Otoferlin (OTOF) p.Q829X mutant messenger RNA (OTOF p.Q829X mRNA)

OTOF p.Q829X mutant messenger RNA is a specific transcript of the OTOF gene containing a nonsense mutation (c.2485C>T) that results in a premature stop codon at the 829th amino acid position (Migliosi et al., 2002). This mutation leads to the production of a truncated, non-functional otoferlin protein or triggers nonsense-mediated decay of the mRNA, effectively resulting in a loss of otoferlin function (UniProt O60244). Otoferlin is a critical calcium sensor located in the inner hair cells of the cochlea, where it facilitates the fusion of synaptic vesicles with the plasma membrane to release neurotransmitters (Yasunaga et al., 1999). The absence of functional otoferlin disrupts the transmission of auditory signals to the auditory nerve, causing a condition known as autosomal recessive deafness 9 (DFNB9) or auditory neuropathy. Therapeutic approaches for patients harboring this mutant mRNA primarily focus on gene replacement therapy using adeno-associated virus (AAV) vectors to deliver a functional OTOF gene. Because the OTOF coding sequence exceeds the packaging capacity of a single AAV, dual-vector systems are employed to reconstitute the full-length protein within the target cells (Lv et al., 2024). Recent clinical successes with these gene therapies, such as DB-OTO and AK-OTOF, have demonstrated the potential to restore hearing sensitivity and speech perception in children with this specific genetic profile (Qi et al., 2024).

Other names

OTOF c.2485C>T mRNAOtoferlin p.Gln829Ter mRNADFNB9 mutant mRNAOtoferlin nonsense mutation mRNA

AAV-mediated gene replacement therapy using dual-vector systems to deliver functional OTOF cDNA and bypass the mutant mRNA defect.