Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal Vascular Condition FEVR

Am J Hum Genet. 2017 Jun 1;100(6):960-968. doi: 10.1016/j.ajhg.2017.05.001.

Evangelia S Panagiotou ¹, Carla Sanjurjo Soriano ¹, James A Poulter ¹, Emma C Lord ¹, Denisa Dzulova ¹, Hiroyuki Kondo ², Atsushi Hiyoshi ³, Brian Hon-Yin Chung ⁴, Yoyo Wing-Yiu Chu ⁴, Connie H Y Lai ⁵, Mark E Tafoya ⁶, Dyah Karjosukarso ⁷, Rob W J Collin ⁷, Joanne Topping ¹, Louise M Downey ⁸, Manir Ali ¹, Chris F Inglehearn ¹, Carmel Toomes ⁹

Affiliations

1 Section of Ophthalmology & Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
2 Department of Ophthalmology, Fukuoka University, Fukuoka 814-0180, Japan; Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
3 Department of Ophthalmology, Fukuoka University, Fukuoka 814-0180, Japan.
4 Department of Paediatrics and Adolescent Medicine, Centre for Genomic Sciences, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
5 Department of Ophthalmology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
6 Pacific Retina Care, Waikele, HI 96797, USA.
7 Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
8 Section of Ophthalmology & Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK; Department of Ophthalmology, Hull Royal Infirmary, Hull HU3 2JZ, UK.
9 Section of Ophthalmology & Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK. Electronic address: c.toomes@leeds.ac.uk.

PMID: 28575650 DOI: 10.1016/j.ajhg.2017.05.001

Abstract

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 four 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-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding β-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720^∗] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs^∗18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that β-catenin signaling plays in the development of the retinal vasculature.

Keywords

CTNNB1; familial exudative vitreoretinopathy.

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