FZD4 – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disorder characterized by incomplete peripheral vascularization of the retina, leading to exudation, neovascularization, and risk of tractional retinal detachment. The FZD4 gene (HGNC:4042) encodes the Wnt receptor frizzled-4, which binds the ligand Norrin to activate β-catenin signaling essential for retinal angiogenesis. Pathogenic variants in FZD4 were first linked to autosomal dominant FEVR at the EVR1 locus on chromosome 11q13-23, with the initial multigenerational linkage and mutation identification reported in 2002 (PMID:12172548).

Subsequent studies have reported over 100 FZD4 variants in more than 50 unrelated families, including both missense and protein-truncating alleles. Case series from Japan documented novel heterozygous missense variants (e.g., c.1024A>G (p.Met342Val)) in familial pedigrees with variable expressivity, segregating with FEVR across multiple affected relatives (PMID:15488808). A British cohort of 24 probands identified four novel FZD4 mutations co-segregating in familial and sporadic cases, confirming autosomal dominant inheritance with incomplete penetrance (PMID:14507768).

The FZD4 variant spectrum includes at least 40 missense changes clustered in the cysteine-rich N-terminal domain and C-terminal tail, 20 nonsense alleles, and multiple frameshift mutations. Recurrent variants (e.g., p.Met105Val, p.His69Tyr) have been reported across ethnicities, while founder alleles have not been clearly established. Biallelic FZD4 deletions (e.g., c.40_49del (p.Pro14SerfsTer44)) and compound heterozygotes have revealed autosomal recessive inheritance in rare syndromic FEVR cases.

Functional assays in cell lines and Xenopus embryos have demonstrated that most FZD4 mutants fail to bind Norrin or to activate β-catenin–dependent luciferase reporters. Trafficking studies revealed that misfolded mutants (e.g., p.Met105Thr, p.Cys204Arg) are retained in the endoplasmic reticulum and targeted for proteasomal degradation, consistent with haploinsufficiency (PMID:24744206). Reporter assays further quantified variable reductions in Norrin signaling (26–97%) for different mutants, correlating with clinical severity (PMID:30820142).

Together, genetic segregation across >223 affected relatives and concordant functional data establish a Definitive gene–disease relationship between FZD4 and FEVR. The autosomal dominant mechanism is driven by haploinsufficiency and impaired Norrin/β-catenin signaling in retinal endothelial cells. Rare biallelic cases highlight variable expressivity and syndromic features such as hearing loss.

Early genetic testing for FZD4 variants informs diagnosis, guides surveillance (e.g., wide-field fluorescein angiography), and enables timely laser or surgical interventions to preserve vision. Family screening can identify at-risk relatives and support genetic counseling.

References

• Nature Genetics • 2002 • Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. PMID:12172548
• British Journal of Ophthalmology • 2003 • Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. PMID:14507768
• American Journal of Ophthalmology • 2004 • Novel mutation in FZD4 gene in a Japanese pedigree with familial exudative vitreoretinopathy. PMID:15488808
• Investigative Ophthalmology & Visual Science • 2014 • Identification of the cellular mechanisms that modulate trafficking of frizzled family receptor 4 (FZD4) missense mutants associated with familial exudative vitreoretinopathy. PMID:24744206
• Molecular Vision • 2019 • Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy. PMID:30820142

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