Deafness, Autosomal Dominant 36

A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-36 (DFNA36) is caused by heterozygous mutation in the transmembrane cochlear-expressed gene-1 (TMC1; 606706) on chromosome 9q21.

See also autosomal recessive deafness, designated DFNB7 or DFNB11 (600974), which is caused by mutation in the same gene.

Clinical Features

Kurima et al. (2002) ascertained a large North American family segregating autosomal dominant nonsyndromic bilateral symmetric sensorineural hearing loss that began at 5 to 10 years of age and rapidly progressed to profound deafness within 10 to 15 years. Affected individuals had no evidence of vestibular deficits in their developmental and medical histories or upon physical examination.

Kitajiri et al. (2007) reported a North American Caucasian family with autosomal dominant nonsyndromic postlingual progressive sensorineural hearing loss. The hearing loss in this family began in the second decade of life and initially affected high frequencies, progressing to profound deafness at all frequencies by the fourth or fifth decade.

Zhao et al. (2014) reported a large 6-generation Chinese family with onset of postlingual, bilateral progressive hearing loss between 5 and 28 years of age. Hearing loss appeared to affect high frequencies with mild or moderate levels at onset, with later involvement of low frequency hearing loss. The deafness eventually progressed to profound levels with a flat audiometric graph. Tinnitis was also present.

Inheritance

The transmission pattern of hearing loss in the family reported by Zhao et al. (2014) was consistent with autosomal dominant inheritance.

Mapping

In a large North American family with autosomal dominant hearing loss, Kurima et al. (2002) found linkage to markers spanning the previously mapped DFNB7/B11 interval on chromosome 9q13-q21. The locus was designated DFNA36.

Molecular Genetics

In affected members of a large North American family with autosomal dominant hearing loss, Kurima et al. (2002) identified a heterozygous mutation in the TMC1 gene (D572N; 606706.0001). In addition, pathogenic TMC1 mutations were identified in 10 families with autosomal recessive deafness DFNB7/B11.

In a North American Caucasian family with autosomal dominant nonsyndromic postlingual progressive sensorineural hearing loss, Kitajiri et al. (2007) found linkage to the DFNA36 locus on chromosome 9q13-q21; analysis of the TMC1 gene revealed heterozygosity for a missense mutation (D572H; 606706.0004). Kitajiri et al. (2007) found that there was a slower progression of hearing loss at all stimulus frequencies in this family compared to the previously reported family with the D572N mutation, suggesting a possible genotype/phenotype correlation.

In affected members of a large 6-generation Chinese family with DFNA36, Zhao et al. (2014) identified a heterozygous missense mutation in the TMC1 gene (M418K; 606706.0007). The substitution was homologous to the M412K mutation in the Bth mouse (see ANIMAL MODEL). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family.

Heterogeneity

Hilgert et al. (2008) reported a Guatemalan family with autosomal dominant nonsyndromic hearing loss. Mid-frequency hearing impairment began in the first decade of life and progressed to affect all frequencies. The rate of progression was faster in the higher frequencies, leading to a downward-sloping audiogram after several decades. Genomewide linkage analysis showed linkage to the DFNA36 locus on 9q with a maximum lod score of 4.44. However, no pathogenic mutations were identified in the TMC1 gene. Instead, a putative asp924-to-val (D924V) variant, was identified in the TJP2 gene (607709) on chromosome 9q12-q13. This variant was not identified in 207 control samples, was located in a conserved residue, and was predicted to have decreased stability by bioinformatic analysis. No other TJP2 mutations were found in 26 additional small families segregating deafness. Hilgert et al. (2008) noted that the D924V variant in TJP2 could not be shown conclusively to be causative of deafness in the Guatemalan family, and suggested that this family may indeed have had a mutation outside of the coding region of the TMC1 gene or in another gene in this region.

Animal Model

In the mouse deaf mutant 'Beethoven' (Bth), Vreugde et al. (2002) identified a met412-to-lys (M412K) missense mutation in the Tmc1 gene; thus, Bth is a mouse model for autosomal dominant DFNA36. Similarly, the recessive deafness mutation 'dn,' which maps to mouse chromosome 19, is a model of profound congenital deafness, DFNB7/DFNB11 (600974), caused by mutation in the TMC1 gene.

Shibata et al. (2016) found that a single intracochlear injection of an artificial microRNA carried in a viral vector slowed progression of hearing loss for up to 35 weeks in the Bth mouse. Initial studies showed that the microRNA chosen selectively suppressed the dominant gain-of-function mutant M412K allele, which is homologous to human M418K (606706.0007). Treated mice also showed improved hair cell survival compared to untreated mice. The findings demonstrated the feasibility of RNA interference-mediated suppression of an endogenous deafness-causing allele to slow progression of autosomal dominant hearing loss before cochlear damage occurs.