High Prevalence of Symptoms of Meniere's Disease in three Families With a Mutation in the COCH Gene

Abstract

We report the genetic analysis of one large Belgian and two small Dutch families with autosomal dominant non-syndromic progressive sensorineural hearing loss associated with vestibular dysfunction. Linkage studies in the Belgian family mapped the disease to the DFNA9 locus on chromosome 14. Mutation analysis of the COCH gene, which is responsible for DFNA9, revealed a missense mutation changing a highly conserved residue. One of the patients, who had an earlier age of onset in comparison with most of the affected family members, was shown to be homozygous for the mutation. After the mutation was found in the Belgian family, we discovered that the same missense mutation was also present in two Dutch families with similar cochleo-vestibular symptoms. In all three families with hearing loss and imbalance problems, >25% of the patients showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing loss. Clinically, these symptoms are consistent with the criteria for Menière's disease. The importance of genetic factors in Menière's disease has been suggested on many occasions, but this study is the first report of a mutation in a gene leading to the symptoms of Menière's disease in a significant portion of the carriers. The COCH gene may be one of the genetic factors contributing to Menière's disease and the possibility of a COCH mutation should be considered in patients with Menière's disease symptoms.

Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease

“…Fransen et al 3 and Verstreken et al 6 reported a large DFNA9 family where, apart from hearing loss and vestibular dysfunction, 25% of the carriers of the COCH mutation suffered from recurrent episodes of dizziness, associated with tinnitus, aural fullness, nausea, and vomiting. Such episodes are very similar to the vertigo attacks encountered in Meniere's disease.…”

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

“…COCH was chosen as a candidate for hearing loss due to its high expression in the Morton fetal cochlear cDNA library (Robertson et al, 1994;Robertson et al, 1997). Mutations in the gene have since been found to be responsible for DFNA9 in a number of families around the world (Robertson et al, 1998;de Kok et al, 1999;Fransen et al, 1999;Kamarinos et al, 2001;Usami et al, 2003;Nagy et al, 2004;Kemperman et al, 2005;Street et al, 2005;Collin et al, 2006;Pauw et al, 2007). But, although this relationship is well-established, mice deficient in Coch do not exhibit hearing loss (Makishima et al, 2005).…”

Absence of COCH mutations in patients with Meniere disease

“…15 Combining genetic linkage analysis and positional candidate gene strategies, three different missense mutations were found in the COCH gene in three US families: V66G, G88E and W117R. 3 Subsequently, a P51S mutation was identified in one large Belgian and two small Dutch families at the DFNA9 locus, 4,19 and a fifth I109N mutation was identified in an Australian family with sensorineural hearing loss beginning in the second or third decade with concomitant vestibular dysfunction. 20 More than 25% of the patients affected with P51S mutation in the European kindreds showed episodes of vertigo, tinnitus and aural fullness with sensorineural hearing loss, which were consistent with the criteria for MD.…”

“…Several mutations have been described in the coagulation factor C homology (COCH) gene (14q12 -13), which cause the autosomal dominant sensorineural hearing loss DFNA9 (OMIM 603196), 3 and a high prevalence of symptoms of MD has been described in three European families with a P51S mutation in exon 4 of COCH gene. 4 A group of British patients with FMD have shown an autosomal dominant inheritance with 60% penetrance, anticipation and an association with the class I HLA Cw7 antigen. 5 Linkage analysis has pointed to chromosome 14, but sequencing has excluded any mutation of the 12 coding exons of COCH gene in the British families.…”