Sun et al. 2026 — Rbm24 Alternative Splicing Is Essential for Cochlear Hair Cell Stereocilia Integrity
Citation
Sun et al. (2026). Alternative splicing of the Rbm24 gene is essential for cochlear hair cell stereocilia integrity and hearing function in mice. PNAS. PMID: 41973913.
Core finding
Rbm24 produces two isoforms via alternative splicing. The isoform including exon 4 is the functionally required form in cochlear hair cells. Selective deletion of exon 4 from Rbm24 in mice causes:
- Stereocilia disorganization in outer hair cells (OHCs)
- Hair cell loss (progressive)
- Hearing loss — functionally confirmed by ABR/DPOAE
The exon 4-containing isoform is highly expressed in OHCs during the critical period of hair bundle morphogenesis.
Key mechanistic detail
RBM24 (RNA-binding motif protein 24) directly binds and regulates the splicing of multiple cochlear transcripts. STRC (stereocilin) is identified as a direct RBM24 splicing target. Loss of the functional RBM24 isoform → altered STRC pre-mRNA processing → defective stereocilin → bundle failure.
Why this matters for DFNB16
RBM24 sits upstream of STRC in a regulatory hierarchy. This is not a parallel pathway — it is a direct regulatory dependency. If RBM24 splicing is disrupted (or underactive), STRC mRNA is mis-spliced and likely non-functional, even if the STRC gene itself is intact.
Implication: In some DFNB16 patients (especially those with hypomorphic or compound het mutations), the problem may be partially at the RBM24 regulatory level, not just the STRC coding sequence.
Computational hooks
- RBM24 exon 4 deletion model — use as reference for “loss of function” in motif scan
- STRC as direct target — scan STRC pre-mRNA for RBM24 binding motifs (TG-repeat + AU-rich GCTCTTC)
- Exon 4-containing isoform = therapeutic target for isoform-specific delivery
Connections
[source]STRC RBM24 Regulatory Hypothesis — this paper is the primary evidence base[see-also]STRC Hearing Loss — mechanistic link between RBM24 splicing and DFNB16[see-also]STRC mRNA Therapy Hypothesis — mRNA delivery of RBM24 exon-4 isoform as therapeutic approach[about]Misha