ORPHA: 90635; DO: 0110593;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q12 | Deafness, autosomal dominant 9 | 601369 | Autosomal dominant | 3 | COCH | 603196 |
A number sign (#) is used with this entry because of evidence that DFNA9 is caused by heterozygous mutation in the cochlin gene (COCH; 603196) on chromosome 14q12.
DFNA9 is an autosomal dominant adult-onset form of progressive sensorineural hearing loss associated with variable vestibular dysfunction (summary by Robertson et al., 2006).
Manolis et al. (1996) reported results of a genetic linkage analysis in a family with nonsyndromic postlingual progressive sensorineural hearing loss. In this family hearing loss was inherited as an autosomal dominant trait which begins at approximately 20 years of age and progresses to total deafness. Manolis et al. (1996) described unique temporal bone histopathologic findings in this family. Affected individuals were found to have mucopolysaccharide depositions in the channels of the cochlear and vestibular nerves. These depositions apparently caused strangulation and degeneration of dendritic fibers. Manolis et al. (1996) noted that others (Khetarpal et al., 1991; Khetarpal, 1993) had reported previous clinical evaluations of this family.
Based on the findings in the 3 affected families, including the family of Manolis et al. (1996), Robertson et al. (1998) described the hearing loss as having its onset between 20 and 30 years of age. Initially it was most profound at high frequencies and displayed variable progression to anacusis by 40 to 50 years of age. Some DFNA9 patients had received cochlear implants and others used hearing aids. A spectrum of clinical vestibular involvement, ranging from lack of symptoms to presence of vertigo, vestibular hypofunction as assessed by electronystagmography and histopathology, had been found.
By linkage analysis in a family with nonsyndromic postlingual progressive sensorineural hearing loss, Manolis et al. (1996) demonstrated that the deafness localized to chromosome 14q12-q13. The maximum lod score (6.19 at theta = 0.0) was obtained with the marker D14S121.
In the original family of Manolis et al. (1996) and 2 additional families with DFNA9 identified with the characteristic histopathologic findings of acidophilic ground substance in the cochlea and vestibular labyrinth, Robertson et al. (1998) described separate mutations in the COCH gene (603196.0001-603196.0003), which is expressed almost exclusively in the inner ear.
Fransen et al. (1999) identified a mutation in the COCH gene (P51S; 603196.0004) in 1 large Belgian and 2 small Dutch families with autosomal dominant nonsyndromic progressive sensorineural hearing loss associated with vestibular dysfunction. Greater than 25% of the patients affected with this mutation showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness, and hearing loss. Fransen et al. (1999) suggested that the COCH gene may be one of the genetic factors contributing to Meniere disease (156000) and that the possibility of a COCH mutation should be considered in patients with Meniere disease symptoms.
Usami et al. (2003) performed COCH mutation analysis in a Japanese population of 23 patients from independent families with autosomal dominant hearing impairment, 4 of whom reported vestibular symptoms, and 20 Meniere disease patients. Usami et al. (2003) concluded that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominant inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction or sporadic Meniere disease. They identified a novel point mutation in the COCH gene (603196.0006) in a patient with autosomal dominant hearing loss and vestibular symptoms.
Street et al. (2005) performed a genomewide scan and linkage analysis in an American pedigree with hearing loss and vestibular and oculomotor disturbances. A maximal pairwise lod score of 7.08 was obtained with marker D14S1021, and a mutation was identified in exon 12 of the COCH gene (603196.0007) that cosegregated with auditory dysfunction. Street et al. (2005) stated that this was the first mutation to be reported outside of the LCCL domain, which is encoded by exons 4 and 5. Hearing loss and vestibular dysfunction was present in a 17-year-old male in this family, the youngest reported age of onset in a DFNA9 family member.
