A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss

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Abstract
The cochlin protein encoded by COCH is an extracellular matrix protein that contains an LCCL domain and two von Willebrand type A domains.1 Interestingly, all mutations causing DFNA9 type deafness disorder affect the LCCL domain of cochlin. In view of the central role of this domain in the DFNA9 disorder, we initiated studies on it to explore the molecular basis of the disease.6 We found that most DFNA9 mutations affected conserved structural elements of the LCCL fold and disrupted the proper folding of this domain; recombinant mutant LCCL domains expressed in Escherichia coli failed to adopt the wild type fold and instead formed insoluble aggregates.7 It is noteworthy that insoluble deposits are detected in temporal bone sections of individuals affected by DFNA9.8 These results support the notion that the DFNA9 mutations may act through a gain of function mechanism; it is the presence of the abnormal protein that causes the disease. According to this view, accumulation of deposits in vestibular and cochlear nerve channels leads to strangulation and progressive degeneration of the dendrites, and loss of cochlear and vestibular neurones.

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