Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 605590

SPLICING FACTOR 3B, SUBUNIT 1; SF3B1

Alternative titles; symbols

SF3B, 155-KD SUBUNIT; SF3B155

SPLICEOSOME-ASSOCIATED PROTEIN, 155-KD; SAP155

HGNC Approved Gene Symbol: SF3B1

Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38) : 2:197,389,784-197,435,093 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

Introns are removed from nuclear pre-mRNA in 2 transesterification reactions. Splicing takes place in a large ribonucleoprotein particle, the spliceosome. Spliceosomal intermediate complexes form on pre-mRNA in the order E, A, B, and C, with the catalytic reactions occurring in complex C. U2 small nuclear ribonucleoproteins (snRNPs; see 180690) are among the proteins essential for spliceosome assembly and mRNA splicing. Functional U2 snRNP is composed of a 12S unit and 2 splicing factors, SF3A, which is composed of 3 proteins (see SF3A1; 605595), and SF3B, which is composed of 4 proteins, including SF3B1 (summary by Kramer et al. (1995), Wang et al. (1998), and Isono et al. (2001)).

Cloning and Expression

By SDS-PAGE fractionation of spliceosomal complex A, micropeptide sequence analysis, database searching, and cDNA library screening, Wang et al. (1998) isolated a cDNA encoding SF3B1, which they called SAP155. Sequence analysis predicted that the 1,304-amino acid protein is 50% identical to the yeast sequence. The C-terminal two-thirds of SF3B1 can align into 22 PP2A (PPP2R1B; 603113)-like repeats, and the nonconserved N terminus contains multiple TPGH and RWDETP motifs but lacks SR domains. Western blot analysis detected the 155-kD protein in the spliceosomal A/B complex and a larger phosphorylated protein in the C complex. The authors showed that the phosphorylation occurs concomitant with the catalytic steps of splicing.

Isono et al. (2001) isolated a cDNA encoding the 146-kD mouse homolog. The amino acid sequence of Sf3b1 was very highly conserved among homologs from Schizosaccharomyces pombe (52.4% identity) to human (99.6%), and the C-terminal 825 residues of these homologs showed even higher identities.

Biochemical Features

Cryoelectron Microscopy

Golas et al. (2003) determined the 3-dimensional structure of the human SF3B complex by single-particle electron cryomicroscopy at a resolution of less than 10 angstroms, allowing identification of protein domains with known structural folds. The best fit of a modeled RNA recognition motif indicates that the protein p14 (607835) is located in the central cavity of the complex. The 22 tandem helical repeats of the protein SF3B155 are located in the outer shell of the complex enclosing p14.

Zhang et al. (2020) reported a 3D cryoelectron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 angstroms and combined it with protein crosslinking data to determine the molecular architecture of this snRNP. The structure revealed that the HEAT domain of SF3B1 interacts with PRP5 (617848) and TATSF1 (300346), and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a branchpoint-interacting stem loop (BSL) that is sandwiched between PRP5, TATSF1, and the SF3B1 HEAT domain. Thus, substantial remodeling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2 branch-site helix. Zhang et al. (2020) concluded that their studies provided a structural explanation of why TATSF1 must be displaced before the stable addition of U2 to the spliceosome, and identified RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.

Gene Function

Using yeast 2-hybrid analysis and pull-down assays of mouse nuclear extracts, Isono et al. (2005) found that Sf3b1 interacted directly with the Polycomb group proteins Pcgf2 (600346) and Rnf2 (608985). Furthermore, Sf3b1 colocalized with Polycomb proteins on the 5-prime regions of individual Hox genes.

Mirtschink et al. (2015) showed that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathologic cardiac hypertrophy through hypoxia-inducible factor 1-alpha (HIF1A; 603348) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A (see 614058) to KHK-C. In mice, heart-specific depletion of Sf3b1 or genetic ablation of khk, but not khk-A alone, suppressed pathologic stress-induced fructose metabolism, growth, and contractile dysfunction, thus defining signaling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathologic growth.

Inoue et al. (2019) integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis, and reported that diverse SF3B1 mutations converge on repression of BRD9 (618465), which is a core component of the noncanonical BAF (603811) chromatin-remodeling complex that also contains GLTSCR1 (605690) and GLTSCR1L (618502). Mutant SF3B1 recognized an aberrant, deep intronic branchpoint within BRD9 and thereby induced the inclusion of a poison exon that was derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 caused the loss of noncanonical BAF at CTCF (604167)-associated loci and promoted melanomagenesis. BRD9 is a potent tumor suppressor in uveal melanoma (155720), such that correcting missplicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppressed tumor growth. Inoue et al. (2019) concluded that their results implicated the disruption of noncanonical BAF in the diverse cancer types that carry SF3B1 mutations and suggested a mechanism-based therapeutic approach for treating these malignancies.

Mapping

Gross (2015) mapped the SF3B1 gene to chromosome 2q33.1 based on an alignment of the SF3B1 sequence (GenBank AF054284) with the genomic sequence (GRCh38).