Yuan et al. (2008) reported a large Chinese family with DFNA9 confirmed by genetic analysis (603196.0008). Age at onset ranged from the second to fifth decade of life, and there was some evidence of genetic anticipation, although the findings may have been due to bias. Most affected family members (82%) had tinnitus at the onset of hearing loss. Hearing loss first affected the high frequencies and later involved all frequencies. Overall, the patients displayed a downward sloping audiogram contour. Although none had clinical vestibular complaints, detailed studies showed evidence for subtle defects.
Hildebrand et al. (2009) reported a 5-generation American family in which members with nonsyndromic sensorineural deafness and vestibular impairment, excluding 2 thought to represent deafness phenocopies, had a P51S mutation in the COCH gene (603196.0004). In addition, 1 member with the P51S mutation had bilateral superior semicircular canal dehiscence (SCCD). The family was related to those reported by Fransen et al. (1999, 2001), providing further evidence of a founder mutation. Hildebrand et al. (2009) recommended high-resolution temporal bone CT in patients with DFNA9-related deafness and screening for COCH in sporadic or familial cases of superior semicircular canal dehiscence.
In 3 unrelated patients with SCCD and no family history of the disorder or of deafness, Crovetto et al. (2012) excluded mutations in the coding exons and intron-exon boundaries of the COCH gene.
In mouse and human inner ear, Robertson et al. (2006) found that cochlin immunostaining was restricted to tissues of mesodermal origin; neuroectodermally derived structures clearly lacked cochlin expression. Robertson et al. (2006) found that temporal bones from patients with DFNA9 showed large amounts of cochlin-immunoreactive eosinophilic acellular deposits contained throughout the spiral ligament, limbus, and osseous spiral lamina. Coch-null mice showed no such material, suggesting that DFNA9-associated mutations result in a dominant-negative effect. Robertson et al. (2006) suggested that the obstruction of these channels in DFNA9 results in secondary neuronal damage and hearing loss.
Makishima et al. (2005) found that Coch -/- mice with no detectable cochlin in the inner ear had auditory brainstem responses to click and pure-tone stimuli indistinguishable from those of wildtype mice. A lacZ reporter assay revealed Coch mRNA expression in nonsensory epithelial and stromal regions of the cochlea and vestibular labyrinth in the mutant mice. Makishima et al. (2005) concluded that DFNA9 may not be caused by COCH haploinsufficiency but by a dominant-negative or gain-of-function effect in nonsensory regions of the inner ear.
Crovetto, M. A., Whyte, J., Sarasola, E., Rodriguez, J. A., Garcia-Barcina, M. J. Absence of COCH gene mutations in patients with superior semicircular canal dehiscence. (Letter) Am. J. Med. Genet. 158A: 251-253, 2012. [PubMed: 22139968] [Full Text: https://doi.org/10.1002/ajmg.a.34377]
Fransen, E., Verstreken, M., Bom, S. J. H., Lemaire, F., Kemperman, M. H., de Kok, Y. J. M., Wuyts, F. L., Verhagen, W. I. M., Huygen, P. L. M., McGuirt, W. T., Smith, R. J. H., van Maldergem, L., Declau, F., Cremers, C. W. R. J., van de Heyning, P. H., Cremers, F. P. M., van Camp, G. A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation. J. Med. Genet. 38: 61-65, 2001. [PubMed: 11332404] [Full Text: https://doi.org/10.1136/jmg.38.1.61]
