Alternative titles; symbols
HGNC Approved Gene Symbol: SRSF1
Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:57,989,038-58,007,246 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
17q22 | Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities | 620489 | Autosomal dominant | 3 |
Alternative mRNA splicing plays an important role in development and differentiation; many transcripts are spliced differently in distinct cell types and tissues. Both constitutive and alternative splicing occurs on spliceosomes, which are complex particles composed of small nuclear ribonucleoproteins (snRNPs) and non-snRNP proteins. The SR family of non-snRNP splicing factors is characterized by the presence of an RNA recognition motif and a serine- and arginine-rich (SR) domain. SR proteins are required at early stages of spliceosome assembly, have distinct but overlapping specificities for different pre-mRNAs, and can alter splice site choice, suggesting that they may be involved in the regulation of alternative splicing in vivo. Two of the SR proteins, ASF/SF2 (SFRS1) and SC35 (SFRS2; 600813), have been extensively characterized (Bermingham et al., 1995).
Krainer et al. (1991) isolated a human cDNA for the pre-mRNA splicing factor referred to as SF2p33, which was later designated SFRS1.
Bermingham et al. (1995) mapped the SFRS1 gene to 17q21.3-q22 by a combination of Southern analysis of somatic cell hybrids and fluorescence in situ hybridization. Recombinant inbred mapping of the mouse Sfrs1 locus and the Sfrs2 locus demonstrated that both genes are located in the part of mouse chromosome 11 that is homologous to human chromosome 17. Thus, the SFRS2 gene is probably located also on 17q.
Stumpf (2023) mapped the SRSF1 gene to chromosome 17q22 based on an alignment of the SRSF1 sequence (GenBank AK312781) with the genomic sequence (GRCh38).
Pollard et al. (2000) sought to determine if the nuclear concentrations of the trans-acting splicing regulators SF2/ASF and HNRNPA1 (164017) and its splice variant, HNRNPA1B, are fundamental in regulating the expression of specific protein isoforms derived from alternative splicing of single pre-mRNA transcripts. SF2/ASF and HNRNPA1/A1B expression was determined in paired upper (corpus) and lower segment myometrial samples taken from individual women at term or during spontaneous labor and compared with nonpregnant control samples using specific monoclonal antibodies. SF2/ASF levels were substantially increased in the lower uterine region, and this was associated with a parallel decrease in levels of HNRNPA1/A1B during gestation. Conversely, the opposite pattern was observed within the upper uterine region during pregnancy, where HNRNPA1/A1B was significantly upregulated and SF2/ASF levels were much lower than those found in the lower uterine segment. The authors concluded that differential expression of HNRNPA1/A1B and SF2/ASF in the upper and lower uterine segments may have a primary role in defining the formation of specific myometrial protein species associated with the known contractile and relaxatory properties of these regions before and during parturition.
Wang et al. (1996) performed a targeted disruption of the ASF/SF2 gene in the chicken B-cell line DT40 and showed that the gene is required for cell viability.
The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Xu et al. (2005) reported a regulated alternative splicing program that is crucial for postnatal heart remodeling in the mouse. They identified the essential splicing factor Asf/Sf2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in Asf/Sf2 displayed an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of calcium/calmodulin-dependent kinase II-delta (CAMK2D; 607708) transcript. This failure resulted in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects.
Ghigna et al. (2005) identified a consensus binding motif for SF2 within an enhancer element in exon 12 of the RON gene (MST1R; 600168). They demonstrated that SF2 binds the enhancer element and regulates skipping of exon 11, resulting in a transcript, delta-RON, that encodes a constitutively active protein that induces cell dissociation, mobility, and invasion of extracellular matrices (i.e., cell scattering). Overexpression of SF2 in a human carcinoma cell line resulted in loss of epithelial phenotype, with acquisition of spindle-shaped morphology, increased cell motility, and aggressive behavior, a phenotype similar to that seen with delta-RON overexpression. Downregulation of SF2 by small interfering RNA reduced the level of delta-RON, which in turn decreased cell motility. Ghigna et al. (2005) concluded that SF2 controls cell scattering by regulating splicing of RON.
