BEST1 – Nanophthalmos

BEST1 encodes bestrophin-1, a chloride channel localized to the basolateral membrane of the retinal pigment epithelium (RPE). Heterozygous mutations in BEST1 are established causes of bestrophinopathies. In five unrelated families with autosomal dominant vitreoretinochoroidopathy (ADVIRC) presenting with nanophthalmos, linkage analysis and sequencing identified three distinct BEST1 variants that concurrently alter amino acid sequence and pre-mRNA splicing (PMID:15452077).

Segregation analysis demonstrated co-inheritance of these splice‐regulatory changes with nanophthalmos in all affected members across five families (7 additional affected relatives) (PMID:15452077). One representative variant is c.257T>C (p.Val86Ala). These mutations cluster in exon 6 and produce dual isoforms: the wild type and an in‐frame deletion lacking critical coding sequence, consistent with a dominant‐negative effect on ocular growth.

Minigene splicing assays confirmed that each variant disrupts canonical splice signals, leading to exon skipping and aberrant bestrophin-1 products in vitro (PMID:15452077). The resulting mispatterned RPE isoforms support a mechanism whereby RPE dysfunction perturbs ocular patterning and axial length regulation.

No studies to date have refuted the association. The combined evidence from multiple families and concordant functional data provides moderate clinical validity for BEST1 in autosomal dominant nanophthalmos. Inclusion of BEST1 in genetic testing panels for nanophthalmos and related developmental eye disorders is warranted for accurate diagnosis and counseling.

References

• Investigative ophthalmology & visual science • 2004 • Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). PMID:15452077

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