Genetic heterogeneity

It is clear that deafness is an extremely heterogeneous disease. There are likely to be hundreds of different genes involved, any one of which can underlie deafness. For syndromic deafness, there are over 400 distinct Mendelian disorders that include deafness as one of the features listed in Online Mendelian Inheritance in Man (OMIM). For non-syndromic deafness, over 100 loci have been found and 36 of the genes have been identified (Van Camp and Smith, 2005; Petit et al., 2001; Bitner-Glindzicz, 2002; Friedman and Griffith, 2003). The genes represent a wide variety of molecules, ranging from myosin motors to transcription factors, ion channels to extracellular matrix components. They are expressed in diverse cell types within the auditory system, but mostly within the inner ear (Van Camp and Smith, 2005, see link to expression). As the genes involved in non-syndromic deafness have been localized, an interesting feature has emerged: recessive deafness is mostly early-onset childhood deafness, while the dominantly inherited forms are more often later-onset progressive hearing losses (Van Camp et al., 1997). The age of onset can vary within and between families, with some cases showing onset in their forties or even later. Furthermore, a number of the genes are involved in both dominant and recessive deafness in different families. MYO7A is a good example of the complexity: it is involved in Usher syndrome type 1B (severe or profound childhood deafness, vestibular dysfunction and progressive retinitis pigmentosa), atypical Usher syndrome with progressive hearing loss and highly variable retinitis pigmentosa, dominant non-syndromic progressive deafness (DFNA11) and recessive non-syndromic deafness (DFNB2). Furthermore, there are at least seven different genes underlying Usher syndrome type 1 (Van Camp and Smith, 2005). This complexity can sometimes be explained by the molecular lesion involved, but not always. Variability in expression and penetrance can be a feature even within a family carrying the same mutation, and this is particularly the case for dominantly inherited deafness.

Heterogeneity is a feature of mouse too, as there are over a hundred different genes identified that are associated with some sort of developmental or functional defect of the auditory system (Anagnostopoulos, 2002). The earliest mouse deafness genes to be found were associated with overt balance defects, because these lead to characteristic head-bobbing and circling behavior, whereas deafness alone is not normally noticed. More recently phenotype-driven screening programs worldwide have specifically sought mutants with hearing impairment alone. Deafness in mice with targeted mutations is more often discovered due to heightened awareness of this phenotype. Hence, we now know of a variety of single genes involved in progressive hearing loss without balance defects. This broadens the range of candidate genes for investigation in human populations with age-related hearing loss. Nonetheless, single genes discovered because of a balance defect are still proving to be very important in understanding human deafness, for several reasons. Milder mutations may lead to hearing loss alone (for example, different CDH23 mutations may cause profound deafness and balance defects or hearing loss alone). Many cases of deafness in childhood show vestibular dysfunction too, although this is often not reflected in overt balance problems (Huygen and Verhagen, 1994). Modifiers may influence the effects of these primary mutations on balance. Thus, any genes found to be involved in deafness in mice should represent good candidates for human deafness whether early or late-onset.

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