ATP-binding cassette sub-family A member 4 (ABCA4) pre-mRNA intron 39 intronic splicing silencer motif (ABCA4 intron 39 ISS)

The ATP-binding cassette sub-family A member 4 (ABCA4) pre-mRNA intron 39 intronic splicing silencer (ISS) motif is a regulatory RNA sequence that modulates the splicing of the ABCA4 transcript (Sangermano et al., 2019). This motif is particularly significant in the context of Stargardt disease, where mutations such as c.5461-10T>C within or near this region lead to aberrant splicing, including exon skipping or the use of cryptic splice sites (Albert et al., 2018). These splicing defects result in a lack of functional ABCA4 protein, which is a flippase responsible for transporting vitamin A derivatives across photoreceptor membranes. The absence of functional ABCA4 leads to the accumulation of toxic lipofuscin in the retina, causing progressive vision loss (Garanto et al., 2019). Therapeutic intervention focuses on using antisense oligonucleotides (ASOs) to bind specifically to this ISS motif. By blocking the recruitment of splicing repressor proteins, these ASOs facilitate the recognition of the correct splice sites, thereby restoring the production of full-length, functional ABCA4 protein and potentially slowing disease progression (Albert et al., 2018). This approach represents a precision medicine strategy for patients carrying specific deep-intronic or splice-site variants in the ABCA4 gene.

Other names

ABCA4 c.5461-10T>C splicing silencerABCA4 intron 39 regulatory elementABCA4 pre-mRNA splicing motifABCA4 deep-intronic variant site

Steric blocking of the intronic splicing silencer motif to prevent binding of splicing repressors and promote correct exon inclusion.