Qing Fu1,2, Mingchu Xu3,4, Xue Chen5, Xunlun Sheng6, Zhisheng Yuan1, Yani Liu6, Huajin Li1, Zixi Sun1, Huiping Li6, Lizhu Yang1, Keqing Wang3,4, Fangxia Zhang6, Yumei Li3,4, Chen Zhao5, Ruifang Sui1, Rui Chen3,4. 1. Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China. 2. Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 4. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. 5. Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. 6. Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First affiliated hospital of Northwest University for Nationalities), Yinchuan, Ningxia, China.
Abstract
BACKGROUND: Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20-30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. METHODS: Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. RESULTS: Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone-rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. CONCLUSIONS: Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
BACKGROUND:Usher syndrome is a genetically heterogeneous disorder featured by combined visual impairment and hearing loss. Despite a dozen of genes involved in Usher syndrome having been identified, the genetic basis remains unknown in 20-30% of patients. In this study, we aimed to identify the novel disease-causing gene of a distinct subtype of Usher syndrome. METHODS: Ophthalmic examinations and hearing tests were performed on patients with Usher syndrome in two consanguineous families. Target capture sequencing was initially performed to screen causative mutations in known retinal disease-causing loci. Whole exome sequencing (WES) and whole genome sequencing (WGS) were applied for identifying novel disease-causing genes. RT-PCR and Sanger sequencing were performed to evaluate the splicing-altering effect of identified CEP78 variants. RESULTS:Patients from the two independent families show a mild Usher syndrome phenotype featured by juvenile or adult-onset cone-rod dystrophy and sensorineural hearing loss. WES and WGS identified two homozygous rare variants that affect mRNA splicing of a ciliary gene CEP78. RT-PCR confirmed that the two variants indeed lead to abnormal splicing, resulting in premature stop of protein translation due to frameshift. CONCLUSIONS: Our results provide evidence that CEP78 is a novel disease-causing gene for Usher syndrome, demonstrating an additional link between ciliopathy and Usher protein network in photoreceptor cells and inner ear hair cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Jacob A Tennessen; Abigail W Bigham; Timothy D O'Connor; Wenqing Fu; Eimear E Kenny; Simon Gravel; Sean McGee; Ron Do; Xiaoming Liu; Goo Jun; Hyun Min Kang; Daniel Jordan; Suzanne M Leal; Stacey Gabriel; Mark J Rieder; Goncalo Abecasis; David Altshuler; Deborah A Nickerson; Eric Boerwinkle; Shamil Sunyaev; Carlos D Bustamante; Michael J Bamshad; Joshua M Akey Journal: Science Date: 2012-05-17 Impact factor: 47.728
Authors: Marie-Laure Fogeron; Hannah Müller; Sophia Schade; Felix Dreher; Verena Lehmann; Anne Kühnel; Anne-Kathrin Scholz; Karl Kashofer; Alexandra Zerck; Beatrix Fauler; Rudi Lurz; Ralf Herwig; Kurt Zatloukal; Hans Lehrach; Johan Gobom; Eckhard Nordhoff; Bodo M H Lange Journal: Nat Commun Date: 2013 Impact factor: 14.919
Authors: Barbara E Tanos; Hui-Ju Yang; Rajesh Soni; Won-Jing Wang; Frank P Macaluso; John M Asara; Meng-Fu Bryan Tsou Journal: Genes Dev Date: 2013-01-15 Impact factor: 11.361
Authors: Bruce M Psaty; Christopher J O'Donnell; Vilmundur Gudnason; Kathryn L Lunetta; Aaron R Folsom; Jerome I Rotter; André G Uitterlinden; Tamara B Harris; Jacqueline C M Witteman; Eric Boerwinkle Journal: Circ Cardiovasc Genet Date: 2009-02
Authors: Rosalie M Nolen; Robert B Hufnagel; Thomas B Friedman; Amy E Turriff; Carmen C Brewer; Christopher K Zalewski; Kelly A King; Talah T Wafa; Andrew J Griffith; Brian P Brooks; Wadih M Zein Journal: Ophthalmic Genet Date: 2020-05-06 Impact factor: 1.803
Authors: Eric Nisenbaum; Torin P Thielhelm; Aida Nourbakhsh; Denise Yan; Susan H Blanton; Yilai Shu; Karl R Koehler; Aziz El-Amraoui; Zhengyi Chen; Byron L Lam; Xuezhong Liu Journal: Ear Hear Date: 2022 Jan/Feb Impact factor: 3.562
Authors: Arif O Khan; Elvir Becirovic; Christian Betz; Christine Neuhaus; Janine Altmüller; Lisa Maria Riedmayr; Susanne Motameny; Gudrun Nürnberg; Peter Nürnberg; Hanno J Bolz Journal: Sci Rep Date: 2017-05-03 Impact factor: 4.379
Authors: Giulia Ascari; Frank Peelman; Pietro Farinelli; Toon Rosseel; Nina Lambrechts; Kirsten A Wunderlich; Matias Wagner; Konstantinos Nikopoulos; Pernille Martens; Irina Balikova; Lara Derycke; Gabriële Holtappels; Olga Krysko; Thalia Van Laethem; Sarah De Jaegere; Brecht Guillemyn; Riet De Rycke; Jan De Bleecker; David Creytens; Jo Van Dorpe; Jan Gerris; Claus Bachert; Christiane Neuhofer; Sophie Walraedt; Almut Bischoff; Lotte B Pedersen; Thomas Klopstock; Carlo Rivolta; Bart P Leroy; Elfride De Baere; Frauke Coppieters Journal: Hum Mutat Date: 2020-02-12 Impact factor: 4.878
Authors: Austin D Igelman; Cristy Ku; Mariana Matioli da Palma; Michalis Georgiou; Elena R Schiff; Byron L Lam; Eeva-Marja Sankila; Jeeyun Ahn; Lindsey Pyers; Ajoy Vincent; Juliana Maria Ferraz Sallum; Wadih M Zein; Jin Kyun Oh; Ramiro S Maldonado; Joseph Ryu; Stephen H Tsang; Michael B Gorin; Andrew R Webster; Michel Michaelides; Paul Yang; Mark E Pennesi Journal: Ophthalmic Genet Date: 2021-07-05 Impact factor: 1.274