Hearing molecules: contributions from genetic deafness

Abstract

Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As functional studies of these molecular elements become available, we can put together the pieces of the puzzle and begin to reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies over the past decade that address the function of the proteins implicated in genetic deafness and to place them in the context of basic molecular mechanisms in hearing. The first part of this review highlights structural and functional features of the cochlea and auditory nerve. This background will provide a context for the second part, which addresses the molecular mechanisms underlying cochlear function as elucidated by genetic causes of deafness.

Early-onset sensorineural hearing loss is a prominent feature of H syndrome

“…It was postulated that hENT3 has an endogenous function in transferring nucleosides into the mitochondria, thereby assisting mitochondrial homeostasis including mitochondrial DNA synthesis/repair [9]. Mitochondria, being responsible for cellular energy production and an essential part of the oxidative phosphorylation pathway, play a major role in hearing [10], and indeed, many mitochondrial DNA mutations have been linked to deafness, alone or accompanied by symptoms in other organs, and 42-72% of patients with mitochondrial disorders have sensorineural hearing loss [10].…”

Inherited hearing loss: molecular genetics and diagnostic testing

“…This opens tensiondependent cation channels, triggering the auditory signaling cascade. The endocochlear potential directs a flow of cations into the hair bundle, which depolarizes the hair cell membrane, opens voltage-dependent calcium channels and releases neurotransmitters, ultimately creating action potentials in the auditory nerve [11,12] . Neurotransmitter release is regulated by the calcium-sensing molecule otoferlin, allowing integrated perception of sound by the cortex [15] .…”

“…The ionic differences between the endolymph and perilymph generate the endocochlear potential, the largest ( ∼ + 80 mV) positive potential found in the human body. The outer wall of the scala media, essentially the metabolic control hub of the cochlea, is bordered by the stria vascularis [11,12] .…”

The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3

“…Fifty recessive loci for nonsyndromic deafness (DFNB) have been reported and 21 DFNB genes have now been identiWed (Eisen and Ryugo 2007). On average about four DFNB loci have been mapped and identiWed for each of the past 5 years (for example; Riazuddin et al 2006a, b;Shahin et al 2006;Shabbir et al 2006;Mburu et al 2003;Ahmed et al 2003;Walsh et al 2002;Zwaenepoel et al 2002).…”