In 11 patients from 10 unrelated families with neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified de novo heterozygous mutations in the SRSF1 gene (see, e.g., 600812.0001-600812.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database; the patients were ascertained through international collaborative efforts, including GeneMatcher. There were missense, nonsense, and frameshift mutations that occurred throughout the protein. Expression of 5 of the missense variants and 1 frameshift variant in Drosophila demonstrated that they caused a loss of SRSF1 splicing activity. Molecular modeling suggested that the missense mutations may result in internal misfolding of the mutant protein. The SRSF1 mutations were associated with a specific epigenetic signature of differentially methylated regions that differed from controls and was consistent with overall hypermethylation, particularly of CpG islands. The findings suggested that haploinsufficiency of SRSF1 can cause a syndromic neurodevelopmental disorder due to a partial loss of SRSF1-mediated splicing activity. Of note, 6 additional individuals with SRSF1 variants were also identified in the study, although the pathogenicity of those SRSF1 variants was unclear. Two variants (H183R and D44N) identified in P8 and P16, respectively, did not show significant abnormalities in functional studies and were considered to be variants of uncertain significance. Two individuals (P6 and P17) carried larger deletions of chromosome 17q22 encompassing the SRSF1 gene, and 3 (P10, P12, and P17) carried genomic variations at more than 1 genetic locus, which may have contributed to the phenotype.
Katsuyama et al. (2019) found that mice with T cell-specific deletion of Srsf1 were viable with normal external features and body weight at birth, but they developed systemic autoimmunity and lupus-like disease. T-cell development was normal in Srsf1 -/- mice, but Srsf1 -/- T cells lost regulation of genes related to T-cell activation, differentiation, and cytokine production, leading to development of hyperactive, inflammatory cytokine-producing T cells. In particular, T cells from Srsf1 -/- mice had reduced expression of Pten (601728), resulting in increased activity of the mTORC1 (see 601231) pathway, which contributed to the proinflammatory and autoimmune phenotypes of T cells. Rapamycin treatment or Pten overexpression reduced proinflammatory cytokine production by T cells and thereby alleviated autoimmune disease in Srsf1 -/- mice. Similarly, in T cells from human patients with systemic lupus erythematosus (SLE; 152700), low SRSF1 levels correlated with reduced PTEN expression, and SRSF1 overexpression increased PTEN levels, suppressed mTORC1 activity, and reduced proinflammatory cytokine production.
In 2 sibs (P2 and P3) and an unrelated patient (P4) with neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified a de novo heterozygous c.478G-A transition (c.478G-A, NM_006924.5) in exon 3 of the SRSF1 gene, resulting in a val160-to-met (V160M) substitution at a conserved residue in the RRM2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The presence of the mutation in 2 sibs suggested parental gonadal mosaicism. Expression of the mutation in Drosophila demonstrated that it caused a loss of SRSF1 splicing activity, resulting in haploinsufficiency.
In a 6-year-old girl (P5) with neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified a de novo heterozygous 1-bp duplication (c.579dup, NM_006924.5) in exon 4 of the SRSF1 gene, predicted to result in a frameshift and premature termination (Val194SerfsTer2) at the end of the RRM2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to escape nonsense-mediated mRNA decay because exon 4 is the last exon of the gene. Expression of the mutation in Drosophila demonstrated that it caused a loss of SRSF1 splicing activity, resulting in haploinsufficiency.
In an 8.5-year-old boy (P9) with neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified a de novo heterozygous c.119G-T transversion (c.119G-T, NM_006924.5) in exon 1 of the SRSF1 gene, resulting in a gly40-to-val (G40V) substitution at a conserved residue in the RRM1 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the mutation in Drosophila demonstrated that it caused a loss of SRSF1 splicing activity, resulting in haploinsufficiency.
