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Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/β-catenin signaling
- Source :
- J Clin Invest
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
Abstract
- Familial exudative vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.
- Subjects :
- 0301 basic medicine
Male
Heterozygote
Angiogenesis
Familial Exudative Vitreoretinopathies
Nerve Tissue Proteins
Biology
medicine.disease_cause
Adherens junction
03 medical and health sciences
Mice
0302 clinical medicine
Exome Sequencing
medicine
Animals
Humans
Amino Acid Sequence
Eye Proteins
beta Catenin
Mice, Knockout
Mutation
Cadherin
Retinal Vessels
LRP5
General Medicine
medicine.disease
Pedigree
Disease Models, Animal
030104 developmental biology
Phenotype
Blood-Brain Barrier
030220 oncology & carcinogenesis
Catenin
Familial exudative vitreoretinopathy
Cancer research
Female
Catenin complex
alpha Catenin
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J Clin Invest
- Accession number :
- edsair.doi.dedup.....4a79a177cc1db7459d85c8be87349ba5