Fransen, E., Verstreken, M., Verhagen, W. I. M., Wuyts, F. L., Huygen, P. L. M., D'Haese, P., Robertson, N. G., Morton, C. C., McGuirt, W. T., Smith, R. J. H., Declau, F., Van de Heyning, P. H., Van Camp, G. High prevalence of symptoms of Meniere's disease in three families with a mutation in the COCH gene. Hum. Molec. Genet. 8: 1425-1429, 1999. [PubMed: 10400989] [Full Text: https://doi.org/10.1093/hmg/8.8.1425]
Hildebrand, M. S., Tack, D., DeLuca, A., Hur, I. A., Van Rybroek, J. M., McMordie, S. J., Muilenburg, A., Hoskinson, D. P., Van Camp, G., Pensak, M. L., Storper, I. S., Huygen, P. L. M., Casavant, T. L., Smith, R. J. H. Mutation in the COCH gene is associated with superior semicircular canal dehiscence. Am. J. Med. Genet. 149A: 280-285, 2009. [PubMed: 19161137] [Full Text: https://doi.org/10.1002/ajmg.a.32618]
Khetarpal, U. Autosomal dominant sensorineural hearing loss: further temporal bone findings. Arch. Otolaryng. Head Neck Surg. 119: 106-108, 1993. [PubMed: 8417734] [Full Text: https://doi.org/10.1001/archotol.1993.01880130108016]
Khetarpal, U., Schuknecht, H. F., Gacek, R. R., Holmes, L. B. Autosomal dominant sensorineural hearing loss: pedigrees, audiologic findings and temporal bone findings in two kindreds. Arch. Otolaryng. Head Neck Surg. 117: 1032-1042, 1991. [PubMed: 1910721] [Full Text: https://doi.org/10.1001/archotol.1991.01870210104022]
Makishima, T., Rodriguez, C. I., Robertson, N. G., Morton, C. C., Stewart, C. L., Griffith, A. J. Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder. Hum. Genet. 118: 29-34, 2005. [PubMed: 16078052] [Full Text: https://doi.org/10.1007/s00439-005-0001-4]
Manolis, E. N., Yandavi, N., Nadol, J. B., Jr., Eavey, R. D., McKenna, M., Rosenbaum, S., Khetarpal, U., Halpin, C., Merchant, S. N., Duyk, G. M., MacRae, C., Seidman, C. E., Seidman, J. G. A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13. Hum. Molec. Genet. 5: 1047-1050, 1996. [PubMed: 8817345] [Full Text: https://doi.org/10.1093/hmg/5.7.1047]
Robertson, N. G., Cremers, C. W. R. J., Huygen, P. L. M., Ikezono, T., Krastins, B., Kremer, H., Kuo, S. F., Liberman, M. C., Merchant, S. N., Miller, C. E., Nadol, J. B., Jr., Sarracino, D. A., Verhagen, W. I. M., Morton, C. C. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum. Molec. Genet. 15: 1071-1085, 2006. [PubMed: 16481359] [Full Text: https://doi.org/10.1093/hmg/ddl022]
Robertson, N. G., Lu, L., Heller, S., Merchant, S. N., Eavey, R. D., McKenna, M., Nadol, J. B., Jr., Miyamoto, R. T., Linthicum, F. H., Jr., Neto, J. F. L., Hudspeth, A. J., Seidman, C. E., Morton, C. C., Seidman, J. G. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nature Genet. 20: 299-303, 1998. [PubMed: 9806553] [Full Text: https://doi.org/10.1038/3118]
Street, V. A., Kallman, J. C., Robertson, N. G., Kuo, S. F., Morton, C. C., Phillips, J. O. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. Am. J. Med. Genet. 139A: 86-95, 2005. [PubMed: 16261627] [Full Text: https://doi.org/10.1002/ajmg.a.30980]
Usami, S., Takahashi, K., Yuge, I., Ohtsuka, A., Namba, A., Abe, S., Fransen, E., Patthy, L., Otting, G., Van Camp, G. Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease. Europ. J. Hum. Genet. 11: 744-478, 2003. [PubMed: 14512963] [Full Text: https://doi.org/10.1038/sj.ejhg.5201043]
Yuan, H. J., Han, D. Y., Sun, Q., Yan, D., Sun, H. J., Tao, R., Cheng, J., Qin, W., Angeli, S., Ouyang, X. M., Yang, S. Z., Feng, L., Cao, J. Y., Feng, G. Y., Wang, Y. F., Dai, P., Zhai, S. Q., Yang, W. Y., He, L., Liu, X. Z. Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families. (Letter) Clin. Genet. 73: 391-394, 2008. [PubMed: 18312449] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.00972.x]