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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 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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Figure 1: CTNNA1 mutations in three families with butterfly-shaped pigment dystrophy.
Figure 2: Retinal images of individuals with butterfly-shaped pigment dystrophy.
Figure 3: Live retinal imaging of mice homozygous for Ctnna1tvrm5.
Figure 4: ERG recordings of Ctnna1tvrm5 mice.
Figure 5: Light micrographs of the Ctnna1tvrm5 posterior eye.
Figure 6: RPE cell dysmorphology.
Figure 7: Human CTNNA1 structural model showing the location of predicted substitutions in the variants described.

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Acknowledgements

We thank S. Kohl and C. Hamel for providing DNA samples of individuals with pattern dystrophies, J. Hansen for help with animal care, and JAX Scientific Services, including Genome Technologies, Histopathology Sciences and Imaging Sciences. This research was supported by Foundation Fighting Blindness Center Grant C-GE-0811-0548-RAD04 to the Radboud University Nijmegen Medical Center, Netherlands Organization for Scientific Research Vidi Innovational Research Award 016.096.309 to A.I.d.H., Nederlandse Oogonderzoek Stichting and Diana Hermens Stichting awards to C.B.H., a Research Foundation–Flanders grant to E.D.B. and B.P.L., FWO Flanders grant 3G079711 to E.D.B., the Belgian Science Policy Office Interuniversity Attraction Poles programme P7/43 award to E.D.B. and B.P.L., Netherlands Organization for Scientific Research Vici Innovational Research Award 865.12.005 to R.R., the Foundation Fighting Blindness (C-CMM-0811-0546-RAD02) to R.R., a US Veterans Administration Medical Research Service grant to N.S.P., a Foundation Fighting Blindness Center Grant to the Cole Eye Institute, Cleveland Clinic, an unrestricted award from Research to Prevent Blindness to the Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, US National Institutes of Health (NIH) and National Eye Institute grant EY016501 to P.M.N. and US NIH National Cancer Institute award P30CA034196 to The Jackson Laboratory.

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N.T.M.S., M.P.K., P.M.N. and A.I.d.H. wrote the manuscript. N.T.M.S., S.A.-L., E.D.B., S.W., S.B., F.S., F.P.M.C., C.J.F.B., B.P.L. and C.B.H. performed clinical examinations in patients and families and/or provided patient samples. M.P.K., W.H., L.S., L.R., G.B.C. and J.R.C. performed genetic studies, live imaging, morphological studies and expression analysis in Ctnna1tvrm5 mice. F.E.S.-K. and T.W.v.M. performed CTNNA1 mutation analysis in patients and families. M.Y. and N.S.P. performed electrophysiology in Ctnna1tvrm5 mice. S.J.L. and R.R. performed coimmunoprecipitations of CTNNA1 with VCL. K.N. provided bioinformatic support for the whole-exome sequencing experiments in family A. M.P.K., C.B.H., P.M.N. and A.I.d.H. supervised the work.

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Correspondence to Anneke I den Hollander.

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Integrated supplementary information

Supplementary Figure 1 Protein sequence alignment of CTNNA1 orthologs.

The amino acids affected by the mutations identified in three families with butterfly-shaped pigment dystrophy (p.Glu307Lys, p.Leu318Ser, p.Ile431Met) and in the Ctnna1tvrm5 mouse (p.Leu436Pro) are completely conserved among vertebrates. CTNNA1 accession numbers: Homo sapiens, NP_001894; Macaca mulatta, NP_001244297; Mus musculus, NP_033948; Rattus norvegicus, NP_001007146; Bos taurus, NP_001030443; Gallus gallus, XP_414513; Danio rerio, NP_571531.

Supplementary Figure 2 Distribution of CTNNA1 in wild-type and Ctnna1tvrm5 mice.

Ocular cryosections from (a,b,g) B6J (+/+; n = 3), (c,d,h) heterozygous (tvrm5/+; n = 3) or (e,f,i) homozygous (tvrm5/tvrm5; n = 3) Ctnna1tvrm5 mutant mice at 1 month of age were stained with antibody to CTNNA1 (red) and DAPI to show nuclei (blue) and imaged by wide-field fluorescence microscopy (a,c,e, red only; b,d,f–i, red and blue merged). Posterior tissue layers are labeled: GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ELM, external limiting membrane; RPE, retinal pigment epithelium; Ch, choroid. Staining of CTNNA1 was evident primarily in the OPL, ELM and RPE, with additional staining of the inner retinal vascular structures. At higher magnification (gi), regularly spaced punctate staining was observed near the apical surface of the RPE, suggesting localization of CTNNA1 to epithelial adherens junctions (arrowheads). Staining was also observed near the basal surface of the RPE. Scale bars in f and i are 20 µm and apply to af and gi, respectively.

