July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Clinical, molecular genetic, and functional analysis of a pedigree with a novel dominant optic atrophy mutation
Author Affiliations & Notes
  • John H Fingert
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Carly van der Heide
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Jessica A. Cooke
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Ben R. Roos
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Ankur Jain
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Kathy Rodine
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Robert F Mullins
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Budd Tucker
    Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
  • Footnotes
    Commercial Relationships   John Fingert, None; Carly van der Heide, None; Jessica Cooke, None; Ben Roos, None; Ankur Jain, None; Kathy Rodine, None; Robert Mullins, None; Budd Tucker, None
  • Footnotes
    Support  NIH P30 EY025580, Hadley-Carver Chair in Glaucoma
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2960. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      John H Fingert, Carly van der Heide, Jessica A. Cooke, Ben R. Roos, Ankur Jain, Kathy Rodine, Robert F Mullins, Budd Tucker; Clinical, molecular genetic, and functional analysis of a pedigree with a novel dominant optic atrophy mutation. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2960.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Dominant optic atrophy is an important cause of visual disability that is most commonly caused by mutations in the OPA1 gene. The purpose of this project is to identify the OPA1 mutation and the mechanism by which it causes dominant optic atrophy in a new pedigree.

Methods : We characterized the phenotype of a small, 2-member pedigree with dominant optic atrophy with 1) color vision testing; 2) optic disc ophthalmoscopy, photography, and OCT; and 3) visual field testing. DNA was collected from a blood sample and fibroblast cells were cultured from a skin biopsy from affected patients. We searched for a disease-causing mutation by sequencing the OPA1 gene. The influence of OPA1 mutations on gene expression was investigated with studies of patient-derived fibroblast cells using qRT-PCR (with OPA1 probes), RNAseq, and Western blot analysis. The influence of mutations on metabolism was further analyzed with oxygen consumption / ATP production (SeaHorse) assays and with electron microscopy of mitochondria.

Results : Patients in the pedigree exhibited classic features of dominant optic atrophy including reduced visual acuity, optic disc pallor, and central visual field defects. A novel 1-base pair deletion, C.2123delA, was detected in the OPA1 gene that is a frameshift mutation and is predicted to cause a premature termination. Analysis of gene expression with RT-PCR and Western blot analysis showed a 50% reduction in OPA1 mRNA and OPA1 protein in fibroblast cells. Transmission electron microscopy showed altered size and numbers of mitochondria in patient fibroblast cells and SeaHorse assays showed decreased oxygen consumption / ATP production.

Conclusions : We have characterized a novel OPA1 mutation, c2123delA, and demonstrated that it likely causes a reduction of OPA1 mRNA and OPA1 protein which strongly suggests this mutation causes optic atrophy via a halploinsufficiency mechanism. Deficiency of OPA1 protein appears to cause mitochondrial abnormalities and dysfunction in energy production. These studies suggest that further analysis of the c.2123delA mutation with iPSC-derived retinal ganglion cell studies (which are underway) will provide important insights into the pathophysiology of dominant optic atrophy as well as potential therapies for this important disease.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

×
×

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.

×