2. Academic Validation
  3. Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

  • Am J Hum Genet. 2017 Apr 6;100(4):592-604. doi: 10.1016/j.ajhg.2017.02.008.
Mingchu Xu 1,  Yajing Angela Xie 2,  Hana Abouzeid 3,  Christopher T Gordon 4,  Alessia Fiorentino 5,  Zixi Sun 6,  Anna Lehman 7,  Ihab S Osman 8,  Rachayata Dharmat 1,  Rosa Riveiro-Alvarez 9,  Linda Bapst-Wicht 3,  Darwin Babino 10,  Gavin Arno 11,  Virginia Busetto 12,  Li Zhao 13,  Hui Li 6,  Miguel A Lopez-Martinez 9,  Liliana F Azevedo 3,  Laurence Hubert 14,  Nikolas Pontikos 15,  Aiden Eblimit 1,  Isabel Lorda-Sanchez 9,  Valeria Kheir 3,  Vincent Plagnol 16,  Myriam Oufadem 4,  Zachry T Soens 1,  Lizhu Yang 6,  Christine Bole-Feysot 17,  Rolph Pfundt 18,  Nathalie Allaman-Pillet 3,  Patrick Nitschké 19,  Michael E Cheetham 5,  Stanislas Lyonnet 20,  Smriti A Agrawal 1,  Huajin Li 6,  Gaëtan Pinton 3,  Michel Michaelides 11,  Claude Besmond 14,  Yumei Li 1,  Zhisheng Yuan 6,  Johannes von Lintig 10,  Andrew R Webster 11,  Hervé Le Hir 21,  Peter Stoilov 22,  UK Inherited Retinal Dystrophy Consortium,  Jeanne Amiel 20,  Alison J Hardcastle 5,  Carmen Ayuso 9,  Ruifang Sui 6,  Rui Chen 23,  Rando Allikmets 24,  Daniel F Schorderet 25
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
  • 3 Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
  • 4 Laboratory of embryology and genetics of congenital malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
  • 5 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
  • 6 Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
  • 7 Department of Medical Genetics, The University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 8 Department of Ophthalmology, Cairo University, Cairo 11562, Egypt.
  • 9 Department of Genetics, Instituto de Investigación Sanitaria - Fundacion Jimenez Diaz (IIS-FJD), 28040 Madrid, Spain; Centros de Investigación Biomédica en Red Enfermedades Raras, Instituto de Salud Carlos III (CIBERER-ISCIII), 28029 Madrid, Spain.
  • 10 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
  • 11 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • 12 Laboratory of embryology and genetics of congenital malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, 75015 Paris, France; Institut de Biologie de l'ENS (IBENS), CNRS UMR 8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, 75005 Paris, France.
  • 13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 14 Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • 15 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Genetics Institute, University College London, London WC1E 6BT, UK.
  • 16 Genetics Institute, University College London, London WC1E 6BT, UK.
  • 17 Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Genomic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • 18 Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, the Netherlands.
  • 19 Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • 20 Laboratory of embryology and genetics of congenital malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
  • 21 Institut de Biologie de l'ENS (IBENS), CNRS UMR 8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, 75005 Paris, France.
  • 22 Department of Biochemistry and Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.
  • 23 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
  • 24 Department of Ophthalmology, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: [email protected].
  • 25 Institute for Research in Ophthalmology, 1950 Sion, Switzerland; University of Lausanne and Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
PMID: 28285769 DOI: 10.1016/j.ajhg.2017.02.008
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.

Keywords

CRISPR-Cas9; CWC27; brachydachtyly; craniofacial defects; neurological defects; retinal degeneration; short stature; spliceosome; syndrome.

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