eprintid: 1546386 rev_number: 62 eprint_status: archive userid: 608 dir: disk0/01/54/63/86 datestamp: 2017-04-03 13:34:25 lastmod: 2021-09-19 23:59:22 status_changed: 2017-04-03 13:34:25 type: article metadata_visibility: show creators_name: Xu, M creators_name: Xie, YA creators_name: Abouzeid, H creators_name: Gordon, CT creators_name: Fiorentino, A creators_name: Sun, Z creators_name: Lehman, A creators_name: Osman, IS creators_name: Dharmat, R creators_name: Riveiro-Alvarez, R creators_name: Bapst-Wicht, L creators_name: Babino, D creators_name: Arno, G creators_name: Busetto, V creators_name: Zhao, L creators_name: Li, H creators_name: Lopez-Martinez, MA creators_name: Azevedo, LF creators_name: Hubert, L creators_name: Pontikos, N creators_name: Eblimit, A creators_name: Lorda-Sanchez, I creators_name: Kheir, V creators_name: Plagnol, V creators_name: Oufadem, M creators_name: Soens, ZT creators_name: Yang, L creators_name: Bole-Feysot, C creators_name: Pfundt, R creators_name: Allaman-Pillet, N creators_name: Nitschké, P creators_name: Cheetham, ME creators_name: Lyonnet, S creators_name: Agrawal, SA creators_name: Li, H creators_name: Pinton, G creators_name: Michaelides, M creators_name: Besmond, C creators_name: Li, Y creators_name: Yuan, Z creators_name: von Lintig, J creators_name: Webster, AR creators_name: Le Hir, H creators_name: Stoilov, P creators_name: UK Inherited Retinal Dystrophy Consortium, . creators_name: Amiel, J creators_name: Hardcastle, AJ creators_name: Ayuso, C creators_name: Sui, R creators_name: Chen, R creators_name: Allikmets, R creators_name: Schorderet, DF title: Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D08 divisions: C08 divisions: D09 divisions: F99 keywords: CRISPR-Cas9, CWC27, brachydachtyly, craniofacial defects, neurological defects, retinal degeneration, short stature, spliceosome, syndrome note: Copyright © 2017 American Society of Human Genetics. This manuscript version is made available under the CC-BY-NC-ND 4.0 license (http://creativecommons.org/licenses/by-nc-nd/4.0/) abstract: 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. date: 2017-04-06 date_type: published official_url: http://dx.doi.org/10.1016/j.ajhg.2017.02.008 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1262269 doi: 10.1016/j.ajhg.2017.02.008 pii: S0002-9297(17)30075-7 lyricists_name: Arno, Gavin lyricists_name: Cheetham, Michael lyricists_name: Fiorentino, Alessia lyricists_name: Hardcastle, Alison lyricists_name: Michaelides, Michel lyricists_name: Plagnol, Vincent lyricists_name: Pontikos, Nikolas lyricists_name: Webster, Andrew lyricists_id: GARNO32 lyricists_id: MECHE52 lyricists_id: AFIOR33 lyricists_id: AJHAR52 lyricists_id: MMICH14 lyricists_id: VYPLA47 lyricists_id: NPONT28 lyricists_id: ARWEB82 actors_name: Hardcastle, Alison actors_id: AJHAR52 actors_role: owner full_text_status: public publication: American Journal of Human Genetics volume: 100 number: 4 pagerange: 592-604 event_location: United States issn: 1537-6605 citation: Xu, M; Xie, YA; Abouzeid, H; Gordon, CT; Fiorentino, A; Sun, Z; Lehman, A; ... Schorderet, DF; + view all <#> 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, .; Amiel, J; Hardcastle, AJ; Ayuso, C; Sui, R; Chen, R; Allikmets, R; Schorderet, DF; - view fewer <#> (2017) Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. American Journal of Human Genetics , 100 (4) pp. 592-604. 10.1016/j.ajhg.2017.02.008 <https://doi.org/10.1016/j.ajhg.2017.02.008>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/1/CWC27_AJHG_MX_020817_accepted.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/7/CWC27_figure1_AJHG.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/13/CWC27_figure2_AJHG.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/19/CWC27_figure3_AJHG.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/24/CWC27_figure4_AJHG.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/33/CWC27_figure5_AJHG.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/1546386/39/CWC27_figure6_AJHG.pdf