Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies
Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2017
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| _version_ | 1826289743287025664 |
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| author | Xu, M Xie, YA Abouzeid, H Gordon, CT Fiorentino, A Sun, Z Lehman, A Osman, IS Dharmat, R Riveiro-Alvarez, R Bapst-Wicht, L Babino, D Arno, G Busetto, V Zhao, L Li, H Lopez-Martinez, MA Azevedo, LF Hubert, L Pontikos, N Eblimit, A Lorda-Sanchez, I Kheir, V Plagnol, V Oufadem, M Soens, ZT Yang, L Bole-Feysot, C Pfundt, R Allaman-Pillet, N Nitschké, P Cheetham, ME Lyonnet, S Agrawal, SA Li, H Pinton, G Michaelides, M Besmond, C Li, Y Yuan, Z Von Lintig, J Webster, AR Le Hir, H Stoilov, P UK Inherited Retinal Dystrophy Consortium Halford, S Amiel, J Hardcastle, AJ Ayuso, C Sui, R Chen, R Allikmets, R Schorderet, DF |
| author_facet | Xu, M Xie, YA Abouzeid, H Gordon, CT Fiorentino, A Sun, Z Lehman, A Osman, IS Dharmat, R Riveiro-Alvarez, R Bapst-Wicht, L Babino, D Arno, G Busetto, V Zhao, L Li, H Lopez-Martinez, MA Azevedo, LF Hubert, L Pontikos, N Eblimit, A Lorda-Sanchez, I Kheir, V Plagnol, V Oufadem, M Soens, ZT Yang, L Bole-Feysot, C Pfundt, R Allaman-Pillet, N Nitschké, P Cheetham, ME Lyonnet, S Agrawal, SA Li, H Pinton, G Michaelides, M Besmond, C Li, Y Yuan, Z Von Lintig, J Webster, AR Le Hir, H Stoilov, P UK Inherited Retinal Dystrophy Consortium Halford, S Amiel, J Hardcastle, AJ Ayuso, C Sui, R Chen, R Allikmets, R Schorderet, DF |
| author_sort | Xu, M |
| collection | OXFORD |
| description | Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network. |
| first_indexed | 2024-03-07T02:33:32Z |
| format | Journal article |
| id | oxford-uuid:a808a1e4-379a-4ff4-84ca-df4324613453 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:33:32Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:a808a1e4-379a-4ff4-84ca-df43246134532022-03-27T02:58:50ZMutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomaliesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a808a1e4-379a-4ff4-84ca-df4324613453EnglishSymplectic Elements at OxfordElsevier2017Xu, MXie, YAAbouzeid, HGordon, CTFiorentino, ASun, ZLehman, AOsman, ISDharmat, RRiveiro-Alvarez, RBapst-Wicht, LBabino, DArno, GBusetto, VZhao, LLi, HLopez-Martinez, MAAzevedo, LFHubert, LPontikos, NEblimit, ALorda-Sanchez, IKheir, VPlagnol, VOufadem, MSoens, ZTYang, LBole-Feysot, CPfundt, RAllaman-Pillet, NNitschké, PCheetham, MELyonnet, SAgrawal, SALi, HPinton, GMichaelides, MBesmond, CLi, YYuan, ZVon Lintig, JWebster, ARLe Hir, HStoilov, PUK Inherited Retinal Dystrophy ConsortiumHalford, SAmiel, JHardcastle, AJAyuso, CSui, RChen, RAllikmets, RSchorderet, DFPre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network. |
| spellingShingle | Xu, M Xie, YA Abouzeid, H Gordon, CT Fiorentino, A Sun, Z Lehman, A Osman, IS Dharmat, R Riveiro-Alvarez, R Bapst-Wicht, L Babino, D Arno, G Busetto, V Zhao, L Li, H Lopez-Martinez, MA Azevedo, LF Hubert, L Pontikos, N Eblimit, A Lorda-Sanchez, I Kheir, V Plagnol, V Oufadem, M Soens, ZT Yang, L Bole-Feysot, C Pfundt, R Allaman-Pillet, N Nitschké, P Cheetham, ME Lyonnet, S Agrawal, SA Li, H Pinton, G Michaelides, M Besmond, C Li, Y Yuan, Z Von Lintig, J Webster, AR Le Hir, H Stoilov, P UK Inherited Retinal Dystrophy Consortium Halford, S Amiel, J Hardcastle, AJ Ayuso, C Sui, R Chen, R Allikmets, R Schorderet, DF Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title | Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title_full | Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title_fullStr | Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title_full_unstemmed | Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title_short | Mutations in the spliceosome component CWC27 cause retinal degeneration with or without additional developmental anomalies |
| title_sort | mutations in the spliceosome component cwc27 cause retinal degeneration with or without additional developmental anomalies |
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