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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gelowani, Violet Creel, Donnell J. Zhao, Li Wang, Hui Ge, Zhongqi Xu, Mingchu Chen, Rui Wang, Feng Hartnett, M. Elizabeth Li, Yumei Eblimit, Aiden Sawyer, Briana L. Wang, Keqing Young, Marielle P. Jenkins, Glen |
| Description | Country affiliation: United States Author Affiliation: Xu M ( 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.); Gelowani V ( 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.); Eblimit A ( 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.); Wang F ( 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.); Young MP ( Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.); Sawyer BL ( Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.); Zhao L ( 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.); Jenkins G ( Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.); Creel DJ ( Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.); Wang K ( 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.); Ge Z ( 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.); Wang H ( 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.); Li Y ( 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.); Hartnett ME ( Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.); Chen R ( 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. |
| ISSN | 01460404 |
| e-ISSN | 15525783 |
| DOI | 10.1167/iovs.15-16778 |
| Journal | Investigative Opthalmology & Visual Science |
| Issue Number | 6 |
| Volume Number | 56 |
| Language | English |
| Publisher | Association for Research in Vision and Ophthalmology |
| Publisher Date | 2015-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Activating Transcription Factor 6 Genetics Macula Lutea Mutation Photoreceptor Cells, Vertebrate Pathology Retinal Diseases Child, Preschool Research Support, N.i.h., Extramural Research Support, N.i.h., Intramural Research Support, Non-u.s. Gov't Discipline Ophthalmology |
| Content Type | Text |
| Resource Type | Article Case study |
| Subject | Ophthalmology Sensory Systems Cellular and Molecular Neuroscience |
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