In a 2-year-old girl (P13) with neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified a de novo heterozygous c.71C-T transition (c.71C-T, NM_006924.5) in exon 1 of the SRSF1 gene, resulting in a pro24-to-leu (P24L) substitution at a conserved residue in the RRM1 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the mutation in Drosophila demonstrated that it caused a loss of SRSF1 splicing activity, resulting in haploinsufficiency.
In an 18-year-old boy (P15) neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (NEDFBA; 620489), Bogaert et al. (2023) identified a de novo heterozygous c.251T-G transversion (c.251T-G, NM_006924.5) in exon 2 of the SRSF1 gene, resulting in a leu84-to-arg (L84R) substitution at a conserved residue at the end of the RRM1 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the mutation in Drosophila demonstrated that it caused a loss of SRSF1 splicing activity, resulting in haploinsufficiency.
Bermingham, J. R., Jr., Arden, K. C., Naumova, A. K., Sapienza, C., Viars, C. S., Fu, X.-D., Khotz, J., Manley, J. L., Rosenfeld, M. G. Chromosomal localization of mouse and human genes encoding the splicing factors ASF/SF2 (SFRS1) and SC-35 (SFRS2). Genomics 29: 70-79, 1995. [PubMed: 8530103] [Full Text: https://doi.org/10.1006/geno.1995.1216]
Bogaert, E., Garde, A., Gautier, T., Rooney, K., Duffourd, Y., LeBlanc, P., van Reempts, E., Tran Mau-Them, F., Wentzensen, I. M., Au, K. S., Richardson, K., Northrup, H., and 52 others. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability. Am. J. Hum. Genet. 110: 790-808, 2023. [PubMed: 37071997] [Full Text: https://doi.org/10.1016/j.ajhg.2023.03.016]
Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P. M., Green, M. R., Riva, S., Biamonti, G. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Molec. Cell 20: 881-890, 2005. [PubMed: 16364913] [Full Text: https://doi.org/10.1016/j.molcel.2005.10.026]
Katsuyama, T., Li, H., Comte, D., Tsokos, G. C., Moulton, V. R. Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity. J. Clin. Invest. 129: 5411-5423, 2019. [PubMed: 31487268] [Full Text: https://doi.org/10.1172/JCI127949]
Krainer, A. R., Mayeda, A., Kozak, D., Binns, G. Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70K, and Drosophila splicing regulators. Cell 66: 383-394, 1991. [PubMed: 1830244] [Full Text: https://doi.org/10.1016/0092-8674(91)90627-b]
Pollard, A. J., Sparey, C., Robson, S. C., Krainer, A. R., Europe-Finner, G. N. Spatio-temporal expression of the trans-acting splicing factors SF2/ASF and heterogeneous ribonuclear proteins A1/A1B in the myometrium of the pregnant human uterus: a molecular mechanism for regulating regional protein isoform expression in vivo. J. Clin. Endocr. Metab. 85: 1928-1936, 2000. [PubMed: 10843177] [Full Text: https://doi.org/10.1210/jcem.85.5.6537]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/29/2023.
Wang, J., Takagaki, Y., Manley, J. L. Targeted disruption of an essential vertebrate gene: ASF/SF2 is required for cell viability. Genes Dev. 10: 2588-2599, 1996. [PubMed: 8895660] [Full Text: https://doi.org/10.1101/gad.10.20.2588]
Xu, X., Yang, D., Ding, J.-H., Wang, W., Chu, P.-H., Dalton, N. D., Wang, H.-Y., Bermingham, J. R., Jr., Ye, Z., Liu, F., Rosenfeld, M. G., Manley, J. L., Ross, J., Jr., Chen, J., Xiao, R.-P., Cheng, H., Fu, X.-D. ASF/SF2-regulated CaMKII-delta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell 120: 59-72, 2005. [PubMed: 15652482] [Full Text: https://doi.org/10.1016/j.cell.2004.11.036]