| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| O75533 | Repeat | 529 | 568 | Note=HEAT 1 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 569 | 603 | Note=HEAT 2 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 604 | 641 | Note=HEAT 3 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 643 | 677 | Note=HEAT 4 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 680 | 718 | Note=HEAT 5 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 763 | 801 | Note=HEAT 6 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 843 | 881 | Note=HEAT 7 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 1010 | 1048 | Note=HEAT 8 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 1052 | 1090 | Note=HEAT 9 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 1122 | 1160 | Note=HEAT 10 | Type=Deletion;Start=145;End=1304 |
| O75533 | Repeat | 1163 | 1201 | Note=HEAT 11 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 124 | 148 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Substitution;Start=140;End=144 |
| O75533 | Region | 124 | 148 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 173 | 360 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 190 | 342 | Note=U2AF homology region%3B mediates interaction with RBM39;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:24795046;Dbxref=PMID:24795046 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 223 | 491 | Note=Interaction with PPP1R8;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:12105215;Dbxref=PMID:12105215 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 529 | 568 | Note=Interaction with SF3B14 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 547 | 550 | Note=Interaction with PHF5A;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 1156 | 1157 | Note=Interaction with PHF5A;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 1248 | 1304 | Note=Interaction with SF3B3 and SF3B5;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| O75533 | Compositional bias | 204 | 224 | Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=145;End=1304 |
| O75533 | Compositional bias | 342 | 356 | Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=145;End=1304 |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| O75533-1 | 1.033 | 143 | 1.081 | 392.049 | 0.571 | 0.687 | 0.872 | 0.919 | 0.831 | 1.107 | 1.381 | 73,74,75,76,77,662,666,699,700,703,704,707,714,741
,744,745,748,752,783,786,787,790,791,793,827,828,8
30,831,832,835,870
|
| O75533-2 | 0.354 | 10 | 0.263 | 5.488 | 0.762 | 0.451 | 0.686 | 0.047 | 0.935 | 0.051 | 4.233 | 22,25,27
|
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| O75533 | Region | 190 | 342 | Note=U2AF homology region%3B mediates interaction with RBM39;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:24795046;Dbxref=PMID:24795046 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 223 | 491 | Note=Interaction with PPP1R8;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:12105215;Dbxref=PMID:12105215 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 529 | 568 | Note=Interaction with SF3B14 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 547 | 550 | Note=Interaction with PHF5A;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 1156 | 1157 | Note=Interaction with PHF5A;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| O75533 | Region | 1248 | 1304 | Note=Interaction with SF3B3 and SF3B5;Ontology_term=ECO:0000269;evidence=ECO:0000269|PubMed:27720643;Dbxref=PMID:27720643 | Type=Deletion;Start=145;End=1304 |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| SF3B1 | 23861464 | SF3B1 mutations are associated with alternative splicing in uveal melanoma. | Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE. | D008545 | Melanoma |
| SF3B1 | 23861464 | SF3B1 mutations are associated with alternative splicing in uveal melanoma. | Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE. | D014604 | Uveal Neoplasms |
| SF3B1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| SF3B1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| SF3B1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
| SF3B1 | 26842708 | Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. | Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1(R625/K666) mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss. Modelling the differential junctions in SF3B1(WT) and SF3B1(R625/K666) cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1(WT) knockdown or overexpression do not reproduce the SF3B1(R625/K666) splice pattern, qualifying SF3B1(R625/K666) as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1(R625/K666)-promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease. | D008545 | Melanoma |
| SF3B1 | 26842708 | Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. | Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1(R625/K666) mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss. Modelling the differential junctions in SF3B1(WT) and SF3B1(R625/K666) cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1(WT) knockdown or overexpression do not reproduce the SF3B1(R625/K666) splice pattern, qualifying SF3B1(R625/K666) as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1(R625/K666)-promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease. | D014604 | Uveal Neoplasms |
Gene summary
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