June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Mutations in the Unfolded Protein Response regulator, ATF6, cause Achromatopsia
Author Affiliations & Notes
  • Susanne Kohl
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Ditta Zobor
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Wei-Chieh Chiang
    Department of Pathology, University of California San Diego, La Jolla, CA
  • Nicole Weisschuh
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Mathias W Seeliger
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Stanley Chang
    Department of Ophthalmology, Columbia University, New York, NY
  • Randal J. Kaufman
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, La Jolla, CA
  • Stephen H Tsang
    Department of Ophthalmology, Columbia University, New York, NY
  • Bernd Wissinger
    Centre for Ophthalmology, Inst for Ophthalmic Rsrch Tuebingen, Tuebingen, Germany
  • Jonathan H. Lin
    Department of Pathology, University of California San Diego, La Jolla, CA
  • Footnotes
    Commercial Relationships Susanne Kohl, None; Ditta Zobor, None; Wei-Chieh Chiang, None; Nicole Weisschuh, None; Mathias Seeliger, None; Stanley Chang, None; Randal Kaufman, None; Stephen Tsang, None; Bernd Wissinger, None; Jonathan Lin, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2865. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Susanne Kohl, Ditta Zobor, Wei-Chieh Chiang, Nicole Weisschuh, Mathias W Seeliger, Stanley Chang, Randal J. Kaufman, Stephen H Tsang, Bernd Wissinger, Jonathan H. Lin, ; Mutations in the Unfolded Protein Response regulator, ATF6, cause Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2865.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, marked photophobia, nystagmus, and severely reduced visual acuity. In our cohort, disease-causing variants in genes encoding components of the cone phototransduction cascade cause ~75% of cases. Here, we examined patients with ACHM lacking disease-causing variants in the known ACHM genes to identify additional genes associated with this rare disorder.

Methods: Genetic analysis included autozygosity mapping, whole exome sequencing, and Sanger-sequencing of ATF6 in over 300 ACHM patients. These studies were complemented by cDNA analysis out of patients’ PaxGene blood to investigate the effect of putative splice site mutations, functional studies to assess the pathogenic effect of a ATF6 missense mutation, as well as functional analysis of the homologous Atf6-/- mouse model.

Results: We identified ten independent ACHM families with 18 affected individuals carrying six homozygous and two compound-heterozygous disease-causing variants in the Activating Transcription Factor 6 (ATF6) gene, a key regulator of the Unfolded Protein Response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. The mutations included two missense, three frame-shifting indel, and three true splice site mutations - as proven by cDNA analysis. Clinically and on optical coherence tomography the patients had evidence of foveal hypoplasia with an essentially absent foveal pit and a variable degree of disruption of the cone photoreceptor layer at the macula. Functionally, we found that an ACHM-associated ATF6 missense variant leads to attenuated ATF6 transcriptional activity in response to ER stress. Young Atf6-/- mice have normal retinal morphology and function, with both rod and cone dysfunction in older mice.

Conclusions: Mutations in ATF6 account for 1% of ACHM cases in our cohort of over 950 independent ACHM families. Inactivating mutations in ATF6 can result in an isolated retinal photoreceptor phenotype despite its ubiquitous expression. This study suggests a crucial and unexpected role of ATF6 in human foveal development and cone photoreceptor function.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×