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Supplementary Figure 3 Expression of Ctnna1 mRNA and CTNNA1 in wild-type and Ctnna1tvrm5 mutant mice.

(a) Relative Ctnna1 mRNA levels at 1 month of age. Ctnna1 expression in heterozygous (tvrm5/+) or homozygous (tvrm5/tvrm5) Ctnna1tvrm5 mice was compared to that of B6J mice by quantitative RT-PCR of RNA extracted from a combined preparation of retina and RPE (retina + RPE; n = 5) or an RPE-enriched sample (RPE; n = 3). No significant changes in mRNA levels were observed (one-way ANOVA, F(2,12) = 0.19, P = 0.83; F(2,6) = 1.10, P = 0.39 for retina + RPE and RPE-enriched analyses, respectively). (b) Western blot of retina + RPE preparations from B6J (+/+), tvrm5/+ and tvrm5/tvrm5 mice at 1 month of age (n = 3 for each group). Relative molecular weights (Mr) determined from protein standards are indicated. Total protein was detected by Ponceau S staining (red), and a single 102-kDa band consistent with CTNNA1 was detected by antibody (white). (c) Quantification of the western blot shown in b indicated no significant change in relative CTNNA1 levels in retina + RPE lysates from heterozygous or homozygous Ctnna1tvrm5 mutant mice as compared to B6J mice (one-way ANOVA, F(2,6) = 0.62, P = 0.57). In a and c, mean values relative to B6J mice are shown with bounds calculated from error propagation; the dashed line at 1.0 indicates expression equivalent to that of B6J mice.

Source data

Supplementary Figure 4 Disease progression in wild-type and Ctnna1tvrm5 mutant mice.

(a) Photoreceptor degeneration as indicated by a decrease in ONL thickness was assessed by OCT in B6J (+/+), heterozygous (tvrm5/+) and homozygous (tvrm5/tvrm5) Ctnna1tvrm5 mice at 1 (n = 3, 4 and 7 mice, respectively), 3 (n = 5, 4 and 3 mice, respectively) and 12–14 (n = 5, 5 and 7 mice, respectively) months of age. Data points indicate mean ONL thickness in the eyes of individual mice measured by OCT ~250 μm from the optic nerve head in each retinal quadrant and averaged; bars show the means ± s.d. of these averaged values among mice. A significant effect of strain on ONL thickness was noted (one-way ANOVA, F(2,11) = 29.7, P < 0.0001; F(2,9) = 19.8, P = 0.0005; F(2,14) = 57.7, P < 0.0001 at 1, 3 and 12–14 months of age, respectively). Multiple comparisons (Tukey post-hoc analysis) indicated significant differences at these ages between homozygous mice and heterozygous mice or B6J mice (*P < 0.002, **P < 0.0001) but not between B6J and heterozygous mice (n.s., P > 0.05). (bd) Progression of mottling in heterozygous Ctnna1tvrm5 mice. Bright-field fundus images obtained at 1 (n = 4 mice), 6 (n = 5) and 12–14 (n = 5) months of age showed increased mottling with age, particularly in the superior temporal retina. (b) Right eye at 1 month of age. (c) Left eye at 6 months of age. (d) Right eye at 12 months of age.

Supplementary Figure 5 Coimmunoprecipitation studies of CTNNA1 and vinculin (VCL).

Wild-type 3×HA-CTNNA1 efficiently coimmunoprecipitated with 3×FLAG-VCL (panel 4, lane 1), and introduction of the CTNNA1 variants c.160C>T; p.Arg54Cys (lane 2), c.919G>A; p.Glu307Lys (lane 3), c.953T>C; p.Leu318Ser (lane 4), c.1293T>G; p.Ile431Met (lane 5) and c.1307T>C; p.Leu436Pro (lane 6) did not significantly affect the binding. Specificity was confirmed by inclusion of the unrelated p63, which failed to coimmunoprecipitate with wild-type vinculin (lane 7). As a positive control, RPGRIP1 efficiently coimmunoprecipitated with nephrocystin-4 (NPHP4; lane 8). Immunoblots of the input are shown in panels 1 and 2, and immunoblots of the FLAG immunoprecipitates are shown in panels 3 and 4. Size markers are depicted in kDa.

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Saksens, N., Krebs, M., Schoenmaker-Koller, F. et al. Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Nat Genet 48, 144–151 (2016). https://doi.org/10.1038/ng.3474

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