ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement.

TitleATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement.
Publication TypeJournal Article
Year of Publication2015
AuthorsXu, M, Gelowani, V, Eblimit, A, Wang, F, Young, MP, Sawyer, BL, Zhao, L, Jenkins, G, Creel, DJ, Wang, K, Ge, Z, Wang, H, Li, Y, M Hartnett, E, Chen, R
JournalInvest Ophthalmol Vis Sci
Date Published2015 Jun
KeywordsActivating Transcription Factor 6, Age Factors, Child, Preschool, Female, Humans, Macula Lutea, Mutation, Photoreceptor Cells, Vertebrate, Retinal Diseases

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.

Alternate JournalInvest. Ophthalmol. Vis. Sci.
PubMed ID26070061
PubMed Central IDPMC4468593
Grant List1S10RR026550 / RR / NCRR NIH HHS / United States
2T32EY007102-21A1 / EY / NEI NIH HHS / United States
HHS-N-260-2007-00001-C / / PHS HHS / United States
R01 EY017011 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
R01EY018571 / EY / NEI NIH HHS / United States
R01EY022356 / EY / NEI NIH HHS / United States
/ / Intramural NIH HHS / United States

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