Modifiers of hearing impairment in humans and mice.

Denise Yan,Xue-Zhong Liu

doi:10.2174/138920210791233054

Abstract

Lack of penetrance and variability of expression are common findings in nonsyndromic hearing loss with autosomal dominant mode of inheritance, but are also seen with recessive inheritance. Now we know that genotype cannot necessarily predict phenotype due to the complexity of the genome, the proteome interacting with the transcriptome, and the dynamically coupled systems that are involved. The contribution of genetic background to phenotypic diversity reflects the additive and interactive (epistasis) effects of multiple genes. Because, individual genes do not act alone but rather in concert with many other genes, it is not surprising that, modifier genes are common source of phenotypic variation in human populations. They can affect the phenotypic outcome of a given genotype by interacting in the same or in a parallel biological pathway as the disease gene. These modifier genes modulate penetrance, dominance, pleiotropy or expressivity in individuals with Mendelian traits and can also be exerted by influencing the severity, the penetrance, the age of onset and the progression of a disease. In this review, we focus on modifier genes that specifically affect hearing loss phenotypes in humans as well as those described in mice. We also include examples of digenic inheritance of deafness, because additive or interactive effects can also result from interaction between two mutant genes.

Highlights

Phenotypic variation in heritable forms of hearing impairment has been reported within families [1,2,3,4] and in individual probands carrying the same genetic mutations [5]
Under a constant nuclear background, a nearly identical degree of mitochondrial dysfunction was observed in cybrid cell lines derived from symptomatic and asymptomatic individuals [44]. These findings strongly indicate that the A1555G mutation is a primary cause of deafness and that nuclear modifier genes play a role in modulating the phenotypic expression of the hearing loss associated with the A1555G mutation
The cadherin 23 (Cdh23) locus has been shown to modify the deafness caused by the Mass1frings mutation in BUB/BnJ strain mice and can account for the phenotypic manifestations differences observed between Frings (Cdh23753G) and BUB/BnJ (Cdh23753A) [75,76]

Summary

Introduction

Phenotypic variation in heritable forms of hearing impairment has been reported within families [1,2,3,4] and in individual probands carrying the same genetic mutations [5]. Mutations in one hearing loss- associated gene may lead to multiple phenotypes, which are known as allelism. Different genetic sources can account for the wide variety of phenotypes observed in individuals with hereditary hearing loss, including genetic heterogeneity, allelic heterogeneity, and genetic background effects or modifier loci.

Results

Conclusion