Mingchu Xu1, Violet Gelowani1, Aiden Eblimit1, Feng Wang1, Marielle P Young2, Briana L Sawyer2, Li Zhao3, Glen Jenkins2, Donnell J Creel2, Keqing Wang1, Zhongqi Ge1, Hui Wang1, Yumei Li1, M Elizabeth Hartnett2, Rui Chen3. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States 2Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States. 2. Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States 2Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States 4Structural and Computational Biology and Molecular Biophysics.
Abstract
PURPOSE: Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. METHODS: Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. RESULTS: The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. CONCLUSIONS: Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.
PURPOSE: Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. METHODS: Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. RESULTS: The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. CONCLUSIONS: Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying humanretinal degeneration.
Authors: Feng Wang; Hui Wang; Han-Fang Tuan; Duy H Nguyen; Vincent Sun; Vafa Keser; Sara J Bowne; Lori S Sullivan; Hongrong Luo; Ling Zhao; Xia Wang; Jacques E Zaneveld; Jason S Salvo; Sorath Siddiqui; Louise Mao; Dianna K Wheaton; David G Birch; Kari E Branham; John R Heckenlively; Cindy Wen; Ken Flagg; Henry Ferreyra; Jacqueline Pei; Ayesha Khan; Huanan Ren; Keqing Wang; Irma Lopez; Raheel Qamar; Juan C Zenteno; Raul Ayala-Ramirez; Beatriz Buentello-Volante; Qing Fu; David A Simpson; Yumei Li; Ruifang Sui; Giuliana Silvestri; Stephen P Daiger; Robert K Koenekoop; Kang Zhang; Rui Chen Journal: Hum Genet Date: 2013-10-24 Impact factor: 4.132
Authors: T M Strom; K Hörtnagel; S Hofmann; F Gekeler; C Scharfe; W Rabl; K D Gerbitz; T Meitinger Journal: Hum Mol Genet Date: 1998-12 Impact factor: 6.150
Authors: Heike Kroeger; Neil Grimsey; Ryan Paxman; Wei-Chieh Chiang; Lars Plate; Ying Jones; Peter X Shaw; JoAnn Trejo; Stephen H Tsang; Evan Powers; Jeffery W Kelly; R Luke Wiseman; Jonathan H Lin Journal: Sci Signal Date: 2018-02-13 Impact factor: 8.192