DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Abstract

The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.

A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

“…The affected individuals in this study, however, display a congenital bilateral severe-to-profound HI profile. This is consistent with knock-out mice (Koo et al 2009; Steffes et al 2012), but also similar to other HI genes that express both an autosomal dominant and recessive inheritance (Liu et al 1998; del Castillo and del Castillo 2017). Compared to the knock-out mouse, we did not observe any vestibulocochlear malformations in affected individual IV:1, assessed via CT-imaging.…”

“…Variants in these genes that cause autosomal dominant forms of NSHI are often missense variants which exert a dominant negative effect on the activity of the wild-type protein or its close interactors (Liu et al 1998; del Castillo and del Castillo 2017). The autosomal dominant forms of NSHI are usually less severe, show more variability in phenotype, and are later in onset and progressive in nature compared to their recessive counterparts.…”

“…The autosomal dominant forms of NSHI are usually less severe, show more variability in phenotype, and are later in onset and progressive in nature compared to their recessive counterparts. The latter often produces a more severe, non-progressive, and pre-lingual HI profile (Liu et al 1998; del Castillo and del Castillo 2017). …”

Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

“…About 200 GJB2 pathogenic mutations have been reported so far [4]. A number of missense mutations may lead to autosomal dominant non-syndromic hearing loss DFNA3 and autosomal dominant syndromic hearing loss associated with hyperproliferative epidermal disorders [5,6]. On the other hand, a majority of GJB2 mutations are inherited in a recessive form and lead to non-syndromic hearing loss DFNB1.…”

Advances in understanding of presbycusis

“…Interestingly, there is also evidence that intolerance to redox stress also plays a role in acceleration of presbycusis among mice and humans. In an exemplary investigation by Fetoni et al, the authors generated an animal model of presbycusis using Gjb2± mice as a model of heterozygous human carriers of 35 del G. Variants in GJB2 , which in codes for gap junction protein connexin 26, are well described and include a large number of deafness‐related mutations (Del Castillo & Del Castillo, ; Zelante et al, ), the majority of which cause nonsyndromic autosomal recessive deafness type 1A (DFNB1A, OMIM6 220290), which accounts for approximately half of nonsyndromic autosomal recessive hearing loss (Kenna, Kimura, Paul, & Adams, ). Fetoni et al () found that Gjb2± mice demonstrated accelerated ARHL and found that these mice demonstrated significant apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, and deregulated expression of genes whose transcriptional control is regulated by nuclear factor erythroid 2‐related factor 2 (Nrf2), a crucial determinant of cellular tolerance to redox stress.…”