ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing

Area of Science:

• Genetics
• Molecular Biology
• Ophthalmology

Background:

• Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a retinal dystrophy within the 'bestrophinopathies' spectrum, often linked to glaucoma and cataract.
• Previous studies indicate ADVIRC arises from BEST1 mutations causing exon skipping and aberrant protein isoforms.
• This research investigates a novel ADVIRC mutation's molecular mechanism.

Discussion:

• The novel c.704T-->C mutation in exon 6 disrupts an exonic splice enhancer (ESE) site, altering splicing factor binding.
• ADVIRC-associated mutations in exon 6 weakened or abolished splicing in an ESE-dependent assay compared to a Best disease mutation.
• Increased binding of ASF/SF2 to ADVIRC-mutated sequences suggests a role in aberrant splicing.

Key Insights:

• A novel BEST1 mutation causing ADVIRC disrupts an exonic splice enhancer (ESE) site.
• This mutation alters the binding of splicing-associated SR proteins, specifically increasing ASF/SF2 affinity.
• The findings suggest the affected region may be part of a composite exonic regulatory element of splicing (CERES) site.

Outlook:

• Further investigation into the role of ASF/SF2 and CERES sites in ADVIRC pathogenesis is warranted.
• Understanding these molecular mechanisms could inform therapeutic strategies for bestrophinopathies.
• This study contributes to the broader understanding of genotype-phenotype correlations in inherited retinal dystrophies.