title: Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.
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.
authors.affiliation: 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.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
authors.forename: Yajing Angela
authors.initials: YA
authors.lastname: Xie
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Hana
authors.initials: H
authors.lastname: Abouzeid
authors.affiliation: 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.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Zixi
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Medical Genetics, The University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Department of Ophthalmology, Cairo University, Cairo 11562, Egypt.
authors.forename: Ihab S
authors.initials: IS
authors.lastname: Osman
authors.affiliation: 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.
authors.forename: Rachayata
authors.initials: R
authors.lastname: Dharmat
authors.affiliation: 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.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riveiro-Alvarez
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Linda
authors.initials: L
authors.lastname: Bapst-Wicht
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Darwin
authors.initials: D
authors.lastname: Babino
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: 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.
authors.forename: Virginia
authors.initials: V
authors.lastname: Busetto
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lopez-Martinez
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Liliana F
authors.initials: LF
authors.lastname: Azevedo
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: 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.
authors.forename: Aiden
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: 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.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorda-Sanchez
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Valeria
authors.initials: V
authors.lastname: Kheir
authors.affiliation: Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: 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.
authors.forename: Myriam
authors.initials: M
authors.lastname: Oufadem
authors.affiliation: 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.
authors.forename: Zachry T
authors.initials: ZT
authors.lastname: Soens
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Lizhu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Genomic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allaman-Pillet
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: 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.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: 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.
authors.forename: Smriti A
authors.initials: SA
authors.lastname: Agrawal
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Huajin
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Pinton
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Besmond
authors.affiliation: 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.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Institut de Biologie de l'ENS (IBENS), CNRS UMR 8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, 75005 Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Hir
authors.affiliation: Department of Biochemistry and Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Stoilov
authors.affiliation: 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.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Sui
authors.affiliation: 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: ruichen@bcm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: 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: rla22@cumc.columbia.edu.
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.affiliation: Institute for Research in Ophthalmology, 1950 Sion, Switzerland; University of Lausanne and Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D021983:Cyclophilins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics*; D055815:Young Adult
chemical_list: C000600171:Cwc27 protein, human; D021983:Cyclophilins; C000617757:CWC27 spliceosome-associated protein, mouse; D019696:Peptidylprolyl Isomerase
keywords: CRISPR-Cas9; CWC27; brachydachtyly; craniofacial defects; neurological defects; retinal degeneration; short stature; spliceosome; syndrome