A model for human hearing impairment

Age-related hearing loss is an extremely common human disease, so what have we learnt so far that might suggest the causes? Does the common disease/common variant model look the most likely model?

If we look firstly at childhood deafness, despite the large number of genes that have been identified, most families with a deaf child still have no molecular diagnosis. The gene most commonly involved in severe or profound childhood deafness is GJB2, encoding the connexin 26 molecule, a component of gap junctions thought to be important for homeostatic control within the cochlear duct. Mutations in this gene account for between 25 and 50% of cases of known recessive congenital severe or profound deafness, and about 10% of sporadic cases. There are still a large number of cases with severe or less severe hearing impairment for which no gene is known. Many of the genes known to be involved in deafness affect only a handful of families. These observations suggest that childhood deafness is probably due to a large number of single gene mutations in different genes, rather than a small set of common polymorphisms, together with some environmental factors such as neonatal problems or infection.

In age-related hearing loss, we know of some single gene mutations that lead to progressive hearing loss with adult onset, mostly dominantly inherited. We know that heritability is relatively high for hearing loss, especially amongst those with onset in middle age. We also know that childhood deafness is extremely heterogeneous, with many different genes involved. All this argues in favour of a similar model for age-related hearing loss as the simplest explanation: many different single genes, rather than a limited number of common gene variants. Extreme heterogeneity would make straightforward case/control association studies difficult. The National Study of Hearing carried out in the UK twenty years ago failed to find association of any biomarkers studied with hearing impairment, which is consistent with extensive heterogeneity. The genes involved with age-related hearing loss could overlap with those involved in childhood deafness, because it is easy to imagine that a milder mutation could lead to later-onset auditory pathology. However, we also know that there are complex interactions that influence auditory function. Firstly, some genes act as modifiers of other genes in determining hearing ability. Secondly, genes interact with environmental factors making some people more or less sensitive to auditory insults. Thirdly, hearing ability may be determined by the summed action of a number of gene variants acting as quantitative trait loci (QTLs). There is evidence from the mouse that the progressive hearing loss observed in many inbred strains of mouse is due to a combination of several QTLs, including the ahl variant of Cdh23 on chromosome 10 mentioned earlier, the Ahl2 locus on chromosome 5, and Ahl3 on chromosome 17 (Noben-Trauth et al., 2003), as well as further QTLs not yet published.

Whichever model explains age-related hearing loss, it is likely that the genes involved will include those that have a specific influence on hearing and not just those involved in systemic aging processes that affect other senses and neural function (see Chapter 8). Looking directly for linked or associated variants in candidate genes suggested by study of early-onset deafness in humans and mouse models may be a useful approach for age-related hearing loss. Choice of the population will be important, and initially individuals at the extremes of the distribution (in terms of age of onset or rate of progression) might be most fruitful (Wright etal., 2003). Once the major genes involved in hearing loss in the human population have been identified, work on understanding their role and developing treatments can be more focussed.

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