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

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.