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

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-b-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 b-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 b-catenin signaling plays in the development of the retinal vasculature.

Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood–brain barrier and blood–retina barrier development and maintenance

“…This bias influences the spectrum of retinal vascular diseases caused by mutations in genes coding for β-catenin signaling components. Hemizygous loss-of-function mutations in NDP cause Norrie disease, heterozygous loss-of-function mutations in CTNNB1, FZD4, TSPAN12, or LRP5 cause familial exudative vitreoretinopathy (FEVR), and compound heterozygous or homozygous mutations in LRP5 cause FEVR or osteoporosis/ pseudoglioma syndrome (40)(41)(42)(43)(44)(45)(46)(47)(48)(49). There are also individuals with retinal vascular disease who have mutations in both copies of FZD4 or TSPAN12, or in two different genes in the Norrin signaling system (48,(50)(51)(52)(53).…”

Norrin restores blood-retinal barrier properties after vascular endothelial growth factor–induced permeability

“…Mutations in the norrin gene (NDP) cause an X-linked retinal dysplasia on the severe end of the spectrum that presents with congenital or early childhood blindness, called Norrie disease (12)(13)(14)(15). The retinal hypo vascularization disorders, referred to as familial exudative vitreopathy (FEVR), are caused by mutations in the genes encoding for norrin receptor FZD4 (16)(17)(18), and co-receptors LRP5 (19)(20)(21)(22), TSPAN12 (16,17,23,24), β-catenin (25,26) and some norrin mutations (27). The hypo vascular phenotype observed in both Norrie and FEVR diseases has been recapitulated in knockout mice models of norrin or the FZD4 receptor complex (1,5,8,(28)(29)(30)(31)(32)(33)(34), in which retinal vascular growth, mural cell recruitment, endothelial differentiation and barrier properties, are affected as a consequence of a low Sox7, Sox17 and Sox18 gene expression (35), or due an increased expression of the Wnt signaling inhibitor APCDD1 (36).…”

Frizzled 4 regulates ventral blood vessel remodeling in the zebrafish retina

“…These mutated genes include: Norrin ( NDP ), Frizzled 4 ( FZD4 ), Low‐density lipoprotein receptor‐related protein 5 ( LRP5 ), Tetraspanin 12 ( TSPAN12 ), Atonal BHLH Transcription Factor 7 ( ATOH7 ), Zinc finger protein 408 ( ZNF408 ), Kinesin Family Member 11 ( KIF11 ), Exudative vitreoretinopathy 3 ( EVR3 ; gene identity remains to be identified), RCC1 and BTB Domain Containing Protein 1 ( RCBTB1 ) and Beta catenin 1 ( CTNNB1 ) . Five of these genes are members of the Wingless/int1 (Wnt) signaling pathway and account for 90% of known genetically‐heritable FEVR cases: mutations in FZD4 (the transmembrane G‐protein couple receptor), LRP5 ( FZD4 co‐receptor), NDP ( FZD4 ligand), TSPAN12 (cofactor), and CTNNB1 (Wnt signaling mediator) have all been identified in humans . Mice with mutations in Norrin , Fzd4 , Tspan12 , or Lrp5 phenotypically recapitulate the FEVR phenotype.…”

“…15 Five of these genes are members of the Wingless/int1 (Wnt) signaling pathway and account for 90% of known genetically-heritable FEVR cases: mutations in FZD4 (the transmembrane G-protein couple receptor), LRP5 (FZD4 co-receptor), NDP (FZD4 ligand), TSPAN12 (cofactor), and CTNNB1 (Wnt signaling mediator) have all been identified in humans. 2,[4][5][6][7][8][9]15 Mice with mutations in Norrin, 16 Fzd4, 17 Tspan12, 18 or Lrp5 19 phenotypically recapitulate the FEVR phenotype.…”