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

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 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 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 revealed increased cell shedding and large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. 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.

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

“…70–73 An equivalent population has not yet been described in normal aged human eyes, although microglia appear in atrophic areas 61, 69, 70 and in association with advanced subretinal drusenoid deposits. 74 Alternatively, several mouse models involving targeted disruption of mechanistically diverse pathways also exhibit ‘sloughed’ RPE 75–80 , supporting the concept that RPE stress responses are a final common pathway to multiple different stressors. What molecular signals prompt RPE to assume migratory behaviors in human GA eyes is unspecified.…”

Noninvasive Electroretinographic Procedures for the Study of the Mouse Retina

“…To better evaluate mouse models for genes expressed in the RPE, we adapted an in vivo direct current ERG (dc-ERG) procedure (Kikiwada, 1968) to monitor these responses in anesthetized mice (Wu et al, 2004b). The value of this analysis is supported by subsequent application, where mouse models have been identified in which dc-ERG abnormalities were documented in the face of normal ERG a- and b-waves (e.g., Edwards et al, 2010; Patil et al, 2014; Collin et al, 2015; Saksens et al, 2016). Basic Protocol 2 describes the approach used to record the mouse dc-ERG.…”

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

“…Over two million people worldwide are affected by inherited retinal degenerations (IRDs), a family of blinding diseases characterized by progressive death and dysfunction of primarily rod and cone photoreceptors 1,2 . Pathogenic variants (PVs) in over 270 genes have been associated with IRDs 3 , many of which were discovered recently by virtue of advances in sequencing technologies [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . However, despite substantial progress in genetic methodologies, current strategies can genetically solve only about 55-60% of IRD cases [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] .…”

“…The remaining missing diagnoses are in part due to new, yet to be discovered IRD genes. However, PVs in each new disease gene are rare, affecting a handful of IRD patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] , suggesting that the missing genetic causality largely lies in the known IRD genes. A considerable proportion of these elusive PVs are due to structural variations (SVs) such as copy number variations (CNVs), or deep intronic variants that affect splicing 36,[39][40][41][42][43][44][45][46][47][48][49] , which are not readily available from the standard output of targeted next generation sequencing (NGS) pipelines.…”