June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Multi-Exon Deletion Alleles of ATF6 Linked to Achromatopsia
Author Affiliations & Notes
  • Kyle Kim
    Pathology, University of California, San Diego, San Diego, California, United States
  • Eun-Jin Lee
    Pathology, University of California, San Diego, San Diego, California, United States
    Ophthalmology, Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • Wei-Chieh Chiang
    Pathology, University of California, San Diego, San Diego, California, United States
  • Heike Kroeger
    Pathology, University of California, San Diego, San Diego, California, United States
  • Chloe Xiaoke Bi
    Pathology, University of California, San Diego, San Diego, California, United States
  • Daniel L Chao
    Ophthalmology, Shiley Eye Institute, University of California, San Diego, La Jolla, California, United States
  • Rebecca Mastey
    Ophthalmology & Visual Sciences, Medical College of Wisconsin, Wisconsin, United States
  • Stephen Tsang
    Ophthalmology, Columbia University, New York City, New York, United States
  • Leon Chea
    Pathology, Stanford Univeristy, Palo Alto, California, United States
  • Britta Baumann
    Institute for Ophthalmic Research, University of Tuebingen, Germany
  • Isabelle S Audo
    Institut de la Vision, Sorbonne Université, France
  • Susanne Kohl
    Institute for Ophthalmic Research, University of Tuebingen, Germany
  • Anthony Moore
    Ophthalmology, UC San Francisco, California, United States
  • Luke Wiseman
    Molecular Experimental Medicine, Scripps Research Institute, La Jolla, California, United States
  • Joseph Carroll
    Ophthalmology & Visual Sciences, Medical College of Wisconsin, Wisconsin, United States
  • Jonathan H Lin
    Pathology, Stanford Univeristy, Palo Alto, California, United States
    Ophthalmology, Stanford University, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Kyle Kim, None; Eun-Jin Lee, None; Wei-Chieh Chiang, None; Heike Kroeger, None; Chloe Bi, None; Daniel Chao, None; Rebecca Mastey, None; Stephen Tsang, None; Leon Chea, None; Britta Baumann, None; Isabelle Audo, None; Susanne Kohl, None; Anthony Moore, None; Luke Wiseman, None; Joseph Carroll, None; Jonathan Lin, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2393. doi:
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      Kyle Kim, Eun-Jin Lee, Wei-Chieh Chiang, Heike Kroeger, Chloe Xiaoke Bi, Daniel L Chao, Rebecca Mastey, Stephen Tsang, Leon Chea, Britta Baumann, Isabelle S Audo, Susanne Kohl, Anthony Moore, Luke Wiseman, Joseph Carroll, Jonathan H Lin; Multi-Exon Deletion Alleles of ATF6 Linked to Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2393.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Achromatopsia (ACHM) is an autosomal recessive cone photoreceptor dysfunction
disease. Patients have congenital severely impaired visual acuity, photoaversion, foveal
hypoplasia, and color vision defects. To date, 11 different ATF6A disease alleles have been
identified in ACHM patients. Here, we identified and characterized two additional multi-exon
spanning ATF6A disease alleles identified in ACHM patients.

Methods : Genetic sequencing were performed in three patients from two families with the cone
dysfunction. All three patients were clinically investigated by spectral domain-optical coherence
tomography (SD-OCT) and electroretinography (ERG). Triple-labeling In situ RNA
hybridization was performed using RNA scope assay. For the experiment, RNA oligo probes
specific for the mRNA of human retinal cone arrestin-3 (Arr3), ATF6A, and ATF6B were used in
vertical cross-sections of the human retina.

Results : A homozygous deletion covering exons 8 to 14 of the ATF6A gene from two siblings
from one family was identified. In another patient, a heterozygous deletion covering exons 2 and
3 of the ATF6A gene was identified. All patients showed evidence of foveal hypoplasia and loss
of photopic ERG response. In addition, recombinant ATF6 proteins bearing these exon deletions
showed significantly impaired transcriptional activity compared to wild-type ATF6. Last, the
RNAscope assay revealed that ATF6A and the related ATF6B transcripts are both expressed in
cones and also throughout all retinal layers of normal human retina.

Conclusions : Overall, our data identifies additional loss-of-function ATF6A disease alleles
associated with human foveal disease and cone dysfunction. Our data also raises the possibility
that ATF6-associated achromatopsia may arise from cone cell-autonomous and cone cell non-
autonomous etiologies.

This is a 2020 ARVO Annual Meeting abstract.

 

Pedigrees and topography of disease-causing mutations identified in the patients. (A) Pedigree drawing of exons 8-14 ATF6 deletion and exons 2-3 ATF6 deletion patients. (B) The amino acid organization, protein topology, and functional domains of ATF6 are shown, and the positions of the ATF6 variants are mapped onto the schematic drawing.

Pedigrees and topography of disease-causing mutations identified in the patients. (A) Pedigree drawing of exons 8-14 ATF6 deletion and exons 2-3 ATF6 deletion patients. (B) The amino acid organization, protein topology, and functional domains of ATF6 are shown, and the positions of the ATF6 variants are mapped onto the schematic drawing.

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