Genetic hearing loss: the journey of discovery to destination – how close are we to therapy?

Hearing loss (HL) is an extremely common neurosensory deficit with a heterogeneous etiology including environmental and genetic causes. The incidence of profound sensorineural HL in the United States is 186 per 100,000 births (Morton and Nance 2006). In developed nations, more than 60% of individuals affected with HL have a genetic etiology that can be classified by the mode of inheritance and the presence or absence of other clinical characteristics that permits the diagnosis of specific syndromes associated with HL (Willems et al. 2000, Tekin et al. 2001; Nance 2003). The vast majority of individuals (70%) have nonsyndromic hearing loss (NSHL) which can be inherited as a recessive (80%), dominant (15%), X-linked or mitochondrial trait (5%). In 30 % of individuals with HL, one may identify a recognizable pattern or syndrome of which nearly 400 forms have been described (Toriello and Smith 2013, Oxford Univ. Press). Among syndromic forms, a few such as Pendred syndrome (Reardon et al. 1997), Usher Syndrome (Petit 2001), or Waardenburg syndrome (Nance 2003; Schultz 2006) occur with a frequency of 1–4% among the deaf. As suggested by analysis of large collections of family data, genetic heterogeneity was expected with HL (Nance and Pandya 2002). As the loci were identified, they were numbered chronologically, and cataloged where DFNB represents recessive inheritance, DFNA represents postlingual dominant forms, and DFN represents X-linked loci. An updated list is maintained at the Hereditary Hearing Loss homepage with loci mapped, genes identified at the locus and references (Hereditary Hearing Loss home page: http://hereditaryhearingloss.org/). In view of our knowledge that a large number of genes are involved with HL, and that mutations in each gene would account for a small proportion of all HL, the discovery that mutations in a single gene GJB2 (DFNB1 locus), encoding connexin 26 (Cx26), accounted for a large proportion of recessive NSHL, came as an unexpected surprise (Kelsell et al. 1997; Pandya et al. 2003). Mutations in Cx26 are the most frequent form of nonsyndromic deafness and its contribution to deafness exceeds 60% in some Western populations (Pandya et al. 2003; Azaiez et al. 2006). Docking of hexameric hemiconnexins on the adjacent surface of two cells forms a complete gap junction which is critical to the flow of ions, especially potassium ions, in the inner ear (Steel and Bussoli 1999). More than 100 mutations of the connexin 26 gene have been reported with some common ethnic specific variants including the 35delG mutation in Caucasians, the 167delT allele in Ashkenazi Jews, and the 235delC allele in Asians (Connexin – Deafness Homepage: http://davinci.crg.es/deafness/). Interestingly, del Castillo et al. (2002) reported a 342 kb deletion spanning the connexin 30 (Cx30) locus, in individuals heterozygous for Cx26, as the cause of their HL. The Cx26 and Cx30 loci are located on 13q11 region within 40 kb of each other; however, the Cx26 locus is not involved in the deletion. Thus, it is unclear if the hearing loss in individuals carrying a mutation in Cx26 and a deletion of Cx30 in trans occurs due to haploinsufficeincy of Cx30 or whether the deletion of Cx30 perturbs the expression of the adjacent normal Cx26 (RodriguezParis and Schrijver 2009). Since the identification of GJB2 as a major cause for nonsyndromic autosomal recessive HL, there has been tremendous progress in elucidating the genetic etiology for both nonsyndromic and syndromic forms of HL, with nearly 1% of the genome coding for transcripts determined to be important in the development and functioning of the hearing apparatus.