A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects

We analysed a Dutch family with autosomal dominant non-syndromic progressiv e sensorineural hearing loss and mapped the underlying gene defect by genet ic linkage analysis to a 11.0 cM region overlapping the DFNAS interval on c hromosome 14q12-q13. Clinical ly, the Dutch family differs from the origina l DFNAS family by a later age at onset and a more clearly established vesti bular impairment, A gene that is highly and specifically expressed in the h uman fetal cochlea and vestibule, COCH (previously described as Coch5B2), w as mapped to the DFNAS critical region. Sequence analysis revealed a 208C-- >T mutation in the COCH gene, resulting in a Pro51Ser substitution in the p redicted protein in all affected individuals of the family but not in unaff ected family members and 200 control individuals. The same mutation was als o identified in three apparently unrelated families with a similar phenotyp e, suggesting the presence of a Dutch founder mutation. The function of COC H is unknown but several characteristics of the protein point to a structur al role in the extracellular matrix. The mutant serine at position 51 is si tuated between cysteines and possibly interferes with proper COCH protein f olding or its interaction with extracellular matrix proteins.