Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

Nat Genet. 2016 Feb;48(2):144-51. doi: 10.1038/ng.3474.

Nicole T M Saksens ¹, Mark P Krebs ², Frederieke E Schoenmaker-Koller ¹, Wanda Hicks ², Minzhong Yu ³ ⁴, Lanying Shi ², Lucy Rowe ², Gayle B Collin ², Jeremy R Charette ², Stef J Letteboer ⁵, Kornelia Neveling ⁵, Tamara W van Moorsel ¹, Sleiman Abu-Ltaif ⁶, Elfride De Baere ⁷, Sophie Walraedt ⁶, Sandro Banfi ⁸ ⁹, Francesca Simonelli ¹⁰, Frans P M Cremers ⁵, Camiel J F Boon ¹ ¹¹, Ronald Roepman ⁵, Bart P Leroy ⁶ ⁷ ¹² ¹³, Neal S Peachey ³ ⁴ ¹⁴, Carel B Hoyng ¹, Patsy M Nishina ², Anneke I den Hollander ¹ ⁵

Affiliations

1 Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
2 The Jackson Laboratory, Bar Harbor, Maine, USA.
3 Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
4 Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
5 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
6 Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
7 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
8 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
9 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
10 Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Naples, Italy.
11 Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
12 Division of Ophthalmology, The Children's Hospital of Ophthalmology, Philadelphia, Pennsylvania, USA.
13 Center for Cellular and Molecular Therapeutics, The Children's Hospital of Ophthalmology, Philadelphia, Pennsylvania, USA.
14 Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.

PMID: 26691986 DOI: 10.1038/ng.3474

Abstract

Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here we report the identification of heterozygous missense mutations in the CTNNA1 gene (encoding α-catenin 1) 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 retinal pigment epithelium (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 demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, indicates that CTNNA1 is involved in maintaining RPE integrity and suggests that Other components that participate in intercellular adhesion may be implicated in macular disease.

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