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Evangelia S. Panagiotou, Carla Sanjurjo Soriano, James A

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1 Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR 
Evangelia S. Panagiotou, Carla Sanjurjo Soriano, James A. Poulter, Emma C. Lord, Denisa Dzulova, Hiroyuki Kondo, Atsushi Hiyoshi, Brian Hon-Yin Chung, Yoyo Wing-Yiu Chu, Connie H.Y. Lai, Mark E. Tafoya, Dyah Karjosukarso, Rob W.J. Collin, Joanne Topping, Louise M. Downey, Manir Ali, Chris F. Inglehearn, Carmel Toomes  The American Journal of Human Genetics  Volume 100, Issue 6, Pages (June 2017) DOI: /j.ajhg Copyright © 2017 American Society of Human Genetics Terms and Conditions

2 Figure 1 Schematic Overview of the Norrin-β-Catenin Pathway
Mutations in the genes encoding the ligand Norrin, the receptors FZD4, LRP5, and TSPAN12, and now the transcriptional activator β-catenin all cause FEVR. For pathway description see main text. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2017 American Society of Human Genetics Terms and Conditions

3 Figure 2 Mutations in CTNNB1 Cause FEVR
(A) The pedigrees of the families and CTNNB1 mutation segregation data. The genotypes for all tested family members are shown below each individual, with M representing the mutant allele and + representing the wild-type allele. Affected individuals are shaded black. The grandmother (I:2) in family F410 is shaded gray because fluorescein angiography examination showed no evidence of peripheral retina avascularity (the hallmark feature of FEVR), although she did show focal retinal degeneration in one eye. The symbol with a dot represents an asymptomatic individual. (B) Schematic representation of CTNNB1 (GenBank: NM_ ) showing the location and sequence traces of the three disease-causing variants identified in this study. (C) Schematic representation of the β-catenin protein domains showing the variants identified in this study. The amino-terminal domain (NTD) spans amino acids 1–137, 12 armadillo repeats (ARM) span amino acids 138–664, the carboxy-terminal domain (CTD) spans 665–781, and the Helix-C domain spans amino acids 667–683. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2017 American Society of Human Genetics Terms and Conditions

4 Figure 3 Phenotype of FEVR-Affected Case Subjects with Heterozygous CTNNB1 Mutations (A and B) Color fundus photograph of the peripheral retina of (A) the right eye and (B) the left eye of the proband (III:2) from family F410 at age 11 years showing retinal holes and tractional retinal detachment. (C and D) Anterior segment photograph of (C) the right eye and (D) the left eye of the proband from family F1321 aged 1 month showing the absence of retinal view or red reflex due to dense vitreous hemorrhage in the right eye and neovascularization of the iris and a retrolenticular fibrovascular plaque obscuring the view of the retina in the left eye. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2017 American Society of Human Genetics Terms and Conditions

5 Figure 4 Functional Assessment of Mutant β-Catenin on Transcription using the TOPflash Luciferase Activity Assay STF cells were transiently transfected with expression constructs for wild-type (WT) or mutant β-catenin (p.Arg710Cys or p.His720∗) or empty vector (pDEST40) alongside a Renilla luciferase plasmid and luciferase activity was measured 48 hr later. The bars represent the firefly/Renilla luciferase ratios for the different constructs. The results are from three independent experiments performed in triplicate. Error bars depict SEM; ∗∗p < 0.01, ∗∗∗p < The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2017 American Society of Human Genetics Terms and Conditions

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