LRP5 – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disorder characterized by peripheral avascularity, neovascularization, retinal folds, and risk for vitreoretinal traction and detachment. Heterozygous and homozygous variants in the Wnt co-receptor gene LRP5 (HGNC:6697) have been reported in both autosomal dominant and recessive forms of FEVR, often with extraocular skeletal manifestations (PMID:16929062).

Genetic studies have identified over 100 unrelated probands with LRP5 variants, including missense (n>60) and loss-of-function alleles (n>30) across multiple cohorts (PMID:25711638). Variants cluster in the extracellular β-propeller domains and include truncating changes such as c.3259C>T (p.Gln1087Ter) (PMID:39197084). Both monoallelic and biallelic mutations co-segregate with FEVR phenotypes in multiple families, with at least four additional affected relatives documented in kindreds with heterozygous alleles.

Segregation analysis across diverse pedigrees confirms penetrance of heterozygous LRP5 variants, with additional affected siblings and parents demonstrating peripheral retinal nonperfusion and characteristic vitreoretinal changes. In consanguineous families, recessive homozygous missense alleles (e.g., p.Gly550Arg) underlie severe early-onset FEVR accompanied by reduced bone mineral density and hyaloid remnants (PMID:16929062).

Functional assays reveal that HBM-associated and FEVR-associated LRP5 mutations impair Norrin/β-catenin signaling by reducing affinity for the antagonist DKK1 and limiting Wnt-mediated receptor activation, with moderate to severe reductions in reporter activity (PMID:15923613). Transgenic mice expressing mutant LRP5 (Gly171Val) recapitulate human high-bone-mass and vascular phenotypes, underscoring the role of LRP5 in retinal angiogenesis and skeletal homeostasis (PMID:12817748).

No significant conflicting reports have been published to date, and the spectrum of LRP5 variants shows consistent genotype–phenotype concordance. The breadth of genetic, segregation, and experimental data supports a definitive association between LRP5 and FEVR.

Key Take-home: LRP5 pathogenic variants cause FEVR through disrupted Wnt/β-catenin signaling; genetic testing of LRP5 informs diagnosis, family counseling, and tailored ophthalmic surveillance.

References

• Investigative ophthalmology & visual science • 2015 • Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients PMID:25711638
• The British journal of ophthalmology • 2006 • Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5 PMID:16929062
• Retinal cases & brief reports • 2024 • Pre-term Familial Exudative Vitreoretinopathy: A Novel Nonsense LRP5 Mutation PMID:39197084
• Human mutation • 2005 • Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes PMID:15981244
• Journal of bone and mineral research • 2003 • High bone mass in mice expressing a mutant LRP5 gene PMID:12817748
• Molecular and cellular biology • 2005 • Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling PMID:15923613

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