Isono et al. (2001) mapped the mouse homolog of human SF3B1 to the central part of chromosome 1 by interspecific backcross analysis. This location was also consistent with the mapping data obtained by using a radiation hybrid panel.

Molecular Genetics

Somatic Mutations

Using whole-exome sequencing of bone marrow cells, Papaemmanuil et al. (2011) found that 6 of 9 patients with myelodysplastic syndrome (MDS; 614286) carried 1 of 2 somatic heterozygous mutations in the SF3B1 gene: a lys700-to-glu (K700E) substitution or a his662-to-gln (H662Q) substitution, in addition to somatic mutations in several other genes. Targeted resequencing of this gene found that 72 (20%) of 354 patients with MDS had mutations in the SF3B1 gene. The majority of the patients (68%) with mutations had refractory anemia with ringed sideroblasts, although 6% had refractory anemia with excess blasts. Mutations in the SF3B1 gene were also found less frequently in bone marrow from patients with other chronic myeloid disorders, such as primary myelofibrosis (254450), essential thrombocythemia (187950), and chronic myelomonocytic leukemia (CMML; see 607785), as well as in acute myeloid leukemia (AML; 601626). Somatic mutations were also found in about 1% of primary solid tumors. The mutations occurred throughout the gene, but were clustered in exons 12 to 15; K700E was the most common mutation, accounting for 59 (55%) of the 108 variants observed. Alignment and in silico studies indicated that the mutations were not severely deleterious, suggesting that the mutant proteins retain structural integrity and some function. Gene expression profiling studies suggested a disturbance of mitochondrial gene networks in stem cells from MDS patients with SF3B1 mutations. Clinically, MDS patients with SF3B1 mutations had higher median white cell count, higher platelet count, higher erythroid hyperplasia, lower proportion of bone marrow blasts, and overall longer survival compared to those without SF3B1 mutations, suggesting a more benign phenotype.

Wang et al. (2011) performed paired tumor and germline whole-exome and whole-genome sequencing from DNA samples in 91 patients with chronic lymphocytic leukemia (CLL; 151400). Nine genes were mutated at significant frequencies, including TP53 (191170) in 15% of patients, ATM (607585) in 9%, MYD88 (602170) in 10%, and NOTCH1 (190198) in 4%. Five novel genes were detected: SF3B1 (605590), ZMYM3 (300061), MAPK1 (176948), FBXW7 (606278), and DDX3X (300160). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene, with mutations occurring in 15% of patients. SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with CLL. Wang et al. (2011) discovered that tumor samples with mutations in SF3B1 had alterations in pre-mRNA splicing.

Using whole-exome sequencing of matched tumor and normal samples from 105 individuals with CLL followed by expansion studies in an additional 174 CLL patients, Quesada et al. (2012) found that 27 (9.7%) of the 279 patients had somatic mutations in the SF3B1 gene. All SF3B1 mutations occurred in the nonidentical HEAT domains, and SF3B1-mutant cases showed enhanced expression of truncated mRNAs of various genes. Clinically, patients with SF3B1 mutations had faster disease progression and poorer overall survival compared to those with other mutations. No SF3B1 mutations were found in 156 cases of non-Hodgkin lymphoma (605027).

Harbour et al. (2013) described mutations occurring exclusively at codon 625 of the SF3B1 gene in low-grade uveal melanoma (155720) with good prognosis.

Animal Model

Isono et al. (2005) found that homozygous Sf3b1-null mouse embryos died during preimplantation development around the 16- to 32-cell stage. Heterozygous animals appeared normal and healthy; however, they exhibited various skeletal alterations along the anterior-posterior axis. Consistent with the axial changes, expression of several Hox genes was anteriorly extended in the paraxial mesoderm and second branchial arch. Isono et al. (2005) concluded that Sf3b1 regulates Hox gene expression in association with Polycomb group proteins.

