The Role of the U5 snRNP in Genetic Disorders and Cancer
Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting th...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.636620/full |
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| author | Katherine A. Wood Katherine A. Wood Megan A. Eadsforth William G. Newman William G. Newman Raymond T. O’Keefe |
| author_facet | Katherine A. Wood Katherine A. Wood Megan A. Eadsforth William G. Newman William G. Newman Raymond T. O’Keefe |
| author_sort | Katherine A. Wood |
| collection | DOAJ |
| description | Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes – variants in PRPF6, PRPF8, and SNRP200 are associated with retinitis pigmentosa (RP), while variants in EFTUD2 and TXNL4A cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (PRPF6, PRPF8, EFTUD2, DDX23, and SNRNP40) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes – RP, craniofacial defects or cancer – is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders. |
| first_indexed | 2024-12-16T15:45:58Z |
| format | Article |
| id | doaj.art-8b8a6ed4612b4b04b531bdbc39e33865 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-16T15:45:58Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-8b8a6ed4612b4b04b531bdbc39e338652022-12-21T22:25:48ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-01-011210.3389/fgene.2021.636620636620The Role of the U5 snRNP in Genetic Disorders and CancerKatherine A. Wood0Katherine A. Wood1Megan A. Eadsforth2William G. Newman3William G. Newman4Raymond T. O’Keefe5Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, United KingdomDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomManchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, United KingdomDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United KingdomPre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes – variants in PRPF6, PRPF8, and SNRP200 are associated with retinitis pigmentosa (RP), while variants in EFTUD2 and TXNL4A cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (PRPF6, PRPF8, EFTUD2, DDX23, and SNRNP40) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes – RP, craniofacial defects or cancer – is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.https://www.frontiersin.org/articles/10.3389/fgene.2021.636620/fulldiseasecancerU5 snRNPpre-mRNA splicingretinitis pigmentosaBurn-McKeown syndrome |
| spellingShingle | Katherine A. Wood Katherine A. Wood Megan A. Eadsforth William G. Newman William G. Newman Raymond T. O’Keefe The Role of the U5 snRNP in Genetic Disorders and Cancer Frontiers in Genetics disease cancer U5 snRNP pre-mRNA splicing retinitis pigmentosa Burn-McKeown syndrome |
| title | The Role of the U5 snRNP in Genetic Disorders and Cancer |
| title_full | The Role of the U5 snRNP in Genetic Disorders and Cancer |
| title_fullStr | The Role of the U5 snRNP in Genetic Disorders and Cancer |
| title_full_unstemmed | The Role of the U5 snRNP in Genetic Disorders and Cancer |
| title_short | The Role of the U5 snRNP in Genetic Disorders and Cancer |
| title_sort | role of the u5 snrnp in genetic disorders and cancer |
| topic | disease cancer U5 snRNP pre-mRNA splicing retinitis pigmentosa Burn-McKeown syndrome |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.636620/full |
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