%0 Journal Article
%T Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies
%A Aiden Eblimit
%A Alessia Fiorentino
%A Alison J. Hardcastle
%A Andrew R. Webster
%A Anna Lehman
%A Carmen Ayuso
%A Christine Bole-Feysot
%A Christopher T. Gordon
%A Claude Besmond
%A Daniel F. Schorderet
%A Darwin Babino
%A Gavin Arno
%A Ga£¿tan Pinton
%A Hana Abouzeid
%A Herv¨¦ Le Hir
%A Huajin Li
%A Hui Li
%A Ihab S. Osman
%A Isabel Lorda-Sanchez
%A Jeanne Amiel
%A Johannes von Lintig
%A Laurence Hubert
%A Liliana F. Azevedo
%A Linda Bapst-Wicht
%A Lizhu Yang
%A Michael E. Cheetham
%A Michel Michaelides
%A Miguel A. Lopez-Martinez
%A Mingchu Xu
%A Myriam Oufadem
%A Nathalie Allaman-Pillet
%A Nikolas Pontikos
%A Patrick Nitschk¨¦
%A Peter Stoilov
%A Rachayata Dharmat
%A Rando Allikmets
%A Rolph Pfundt
%A Rosa Riveiro-Alvarez
%A Rui Chen
%A Ruifang Sui
%A Smriti A. Agrawal
%A Stanislas Lyonnet
%A UK Inherited Retinal Dystrophy Consortium
%A Valeria Kheir
%A Vincent Plagnol
%A Virginia Busetto
%A Yajing (Angela) Xie
%A Yumei Li
%A Zachry T. Soens
%A Zhisheng Yuan
%A Zixi Sun
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2017.02.008
%X 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
%K CWC27
%K spliceosome
%K retinal degeneration
%K brachydachtyly
%K craniofacial defects
%K neurological defects
%K short stature
%K syndrome
%K CRISPR-Cas9
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384039/