Multiexon deletion alleles of ATF6 linked to achromatopsia

JCI Insight. 2020 Apr 9;5(7):e136041. doi: 10.1172/jci.insight.136041.


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.

Keywords: Cell stress; Ophthalmology.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activating Transcription Factor 6 / genetics*
  • Adolescent
  • Alleles*
  • Base Sequence*
  • Color Vision Defects / genetics*
  • Exons*
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Sequence Deletion*


  • ATF6 protein, human
  • Activating Transcription Factor 6

Supplementary concepts

  • Achromatopsia 3