Multiexon deletion alleles of ATF6 linked to achromatopsia.

Autor: Lee EJ; Department of Ophthalmology, Shiley Eye Institute, and.; Department of Pathology, UCSD, San Diego, California, USA.; Department of Ophthalmology, Stanford University, Stanford, California, USA., Chiang WJ; Department of Pathology, UCSD, San Diego, California, USA.; Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan., Kroeger H; Department of Pathology, UCSD, San Diego, California, USA.; Department of Cellular Biology, University of Georgia, Athens, Georgia, USA., Bi CX; Department of Pathology, UCSD, San Diego, California, USA., Chao DL; Department of Ophthalmology, Shiley Eye Institute, and., Skowronska-Krawczyk D; Department of Ophthalmology, Shiley Eye Institute, and., Mastey RR; Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Tsang SH; Departments of Ophthalmology and Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA., Chea L; Department of Pathology, Stanford University, Stanford, California, USA., Kim K; Department of Pathology, UCSD, San Diego, California, USA., Lambert SR; Department of Ophthalmology, Stanford University, Stanford, California, USA., Grandjean JM; Department of Molecular Medicine, The Scripps Research Institute, San Diego, California, USA., Baumann B; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Audo I; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DGOS CIC1423, Paris, France., Kohl S; Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany., Moore AT; Department of Ophthalmology, UCSF, San Francisco, California, USA., Wiseman RL; Department of Molecular Medicine, The Scripps Research Institute, San Diego, California, USA., Carroll J; Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Lin JH; Department of Ophthalmology, Stanford University, Stanford, California, USA.; Department of Pathology, Stanford University, Stanford, California, USA.; VA Palo Alto Healthcare System, Palo Alto, California, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2020 Apr 09; Vol. 5 (7). Date of Electronic Publication: 2020 Apr 09.
DOI: 10.1172/jci.insight.136041
Abstrakt: 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: MEDLINE