Des défauts dans la signalisation cellulaire médiant la β-catenine cause la condition vasculaire rétinienne FEVR

Aperçu: G.M.

La vitreoretinopathie exsudative familiale (FEVR) est un trouble de la cécité héréditaire caractérisé par le développement anormal du système vasculaire de la rétine. La majorité des mutations identifiées dans la FEVR se retrouvent dans quatre gènes qui codent le complexe récepteur (FZD4, LRP5 et TSPAN12) et le ligand (NPD) d'une voie moléculaire qui contrôle l'angiogenèse, la voie de signalisation Norrin-β-catenin.  

L'étude rapporte  ici l'identification de mutations dans CTNNB1, le gène codant pour la β-caténine, comme cause de la FEVR. 

Des études antérieures ont signalé des mutations de CTNNB1 de novo hétérozygotes comme cause d'une déficience intellectuelle syndromique (ID) et d'un "trouble du spectre de l'autisme", et les mutations somatiques sont liées à de nombreux cancers.

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

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

Panagiotou ES¹, Sanjurjo Soriano C¹, Poulter JA¹, Lord EC¹, Dzulova D¹, Kondo H², Hiyoshi A³, Chung BH⁴, Chu YW⁴, Lai CHY⁵, Tafoya ME⁶, Karjosukarso D⁷, Collin RWJ⁷, Topping J¹, Downey LM⁸, Ali M¹, Inglehearn CF¹, Toomes C⁹.

Author information

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

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.

Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PMID: 28575650

DOI: 10.1016/j.ajhg.2017.05.001