Multiexon deletion alleles of ATF6 linked to achromatopsia
| Autor: | Daniel L. Chao, Jonathan H. Lin, Anthony T. Moore, Isabelle Audo, Rebecca Mastey, Chloe Xiaoke Bi, Dorota Skowronska-Krawczyk, Britta Baumann, Kyle Kim, Leon Chea, Wei-Chieh Chiang, Susanne Kohl, R. Luke Wiseman, Joseph Carroll, Eun-Jin Lee, Scott R. Lambert, Heike Kroeger, Julia M. D. Grandjean, Stephen H. Tsang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Achromatopsia Adolescent genetic structures Color Vision Defects Biology Exon chemistry.chemical_compound medicine Humans Allele Gene Alleles Sequence Deletion Genetics Retina Base Sequence medicine.diagnostic_test Retinal Exons General Medicine medicine.disease eye diseases Activating Transcription Factor 6 HEK293 Cells medicine.anatomical_structure chemistry Female Trans-acting Research Article Electroretinography |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.136041 |
| Popis: | Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8-14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease. |
| Databáze: | OpenAIRE |
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