COCH – Autosomal Dominant Nonsyndromic Hearing Loss

COCH encodes cochlin, the most abundant secreted protein in the inner ear. Heterozygous mutations in COCH cause autosomal dominant nonsyndromic hearing loss (DFNA9) with or without vestibular dysfunction (Autosomal Dominant Nonsyndromic Hearing Loss). Patients typically present with late-onset, progressive sensorineural hearing impairment and variable vestibular hyporeflexia (HP:0000365; HP:0001751; HP:0001756).

Genetic evidence supporting a strong gene–disease association includes reports of at least 21 unrelated probands with distinct pathogenic COCH variants across more than 15 families, with segregation of disease in multiple pedigrees (21 probands) (PMID:25230692). A recurrent pathogenic coding change c.485G>A (p.Cys162Tyr) segregates with hearing loss in two independent Chinese families (PMID:22931125). Overall, 18 distinct missense and nonsense variants in COCH have been reported in DFNA9 families, affecting LCCL and vWFA domains and demonstrating co-segregation in affected relatives.

The variant spectrum includes missense changes in the LCCL domain (e.g. c.263G>A (p.Gly88Glu), c.349T>C (p.Trp117Arg)), vWFA domains (e.g. c.485G>A (p.Cys162Tyr)), and a frameshift beyond vWFA leading to p.Asp544ValfsTer3. No founder alleles have been definitively described, but several variants recur in East Asian cohorts. Carrier frequency data remain limited, consistent with the rarity of dominant DFNA9.

Functional studies demonstrate that DFNA9-linked missense mutations disrupt cochlin folding, post-translational processing, and secretion. Mutants show ER/Golgi retention and form stable disulfide-bonded dimers and higher-order aggregates, whereas wild-type cochlin is efficiently secreted and proteolytically cleaved (PMID:12843317; PMID:20228067; PMID:22610276). Rescue of secretion defects has not yet been reported.

Pathogenic mechanisms include dominant-negative and gain-of-function effects whereby mutant cochlin aggregates extracellularly, sequesters wild-type protein, and perturbs extracellular matrix interactions in the inner ear. There is concordance between the domain location of variants, the severity of vestibular versus auditory phenotypes, and cellular aggregation propensity.

In summary, extensive genetic and experimental data classify the COCH–DFNA9 association as Strong. Further natural history studies and therapeutic targeting of cochlin aggregation may inform clinical management. Key Take-home: COCH mutation screening is clinically indicated in patients with late-onset progressive sensorineural hearing loss, particularly with vestibular involvement.

References

• Journal of molecular medicine (Berlin, Germany) • 2012 • A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. PMID:22610276
• Journal of medical genetics • 2003 • Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. PMID:12843317
• The Journal of biological chemistry • 2010 • Role of protein misfolding in DFNA9 hearing loss. PMID:20228067
• Clinical genetics • 2013 • Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. PMID:22931125
• Human mutation • 2014 • Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder. PMID:25230692

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