BEST1 – Retinitis Pigmentosa

The BEST1 gene encodes the bestrophin-1 chloride channel at the basolateral membrane of the retinal pigment epithelium (BEST1) and is classically implicated in macular dystrophies. Rare heterozygous BEST1 variants have also been reported in peripheral photoreceptor degeneration consistent with Retinitis pigmentosa (PMID:29503890).

A solitary simplex RP proband exhibited bone-spicule pigmentation, extinguished ERG and abnormal EOG, and harbored a novel de novo heterozygous BEST1 deletion not present in either parent (PMID:29503890).

Burgess et al. described four unrelated patients with autosomal-dominant RP carrying rare BEST1 missense variants, including c.418C>G (p.Leu140Val) and c.682G>A (p.Asp228Asn), each absent in population controls (PMID:19853238). Subsequently, two Chinese families revealed a novel frameshift c.345_346insGGCAAGGACG (p.Glu119GlyfsTer116) co-segregating with RP in one pedigree, often in the presence of an USH2A variant, suggesting potential digenic modulation (PMID:35186678).

Beyond the single RP family with the frameshift allele, no additional affected relatives have been reported, and familial segregation of RP-associated BEST1 variants remains limited.

Electrophysiological studies demonstrate that c.418C>G (p.Leu140Val) and c.682G>A (p.Asp228Asn) markedly reduce Cl⁻ current and mislocalize bestrophin-1 in polarized epithelial models, consistent with a loss-of-function mechanism (PMID:19853238).

While BEST1 is definitively linked to macular dystrophies, its role in RP is currently limited by sparse proband data, minimal segregation, and possible modifier-gene interactions. BEST1 variant screening may be considered in atypical RP presentations, particularly when macular involvement or digenic risk alleles are present.

References

• American journal of ophthalmology case reports • 2016 • Retinitis pigmentosa associated with a mutation in BEST1. PMID:29503890
• Ophthalmic Genetics • 2022 • Clinical heterogeneity of patients with novel BEST1 mutations. PMID:35186678
• American journal of human genetics • 2009 • Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. PMID:19853238

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