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A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss
  1. I Nagy1,
  2. M Horváth2,
  3. M Trexler1,
  4. G Répássy2,
  5. L Patthy1
  1. 1Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary
  2. 2Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary
  1. Correspondence to:
 Dr L Patthy
 Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Karolina ut 29, Budapest, H-1113 Hungary;

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Recently the causative gene of autosomal dominant sensorineural nonsyndromic late onset hearing loss (DFNA9) has been identified as the COCH gene, which lies in the DFNA9 region of human chromosome 14 (gene map locus 14q12–q13). Molecular analysis of cases of DFNA9 have identified several families with five different mutations in this gene.1–5

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.

Our present investigation was aimed at identifying novel mutations affecting the LCCL domain of cochlin in order to gain more insight into the pathomechanism of DFNA9. Hungarian patients selected according to the diagnostic criteria of DFNA9 were screened for the presence of mutations affecting the LCCL domain. These studies identified one person heterozygous for a novel mutation in the coding region of …

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