REEP6 – Retinitis Pigmentosa 77

REEP6 encodes a membrane‐shaping adapter protein critical for endoplasmic reticulum (ER) structure in photoreceptors. Biallelic REEP6 variants cause autosomal recessive retinitis pigmentosa 77 (Retinitis Pigmentosa 77), characterized by progressive rod‐cone degeneration and night blindness.

Genetic studies identified biallelic REEP6 variants in 10 individuals from 8 unrelated families: seven individuals from five families in a multinational cohort (PMID:27889058) and three probands from three Chinese families (PMID:33917198). All affected individuals presented with typical RP fundus changes and electroretinogram abnormalities. No dominant or X‐linked inheritance has been observed.

The variant spectrum includes missense (n = 2, e.g., c.404T>C (p.Leu135Pro)), frameshift (n = 6, e.g., c.468delC (p.Asn156LysfsTer14)), splice‐site (n = 4, e.g., c.598+1G>C), and genomic rearrangements disrupting exon 1. The missense variant c.268G>C (p.Val90Leu) recurs in Chinese patients, suggesting a founder or hotspot allele (PMID:33917198).

Functional assays in cultured cells demonstrate that missense and frameshift REEP6 variant proteins are unstable, misfold, and form intracellular inclusions, consistent with loss of function (PMID:27889058; PMID:33917198). A PLoS One study of REEP6 and related isoforms confirmed REEP6’s role in ER cargo capacity and GPCR trafficking (PMID:24098485).

In vivo, CRISPR-Cas9 knock-in mice harboring the p.Leu135Pro variant recapitulate early‐onset rod degeneration and ERG deficits (PMID:27889058). AAV8-mediated delivery of the retina-specific isoform Reep6.1 rescues photoreceptor structure and function, restoring guanylyl cyclase 1 localization and photoresponse in mutant mice (PMID:30101608).

No studies have reported healthy individuals with biallelic loss‐of‐function REEP6 variants or convincing evidence disputing the association. The cumulative genetic and experimental data support a strong causal role for REEP6 loss of function in RP 77.

Key Take-home: REEP6 should be included in diagnostic gene panels for autosomal recessive retinitis pigmentosa, and gene replacement therapy targeting REEP6 offers a promising therapeutic avenue.

References

• American Journal of Human Genetics • 2016 • Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. PMID:27889058
• Genes • 2021 • Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population. PMID:33917198
• Human Gene Therapy • 2019 • Gene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice. PMID:30101608
• PLoS One • 2013 • REEPs are membrane shaping adapter proteins that modulate specific G protein-coupled receptor trafficking by affecting ER cargo capacity. PMID:24098485

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