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Carmel Toomes, Evangelia S Panagiotou, James A. Poulter, Carla Sanjurjo Soriano, Hiroyuki Kondo, Atsushi Hiyoshi, Hon-Yin Brian Chung, Mark E Tafoya, Manir Ali, Chris F Inglehearn; Defects in the cell signaling mediator β-catenin (CTNNB1) cause the retinal vascular condition FEVR. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2788.
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© ARVO (1962-2015); The Authors (2016-present)
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within 4 genes that encode the receptor complex (FZD4, LRP5 and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the norrin-β-catenin signaling pathway. However, half of all FEVR cases do not harbor mutations in the known FEVR genes so the aim of this study was to identify new genes underlying FEVR.
Whole exome sequencing (WES) was performed on the Illumina HiSeq3000 using the Agilent SureSelect capture reagent. Data was aligned using Novoalign and processed using Picard and GATK. The coding sequence of CTNNB1 was screened by Sanger sequencing. A cell based-luciferase reporter assay for β-catenin transcription (TOPflash) was used to assess the pathogenicity of the CTNNB1 mutations.
A cohort of 36 unrelated individuals with a diagnosis of FEVR but without mutations in the known FEVR genes formed the basis of this study. WES in 12 of these subjects and screening of CTNNB1 by Sanger sequencing in the remaining 24, led to the identification of three families carrying mutations in CTNNB1, the gene encoding β-catenin. Heterozygous mutations in two dominant non-syndromic FEVR families were identified (c.2142_2157dup, p.(His720*) and c.2128C>T, p.(Arg710Cys)) along with a de novo mutation in a sporadic newborn child (c.1434_1435insC, p.(Glu479Argfs*18)). This child was originally diagnosed with FEVR but clinical review following this genetic result confirmed the presence of additional features consistent with syndromic intellectual disability (ID). Both familial mutations are predicted to produce β-catenin with a defective carboxy-terminal domain and cell-based TOPflash assays showed that these alter β-catenin signaling.
Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic ID and autism spectrum disorder and somatic mutations are linked to various malignancies. However, this is the first report of a familial disease caused by CTNNB1 mutations, and the first confirmation that CTNNB1 mutations can cause non-syndromic FEVR, further establishing the role that β-catenin signaling plays in the development of the retinal vasculature.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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