An introduction to the genetics of normal and defective hearing.

The recent rapid development of molecular biology techniques applied to the genetics of normal and defective hearing shed a new light on old questions regarding hearing and deafness. Genes are DNA sequences that determine characteristics, normally by specifying the sequence of aminoacids in a protein. The majority of genes is located in the chromosomes (human chromosomes have perhaps 80,000 pairs of genes). In addition there are 37 mithochondrial genes which are inherited only from the mother. One method used to identify candidate genes based on their function or pattern of tissue expression involves the construction of cDNA libraries from the target organ or tissue, in this case from the cochlea. The construction and characterization of cochlear cDNA libraries from humans and other species provide an important resource for rapid identification of cochlear genes involved in normal hearing and hearing disorders. Studies of the molecular genetics of the inner ear are hampered by the relative inaccessibility of the cochlea, by the limited number of cochlear and vestibular cells, and by our inability to maintain many of these cell types in long-term cultures. Several rodent inner-ear cDNA libraries and a human foetal cochlear cDNA library have already been constructed. Human and rodent cochlea-subtracted cDNA libraries are very useful for identifying genes controlling the development and maintenance of hearing. cDNA libraries constructed at different stages of development, and subtracted from each other, could be instrumental in identifying genes important at each stage of cochlear development. In addition, these libraries have the potential of fostering the identification of other proteins unique to the cochlea and will contribute to the identification, characterization, and functional analysis of these cochlea-specific proteins. Another important application of cDNA libraries is in identifying hearing-loss genes. Once the candidate gene for a given type of hearing loss is cloned and decoded, the structure of its protein product can be determined. This will provide insights into the biochemical function of the gene product in normal cochlear tissue, and will show why the genetic mutation results in hearing loss, that is, the recent identification of the myosin VIIa gene in Usher type IB. In addition, through the use of homologous recombination and transgenic technology, in vivo mouse models of inner-ear genetic disorders can be created. To date, 350 different genetic conditions associated with hearing impairment have been described, and during the past five years several of the genes involved in these form have already been mapped and identified.