title: ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Violet
authors.initials: V
authors.lastname: Gelowani
authors.affiliation: 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.
authors.forename: Aiden
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Marielle P
authors.initials: MP
authors.lastname: Young
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Briana L
authors.initials: BL
authors.lastname: Sawyer
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Glen
authors.initials: G
authors.lastname: Jenkins
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Donnell J
authors.initials: DJ
authors.lastname: Creel
authors.affiliation: 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.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Ge
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hartnett
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics*; D000367:Age Factors; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008266:Macula Lutea; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6