RCBTB1 and Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an autosomal dominant retinal vascular disorder characterized by avascular peripheral retina, neovascularization, and risk of retinal detachment. Known genes account for ~50% of cases, leaving additional genetic contributors to be defined. RCBTB1 (RCBTB1, HGNC:18243) was proposed as a novel FEVR locus based on heterozygous truncating variants and functional studies supporting a haploinsufficiency mechanism ([PMID:26908610]).

In the initial report, two distinct heterozygous frameshift mutations in RCBTB1—c.707del (p.Asn236fs) and c.1172+1G>A—were identified in three unrelated Taiwanese probands with FEVR, consistent with autosomal dominant inheritance and no additional affected relatives ([PMID:26908610]). No segregation beyond probands was described. Variant spectrum in this cohort was limited to truncating alleles.

Functional assays demonstrated ~50% reduced RCBTB1 protein levels in patient-derived lymphoblastoid cells, implicating haploinsufficiency, and shRNA knockdown impaired β-catenin nuclear accumulation under Norrin/Wnt3a stimulation in reporter assays. Zebrafish rcbtb1 knockdown recapitulated intersegmental and intraocular vascular anomalies, aligning with human FEVR pathology ([PMID:26908610]).

However, a subsequent large cohort analysis of 6,303 unrelated families failed to show enrichment of heterozygous truncating RCBTB1 alleles in FEVR versus controls. Twenty-eight unrelated individuals harbored truncations across diverse ophthalmic and unaffected phenotypes, and segregation analysis did not support pathogenicity of monoallelic variants in FEVR ([PMID:33104391]).

Integration of genetic and experimental data suggests that while RCBTB1 deficiency disrupts Norrin/FZD4 signaling and angiogenesis in model systems, the limited number of heterozygous cases and lack of replication in large cohorts dispute a causal role in autosomal dominant FEVR. Additional genetic studies in diverse populations are needed before clinical implementation.

Key Take-home: RCBTB1 haploinsufficiency perturbs Norrin-mediated Wnt signaling but current genetic data conflict on its role in dominant FEVR, warranting further validation before diagnostic use.

References

• Human Molecular Genetics • 2016 • Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy. PMID:26908610
• Current Eye Research • 2021 • Variants in RCBTB1 are Associated with Autosomal Recessive Retinitis Pigmentosa but Not Autosomal Dominant FEVR. PMID:33104391

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