REFERENCES

1. Golas, M. M., Sander, B., Will, C. L., Luhrmann, R., Stark, H.Molecular architecture of the multiprotein splicing factor SF3b. Science 300: 980-984, 2003. [PubMed: 12738865] [Full Text: https://doi.org/10.1126/science.1084155\]
2. Gross, M. B.Personal Communication. Baltimore, Md. 2/17/2015.
3. Harbour, J. W., Roberson, E. D. O., Anbunathan, H., Onken, M. D., Worley, L. A., Bowcock, A. M.Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nature Genet. 45: 133-135, 2013. [PubMed: 23313955] [Full Text: https://doi.org/10.1038/ng.2523\]
4. Inoue, D., Chew, G.-L., Liu, B., Michel, B. C., Pangallo, J., D'Avino, A. R., Hitchman, T., North, K., Lee, S. C.-W., Bitner, L., Block, A., Moore, A. R., and 10 others.Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature 574: 432-436, 2019. [PubMed: 31597964] [Full Text: https://doi.org/10.1038/s41586-019-1646-9\]
5. Isono, K., Abe, K., Tomaru, Y., Okazaki, Y., Hayashizaki, Y., Koseki, H.Molecular cloning, genetic mapping, and expression of the mouse Sf3b1 (SAP155) gene for the U2 snRNP component of spliceosome. Mammalian Genome 12: 192-198, 2001. [PubMed: 11252167] [Full Text: https://doi.org/10.1007/s003350010258\]
6. Isono, K., Mizutani-Koseki, Y., Komori, T., Schmidt-Zachmann, M. S., Koseki, H.Mammalian Polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes Dev. 19: 536-541, 2005. [PubMed: 15741318] [Full Text: https://doi.org/10.1101/gad.1284605\]
7. Kramer, A., Mulhauser, F., Wersig, C., Groning, K., Bilbe, G.Mammalian splicing factor SF3a120 represents a new member of the SURP family of proteins and is homologous to the essential splicing factor PRP21p of Saccharomyces cerevisiae. RNA 1: 260-272, 1995. [PubMed: 7489498]
8. Mirtschink, P., Krishnan, J., Grimm, F., Sarre, A., Horl, M., Kayikci, M., Fankhauser, N., Christinat, Y., Cortijo, C., Feehan, O., Vukolic, A., Sossalla, S., Stehr, S. N., Ule, J., Zamboni, N., Pedrazzini, T., Krek, W.HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522: 444-449, 2015. [PubMed: 26083752] [Full Text: https://doi.org/10.1038/nature14508\]
9. Papaemmanuil, E., Cazzola, M., Boultwood, J., Malcovati, L., Vyas, P., Bowen, D., Pellagatti, A., Wainscoat, J. S., Hellstrom-Lindberg, E., Gambacorti-Passerini, C., Godfrey, A. L., Rapado, I., and 36 others.Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. New Eng. J. Med. 365: 1384-1395, 2011. [PubMed: 21995386] [Full Text: https://doi.org/10.1056/NEJMoa1103283\]
10. Quesada, V., Conde, L., Villamor, N., Ordonez, G. R., Jares, P., Bassaganyas, L., Ramsay, A. J., Bea, S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., and 29 others.Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature Genet. 44: 47-52, 2012. [PubMed: 22158541] [Full Text: https://doi.org/10.1038/ng.1032\]
11. Wang, C., Chua, K., Seghezzi, W., Lees, E., Gozani, O., Reed, R.Phosphorylation of spliceosomal protein SAP 155 coupled with splicing catalysis. Genes Dev. 12: 1409-1414, 1998. [PubMed: 9585501] [Full Text: https://doi.org/10.1101/gad.12.10.1409\]
12. Wang, L., Lawrence, M. S., Wan, Y., Stojanov, P., Sougnez, C., Stevenson, K., Werner, L., Sivachenko, A., DeLuca, D. S., Zhang, L., Zhang, W., Vartanov, A. R., and 17 others.SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. New Eng. J. Med. 365: 2497-2506, 2011. [PubMed: 22150006] [Full Text: https://doi.org/10.1056/NEJMoa1109016\]
13. Zhang, Z., Will, C. L., Bertram, K., Dybkov, O., Hartmuth, K., Agafonov, D. E., Hofele, R., Urlaub, H., Kastner, B., Luhrmann, R., Stark, H.Molecular architecture of the human 17S U2 snRNP. Nature 583: 310-313, 2020. [PubMed: 32494006] [Full Text: https://doi.org/10.1038/s41586-020-2344-3\]

Contributors:

Ada Hamosh - updated : 10/01/2020
Ada Hamosh - updated : 04/09/2020
Ada Hamosh - updated : 10/01/2015
Matthew B. Gross - updated : 2/17/2015
Ada Hamosh - updated : 9/5/2014
Ada Hamosh - updated : 4/11/2013
Cassandra L. Kniffin - updated : 1/25/2012
Cassandra L. Kniffin - updated : 10/24/2011
Patricia A. Hartz - updated : 4/19/2005
Ada Hamosh - updated : 5/29/2003
Victor A. McKusick - updated : 6/4/2001

Creation Date:

Paul J. Converse : 1/26/2001

Edit History:

alopez : 10/01/2020
alopez : 04/09/2020
carol : 10/04/2016
alopez : 10/01/2015
alopez : 6/3/2015
mgross : 2/17/2015
alopez : 9/5/2014
alopez : 9/5/2014
alopez : 4/11/2013
mgross : 2/16/2012
carol : 2/1/2012
ckniffin : 1/25/2012
carol : 10/25/2011
terry : 10/25/2011
ckniffin : 10/24/2011
mgross : 4/21/2005
terry : 4/19/2005
alopez : 5/29/2003
terry : 5/29/2003
mcapotos : 6/6/2001
mcapotos : 6/5/2001
terry : 6/4/2001
mgross : 1/26/2001