September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity
Author Affiliations & Notes
  • Anneke I Den Hollander
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Nicole T.M. Saksens
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Mark P Krebs
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Elfride De Baere
    Center for Medical Genetics, Ghent University, Ghent, Belgium
  • Frans P Cremers
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Camiel J F Boon
    Ophthalmology, Leiden University Medical Center, Leiden, Netherlands
  • Ronald Roepman
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Bart Peter Leroy
    Ophthalmology, Ghent University, Ghent, Belgium
  • Neal S Peachey
    Ophthalmic Research, Cole Eye Institute, Cleveland, Ohio, United States
  • Carel C B Hoyng
    Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Patsy M Nishina
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Footnotes
    Commercial Relationships   Anneke Den Hollander, None; Nicole Saksens, None; Mark Krebs, None; Elfride De Baere, None; Frans Cremers, None; Camiel Boon, None; Ronald Roepman, None; Bart Leroy, None; Neal Peachey, None; Carel Hoyng, None; Patsy Nishina, None
  • Footnotes
    Support  Foundation Fighting Blindness Center Grant C-GE-0811-0548-RAD04, Netherlands Organization for Scientific Research Vidi Innovational Research Award 016.096.309, U.S. Veterans Administration Medical Research Service grant, Foundation Fighting Blindness Center Grant to the Cole Eye Institute, Research to Prevent Blindness, NIH/NEI grant EY016501, and NIH/NCI award P30CA034196
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Anneke I Den Hollander, Nicole T.M. Saksens, Mark P Krebs, Elfride De Baere, Frans P Cremers, Camiel J F Boon, Ronald Roepman, Bart Peter Leroy, Neal S Peachey, Carel C B Hoyng, Patsy M Nishina; Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Abstract

Purpose : Butterfly-shaped pigment dystrophy belongs to a group of autosomal dominant pattern dystrophies of the retinal pigment epithelium (RPE). Mutations in the PRPH2 gene have previously been identified in individuals with butterfly-shaped pigment dystrophy. The aims of this study were to identify the cause of butterfly-shaped pigment dystrophy in a large Dutch family in which the involvement of the PRPH2 gene was excluded, to identify mutations in the causative gene in additional families, and to characterize a mouse mutant caused by a mutation in the same gene.

Methods : Whole exome sequencing (WES) was performed in two affected individuals of the Dutch family, and was filtered for shared variants within the linkage interval on 5q21.2-q33.2. All coding exons of the CTNNA1 gene were analysed in 93 unrelated probands with butterfly-shaped pigment dystrophy and other pattern dystrophies by Sanger sequencing. An indirect ophthalmoscopy screen of mice from a B6J mutagenesis program identified a mutant, tvrm5, that showed widespread fundus mottling and occasional bright spots. Linkage analysis of a tvrm5 x DBA/2J intercross and subsequent WES analysis were performed to identify the genetic defect. Trvm5 mice were characterized by brightfield fundus imaging, dc-ERG electrophysiology, histology and staining of RPE/choroid/sclera flatmounts.

Results : Heterozygous missense mutations were identified in the α-catenin 1 (CTNNA1) gene in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the RPE of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice revealed increased cell shedding and large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis.

Conclusions : This study identifies CTNNA1 gene variants as a cause of macular dystrophy, suggests that CTNNA1 is involved in maintaining RPE integrity, and suggests that other components that participate in intercellular adhesion may be implicated in macular disease.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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