REEP6 – Retinitis Pigmentosa

The association between REEP6 and retinitis pigmentosa is supported by robust clinical and experimental evidence. Multiple independent studies have identified biallelic (autosomal recessive) loss-of-function variants in REEP6 in patients exhibiting night blindness (nyctalopia) and constricted peripheral visual fields. One pivotal case report described a sporadic rod‑cone dystrophy patient harboring a homozygous nonsense variant, c.267G>A (p.Trp89Ter), establishing a direct link between REEP6 dysfunction and photoreceptor degeneration (PMID:29120066).

A comprehensive multi‐patient study further substantiated this association by identifying REEP6 mutations in seven affected individuals from five unrelated families, with segregation data showing co‐segregation of biallelic variants with the retinitis pigmentosa phenotype (PMID:27889058). These findings underscore the recurrence of typical loss‑of‑function alleles, including the recurrent c.267G>A (p.Trp89Ter) variant, across different cohorts.

Genetic evidence is bolstered by the diversity of variant types observed. Aside from nonsense changes, additional frameshift, splice, and insertion/deletion events have been reported, collectively emphasizing a consistent deleterious effect on REEP6 protein function. The autosomal recessive inheritance pattern is further evidenced by the familial segregation of these pathogenic variants among affected relatives (PMID:27889058; PMID:29120066).

In-depth functional studies using both patient‑derived cells and animal models have demonstrated that REEP6 deficiency leads to disrupted protein trafficking and subsequent photoreceptor degeneration. Notably, gene replacement therapy in REEP6‑mutant mice resulted in significant restoration of photoreceptor function and improved retinal morphology, directly corroborating the pathogenic mechanism (PMID:30101608). Such experimental recapitulation of the human phenotype further substantiates the clinical relevance of the genetic findings.

Collectively, the genetic and functional data converge to assert a strong association between REEP6 mutations and autosomal recessive retinitis pigmentosa. The evidence spans single‐patient case reports, multi‑family segregation studies, and compelling experimental validation across different model systems. In addition, the recurrence of loss‑of‑function variants and the robust phenotypic rescue observed in gene therapy experiments offer a clear mechanistic insight into the disease process.

Key take‑home: Genetic testing for REEP6 variants provides critical diagnostic information for retinitis pigmentosa and may inform future therapeutic strategies.

References

• Clinical Genetics • 2018 • A novel nonsense variant in REEP6 is involved in a sporadic rod‑cone dystrophy case PMID:29120066
• American Journal of Human Genetics • 2016 • Mutations in REEP6 Cause Autosomal‑Recessive Retinitis Pigmentosa PMID:27889058
• Human Gene Therapy • 2019 • Gene Therapy Rescues Retinal Degeneration in Receptor Expression‑Enhancing Protein 6 Mutant Mice PMID:30101608

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