OTOF – Auditory Neuropathy

OTOF encodes otoferlin, a multi-C2 domain protein essential for Ca²⁺-dependent synaptic vesicle exocytosis at the cochlear inner hair cell ribbon synapse. Biallelic pathogenic variants in OTOF cause non-syndromic autosomal recessive auditory neuropathy spectrum disorder (ANSD), characterized by preserved otoacoustic emissions with absent or severely abnormal auditory brainstem responses (PMID:20230791).

Inheritance is autosomal recessive with robust genetic evidence across diverse populations. Pathogenic OTOF variants have been identified in >200 individuals with ANSD: for example, 7 of 11 Brazilian AN probands carried OTOF mutations (PMID:19461658), 14 of 34 Chinese congenital ANSD infants harbored two or three mutant alleles (PMID:26818607), and 39 of 2,265 Japanese ARSNHL cases had biallelic OTOF mutations (PMID:31095577). Segregation was documented in multiple consanguineous families, including three siblings homozygous for c.3106delG (p.Glu1037del) presenting with temperature-sensitive ANSD (PMID:20230791).

The variant spectrum exceeds 100 alleles, spanning missense (e.g., c.2447G>A (p.Arg816His) (PMID:24001616)), frameshift (c.1236delC (p.Asp412GlufsTer13) (PMID:30065612)), canonical splice-site (IVS28+1G>T) (PMID:24135434)), and large multi-exon duplications (PMID:40004445). Recurrent founder alleles such as p.E1700Q in Taiwanese and p.R1939Q in Japanese patients further underpin allele-specific screening strategies (PMID:20224275; PMID:22575033).

Epidemiologically, OTOF mutations account for ~40% of congenital ANSD in Chinese infants and 56.5% of Japanese ANSD pedigrees. In pooled ARSNHL cohorts, OTOF contributes to 1.7–7.7% of cases, emphasizing its priority in diagnostic panels.

Functional assays in Otof⁻/⁻ and missense mouse models demonstrate profound deafness with preserved vestibular function, confirming otoferlin’s role as a Ca²⁺ sensor in hair cell exocytosis (PMID:17967520). In vitro studies show that truncation of the transmembrane domain impairs membrane docking and vesicle fusion, aligning with human phenotypes (PMID:33979209).

Integration of extensive genetic and functional data supports a definitive gene–disease relationship between recessive OTOF loss-of-function and auditory neuropathy. Molecular diagnosis of OTOF-related ANSD enables early cochlear implantation, improving speech and hearing outcomes. Key Take-home: OTOF testing should be prioritized in infants with preserved otoacoustic emissions and abnormal auditory brainstem responses to guide timely intervention.

References

• Biochemical and biophysical research communications • 2010 • Temperature-sensitive auditory neuropathy associated with an otoferlin mutation: Deafening fever! PMID:20230791
• International Journal of Pediatric Otorhinolaryngology • 2013 • Identification of novel OTOF compound heterozygous mutations by targeted next-generation sequencing in a Chinese patient with auditory neuropathy spectrum disorder. PMID:24001616
• Audiology & neuro-otology • 2013 • A novel otoferlin splice-site mutation in siblings with auditory neuropathy spectrum disorder. PMID:24135434
• Current Genomics • 2018 • An OTOF Frameshift Variant Associated with Auditory Neuropathy Spectrum Disorder. PMID:30065612
• Journal of human genetics • 2009 • Novel OTOF mutations in Brazilian patients with auditory neuropathy. PMID:19461658
• Hearing Research • 2007 • A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9. PMID:17967520

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