OTOF – Autosomal Recessive Nonsyndromic Hearing Loss 9 (DFNB9)

OTOF encodes otoferlin, a multi‐C2 domain Ca²⁺ sensor essential for synaptic vesicle exocytosis at inner hair cell ribbon synapses. Autosomal recessive pathogenic variants in OTOF cause autosomal recessive nonsyndromic hearing loss 9 (DFNB9).

Genetic studies in diverse populations confirm AR inheritance with robust segregation. In 76 unrelated Chinese ANSD patients, OTOF variants were identified (PMID:21935370), and 11 Korean DFNB9 patients carried recurrent and novel alleles (PMID:30482216). Segregation was observed in at least 5 additional affected relatives across consanguineous families. The variant spectrum includes loss-of-function alleles—nonsense, frameshift and splice site—and missense changes, exemplified by c.1236del (p.Asp412GlufsTer13) in a Chinese ANSD pedigree (PMID:30065612).

Functional assays and animal models establish a haploinsufficiency mechanism. ENU‐induced Otof(deaf5Jcs) mice bearing a C2B missense mutation lack otoferlin expression and display absent exocytosis with profound deafness (PMID:17967520). A zebrafish transmembrane‐domain truncation mutant shows synaptic ribbon deficits, impaired endocytosis and delayed hair cell development (PMID:33979209).

Protein interaction studies reveal otoferlin binding partners Rab8b and myosin VI, implicating roles in trans-Golgi trafficking and basolateral synaptic maintenance (PMID:18772196; PMID:19417007). Rescue of synaptic function by wild-type otoferlin in vitro further supports pathogenicity.

No conflicting reports have disputed OTOF's role in DFNB9 or suggested alternative phenotypes. The convergence of genetic, segregation and functional data over two decades fulfills ClinGen criteria for a Definitive gene–disease relationship.

Key take-home: Screening of OTOF for LoF and domain-disrupting variants is critical for the genetic diagnosis of DFNB9 and informs early cochlear implantation strategies.

References

• PLoS One • 2011 • Variants of OTOF and PJVK genes in Chinese patients with auditory neuropathy spectrum disorder PMID:21935370
• Journal of Translational Medicine • 2018 • Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics PMID:30482216
• Current Genomics • 2018 • An OTOF Frameshift Variant Associated with Auditory Neuropathy Spectrum Disorder PMID:30065612
• Hearing Research • 2007 • A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9 PMID:17967520
• Molecular Biology of the Cell • 2021 • Truncation of the otoferlin transmembrane domain alters the development of hair cells and reduces membrane docking PMID:33979209
• Human Molecular Genetics • 2008 • Rab8b GTPase, a protein transport regulator, is an interacting partner of otoferlin, defective in a human autosomal recessive deafness form PMID:18772196
• Human Molecular Genetics • 2009 • Otoferlin interacts with myosin VI: implications for maintenance of the basolateral synaptic structure of the inner hair cell PMID:19417007

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