July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Variants in myelin regulatory factor (MYRF) cause autosomal dominant nanophthalmos.
Author Affiliations & Notes
  • Lev Prasov
    Ophthalmic Genetics Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Sarah J Garnai
    Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Michelle Brinkmeier
    Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
  • Ben Emery
    Jungers Center for Neurosciences Research, Oregon Health and Sciences University, Portland, Oregon, United States
  • Tomas S Aleman
    Scheie Eye Institute, Philadelphia, Pennsylvania, United States
    Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Louise C Pyle
    Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Biliana O Veleva-Rotse
    Jungers Center for Neurosciences Research, Oregon Health and Sciences University, Portland, Oregon, United States
  • Robert Sisk
    Cincinnati Eye Institute, Cincinnati, Ohio, United States
  • Sayoko Eileen Moroi
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Steven M Archer
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Laurel Wiinikka-Buesser
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Frank W Rozsa
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Gregory L Skuta
    Dean McGee Eye Institute, Oklahoma City, Oklahoma, United States
  • Sally Camper
    Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
  • Julia Richards
    Ophthalmology, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Lev Prasov, None; Sarah Garnai, None; Michelle Brinkmeier, None; Ben Emery, None; Tomas Aleman, None; Louise Pyle, None; Biliana Veleva-Rotse, None; Robert Sisk, None; Sayoko Moroi, None; Steven Archer, None; Laurel Wiinikka-Buesser, None; Frank Rozsa, None; Gregory Skuta, None; Sally Camper, None; Julia Richards, None
  • Footnotes
    Support  Knights Templar Eye Foundation Career Starter Award; Alliance for Vision Award; National Eye Institute Vision Core Grant P30 EY007003; Michigan Ophthalmology Trainee Career Development Award; Research to Prevent Blindness
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5420. doi:
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    • Get Citation

      Lev Prasov, Sarah J Garnai, Michelle Brinkmeier, Ben Emery, Tomas S Aleman, Louise C Pyle, Biliana O Veleva-Rotse, Robert Sisk, Sayoko Eileen Moroi, Steven M Archer, Laurel Wiinikka-Buesser, Frank W Rozsa, Gregory L Skuta, Sally Camper, Julia Richards; Variants in myelin regulatory factor (MYRF) cause autosomal dominant nanophthalmos.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5420.

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

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Abstract

Purpose : Nanophthalmos is part of a spectrum of genetic disorders, characterized by a small structurally normal eye. A large 5-generation family with autosomal dominant nanophthalmos was previously identified and mapped to the NNO1 locus on chromosome 11. Here, we evaluate myelin regulatory factor (MYRF) as a candidate gene for nanophthalmos and uncover its role in eye development.

Methods : We used combined linkage and pooled exome sequencing approaches to fine map and sequence coding genes in the NNO1 locus. A pooled sample of all affected individuals and a subtractive pool of unaffected individuals were enriched for the exome and sequenced using the IlluminaHighSeq platform. Sixty unrelated probands were screened for variants in MYRF, and a syndromic patient carrying an MYRF mutation underwent ophthalmic examination. To validate the most promising candidate gene, Myrf conditional knockout mice were generated using the Rx promoter to inactivate Myrf in the early retina and retinal pigment epithelium. Mouse eyes were analyzed by histology and immunohistochemistry.

Results : Of three candidate variants within the 3.5 Mb non-recombinant interval on chromosome 11q12 between D11S4191 and D11S188, the MYRF c.3376-1G>A (p.Gly1126Valfs*31) splice site mutation was the most promising, as the MYRF gene was expressed in the eye and had an unknown eye phenotype. One unrelated syndromic child carrying an MYRF mutation was found to have axial hyperopia (+7.0D, 17 mm eye). No other mutations were found in 60 unrelated nanophthalmos/high hyperopia probands. The phenotype in Myrf conditional knockout mice revealed patchy loss of pigmentation of the retinal pigment epithelium and retinal degeneration. Eyes from Myrf knockout mice had decreased levels and altered localization of TMEM98, a known nanophthalmos gene. Furthermore, MYRF was found to directly interact with TMEM98 by co-immunoprecipitation experiments.

Conclusions : Our results suggest that rare variants in MYRF cause autosomal dominant isolated and syndromic nanophthalmos. They have potential implications for counseling of the NNO1 family and syndromic MYRF patients. Furthermore, our studies enhance our understanding of eye growth and development by identifying a new gene and new pathway, which may ultimately lead to new therapies for refractive error.

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

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