June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Mutations in spliceosome-associated protein homolog CWC27 lead to a spectrum of syndromic and nonsydromic retinal degeneration disease
Author Affiliations & Notes
  • Rui Chen
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • mingchu xu
    Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Yajing Xie
    Department of Ophthalmology, Columbia University, New York, New York, United States
  • Hana Abouzeid
    Institute for Research in Ophthalmology, Sion, Switzerland
  • Christopher Gordon
    Université Paris Descartes, Institut Imagine, Paris, France
  • Alessia Fiorentino
    Institute of Ophthalmology, University College London, London, United Kingdom
  • Zixi Sun
    Department of Ophthalmology, Peking Union Medical School, Beijing, China
  • Anna Lehman
    Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada
  • Carmen Ayuso
    Department of Genetics, Instituto de Investigacion Sanitaria-University Hospital Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain
  • Alison J Hardcastle
    Institute of Ophthalmology, University College London, London, United Kingdom
  • Ruifang Sui
    Department of Ophthalmology, Peking Union Medical School, Beijing, China
  • Rando Allikmets
    Department of Ophthalmology, Columbia University, New York, New York, United States
  • Daniel F Schorderet
    Institute for Research in Ophthalmology, Sion, Switzerland
  • Footnotes
    Commercial Relationships   Rui Chen, None; mingchu xu, None; Yajing Xie, None; Hana Abouzeid, None; Christopher Gordon, None; Alessia Fiorentino, None; Zixi Sun, None; Anna Lehman, None; Carmen Ayuso, None; Alison Hardcastle, None; Ruifang Sui, None; Rando Allikmets, None; Daniel Schorderet, None
  • Footnotes
    Support  NIH Grant EY018571, EY002520. Retinal Research Foundation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3818. doi:
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      Rui Chen, mingchu xu, Yajing Xie, Hana Abouzeid, Christopher Gordon, Alessia Fiorentino, Zixi Sun, Anna Lehman, Carmen Ayuso, Alison J Hardcastle, Ruifang Sui, Rando Allikmets, Daniel F Schorderet; Mutations in spliceosome-associated protein homolog CWC27 lead to a spectrum of syndromic and nonsydromic retinal degeneration disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3818.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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 phenotypes in humans: skeletal and craniofacial developmental defects or non-syndromic retinitis pigmentosa (RP). We aim at identify additional spliceosome components whose mutation leads to RP.

Methods : Whole exome and whole genome sequencing were performed to identify mutations in a large cohort of patients with inherited retinal diseases. Knock out and knock in mice that carry the same mutation as identified in patients were generated for phenotyping validation and subsequent functional studies.

Results : We have identified CWC27 as the first spliceosome-associated protein that is linked to a spectrum of disease phenotypes when mutated. Mutations in CWC27 have been found in seven unrelated families that show a range of clinical phenotypes, ranging from retinal degeneration coupled with abnormal skeleton, craniofacial, and neurodevelopment defects to nonsyndromic Leber congenital Amaurosis (LCA) and RP. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models. Cwc27 complete knockout mice show significant pre-weaning lethality, and the viable mice present growth retardation and retinal abnormalities. CRISPR-Cas system generated another Cwc27 mutant knock in mouse line with a frameshift mutation near the C-terminal. These mice show no lethality with only retinal degeneration, mimicking the nonsyndromic LCA/RP phenotype.

Conclusions : Our finding established a novel disease-causing gene CWC27 for an LCA/RP-related Mendelian phenotype spectrum. Furthermore, the Cwc27 knock out and knock in mice will serve as unique animal models to reveal the role of spliceosome factors in retinal function maintenance and global development process.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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