Project, Exome Variant Server, and ExAC databases. Both mutations were located at conserved residues in the second coiled-coil domain of the protein. No clinical features were reported and no familial segregation was performed.
Thomas-Jinu et al. (2017) characterized sfpq-null zebrafish. The zebrafish larvae had abnormal brain patterning, including lack of rhombomere boundaries and lack of maintenance of mid/hindbrain boundaries. The mutant fish also exhibited absence of axons in the majority of motor neurons. Gene expression studies in mutant zebrafish embryos demonstrated 571 differentially expressed genes, most of which were downregulated, associated with pathways including cell adhesion, cell junctions, neuronal/synaptic structure, and Wnt signaling. In wildtype fish, sfpq protein was found to be expressed in both the nucleus and axons of motor neurons. Injection of a cytoplasmic version of SFPQ in sfpq-null zebrafish resulted in rescue of motor axon growth, thus providing evidence for a cytoplasmic function of SFPQ. Thomas-Jinu et al. (2017) next injected the sfpq-null zebrafish with mRNA encoding for SFPQ with an L534I or N533H mutation, which were identified in patients with familial amyotrophic lateral sclerosis. Motor axons in the zebrafish were shorter and excessively branched compared to those in sfpq-null zebrafish injected with wildtype SFPQ mRNA.
Clark, J., Lu, Y.-J., Sidhar, S. K., Parker, C., Gill, S., Smedley, D., Hamoudi, R., Linehan, W. M., Shipley, J., Cooper, C. S. Fusion of splicing factor genes PSF and NonO (p54-nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene 15: 2233-2239, 1997. [PubMed: 9393982] [Full Text: https://doi.org/10.1038/sj.onc.1201394]
Duong, H. A., Robles, M. S., Knutti, D., Weitz, C. J. A molecular mechanism for circadian clock negative feedback. Science 332: 1436-1439, 2011. [PubMed: 21680841] [Full Text: https://doi.org/10.1126/science.1196766]
Patton, J. G., Porro, E. B., Galceran, J., Tempst, P., Nadal-Ginard, B. Cloning and characterization of PSF, a novel pre-mRNA splicing factor. Genes Dev. 7: 393-406, 1993. [PubMed: 8449401] [Full Text: https://doi.org/10.1101/gad.7.3.393]
Thomas-Jinu, S., Gordon, P. M., Fielding, T., Taylor, R., Smith, B. N., Snowden, V., Blanc, E., Vance, C., Topp, S., Wong, C. H., Bielen, H., Williams, K. L., and 9 others. Non-nuclear pool of splicing factor SFPQ regulates axonal transcripts required for normal motor development. Neuron 94: 322-336.e5, 2017. Note: Erratum: Neuron 94: 931 only, 2017. [PubMed: 28392072] [Full Text: https://doi.org/10.1016/j.neuron.2017.03.026]