Overview

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The Ear

The auditory system bears one of the most intricate mechanisms of sensation ability in humans. The inner ear, a fluid-filled organ, is responsible for transforming the mechanical energy of the sound waves into electrical stimuli, which will eventually be translated in the brain. Anatomically, the inner ear is divided into the auditory and vestibular systems. While the auditory system is responsible for sound sensation, the vestibular system is responsible for three dimensional orientation and gravity perception. The similarities between these two systems often leads to balance disorders in hearing impaired individuals. The auditory system is composed of a snail-shaped cochlea. The cochlea is a fluid-filled tube coiled in a spiral shape around the modiolus. Upon viewing a longitudinal cross section, the cochlear canal is divided into three compartments (scalae). The scala media filled with endolymph, lies between two larger perilymphatic filled compartments, the scala vestibuli and scala tympani.

 

Causes of hearing loss

Similar to other sensory loss, hearing impairment has a wide spectrum of etiologies originating from both environmental and genetic factors. Prolonged exposure to high intensity sound poses high risk for auditory function and can lower hearing thresholds. Acoustic trauma, as a result of a sudden loud noise, can lead to temporary and/or permanent hearing impairment. Among environmental factors, different viral infections, as well as neonatal anoxia and hyperbilirubinemia, can also cause permanent hearing defects. Long term augmentation of ototoxic drugs such as aminoglycoside and gentamicin antibiotics has an adverse effect on the auditory system and accounts for hearing defects. Unlike the genetics factors dictated by hereditary information, some of the environmental factors can be reduced and avoided by raising awareness for appropriate protection.

Genetic insults contributing to hearing defects poses greater challenges. The clinical heterogeneity of hearing loss is characterized by common classifications based on several parameters such as onset, severity and the presence of additional clinical manifestations other than deafness. Hearing loss that occurs prior to speech acquisition is termed prelingual deafness, either congenital or appearing after birth. A hearing disability that appears early in childhood can have a major consequence on language acquisition. Age related hearing loss (ARHL) affects the elderly population with high prevalence and its appearance and progression is influenced by both genetic and environmental factors. About 60% of the population over the age of 65 suffers from different degrees of hearing loss, with a decline in sensitivity to sound, accompanied with reduced speech perception. Hearing loss is also categorized based on the frequency loss and the severity of hearing thresholds. High tone loss refers to reduced sensitivity of high frequency acoustic stimulus, as opposed to low tone loss for the low frequencies. The terms profound, mild and moderate describe the descending order of different severity levels of hearing impairments. When hearing loss is the only apparent abnormality, it is referred to as non-syndromic hearing loss (NSHL). In other cases hearing loss occurs along with a variety of other malformations and thus is designated as syndromic hearing loss (SHL).

 

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Genetics of deafness

Given the complexity of the hearing mechanism, it should come as no surprise that a panoply of genes have been discovered to be involved in hearing loss. To date, more than 50 genes and 80 additional loci have been linked to various degrees of hearing impairment (Figure 2). Taking advantage of standardized nomenclature, a common classification of the loci and genes for hearing impairment has been established (HUGO Gene Nomenclature Committee). Depending on the inheritance mode, the nonsyndromic genes or loci are classified accordingly: DFNA (dominant), DFNB (recessive), DFNX (X-linked), DFNY (Y-linked), and DFNM (modifier). Additional specific symbols are used for different forms of hearing loss including otosclerosis (OTSC), auditory neuropathy (AUNA), and mitochondrial (MRTNR, MTTS) genes. For each locus, the relevant symbol is depicted with a number next to it, designated by the chronological order of its discovery. Routinely updated, the Hereditary Hearing Loss Homepage provides an open and reliable resource for all listed genes and loci.

 

Epigenetics of the auditory system

The regulation of the expression of genes in a temporal and spatial precise manner has driven scientists worldwide to pose questions, develop assays, develop theories and verify them to understand human health and disease. Genes are known to serve as the blueprint for the molecular machine comprising cell body and function, and they have been the focus of exploring tissue development and disease. The mapping the human genome opened a Pandora’s box of queries regarding the role of the non-coding portion of the genome. The scientific community has come to realize that role of the non-coding portion of genome, approximately 97%, is in regulation. Deciphering the complex relationship between the regulatory elements’ sequence and their context as part of the epigenome has revealed a level of complexity in gene expression regulation beyond our wildest dreams. Very little has been examined in the inner ear thus far. Our group has set out to produce an epigenetic blueprint of the inner ear sensory epithelium.

Our laboratory has pioneered the thorough characterization of time-point specific non-coding RNAs, analyzing them for predicted functionality and validating top candidates in the mouse inner ear sensory epithelium. We are the first to produce nucleotide resolution DNA methylation maps and DNA methylation dynamics through sensory epithelium development and maturation.

 

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microRNAs

microRNAs (miRNA) are small non-coding RNAs that regulate gene expression through the RNA interference (RNAi) pathway. By binding to sequences in untranslated regions of messenger RNAs (mRNAs), miRNAs can inhibit them by translational suppression and destabilization by complementarity of specific seed sequences to the target mRNAs. miRNA interference may have a crucial role in the development and maintenance of cells and tissues of the auditory complex. Using Next-Generation Sequencing (NGS), we identified 455 miRNAs expressed in cochlear and vestibular sensory epithelium of the mouse inner ear. miRNA profiling revealed that miR-182-5p, miR-181a-5p, miR-26a-5p and miR-204-5p were the most highly expressed miRNAs. The expression pattern was quite uneven in the cochlea, with almost 50% of the reads attributed to miR-182-5p, a miRNA known to be crucial for cone photoreceptors of the eye. Using bioinformatics tools, we make predictions regarding their targets, which are further categorized according to their biological activity and/or molecular function

lincRNAs

Long intergenic non-coding RNAs (lincRNAs) are a class of RNAs that impose genetic regulation on mammalian genomes. lincRNAs are differentiated from other non-coding RNA classes based on their length of transcripts of >200 nucleotides. Despite sharing some similarities with mRNAs, they are not translated, are less abundant and are expressed with higher tissue specificity. The functions of lincRNAs are versatile, they are highly regulated, and their expression linked to development and disease. The genomic regulation of components of the inner ear, the cochlea and the vestibule, is highly complex and determined throughout development. As a result, we hypothesize that lincRNAs are crucial genetic players in the development of the inner ear. We have built a catalogue of lincRNA genes that are expressed in the sensory portion of the mouse inner ear during development, to enable subsequent exploration of lincRNA function. RNA from auditory and vestibular sensory epithelia from developmental stages was subjected to high-throughput RNA sequencing (RNA-seq). The reads were filtered using a specifically developed bioinformatic pipeline. We identified 1920 lincRNAs, of which 403 are novel un-annotated lincRNA genes. A set of logical criteria was derived to narrow down the list of candidate genes to study further, including profiling in the whole animal, tissue, developmental stage expression and investigation of the specific mode of action. We anticipate that a clearly defined study of the lincRNA level of regulation will provide critical data about the auditory and vestibular neurosensory systems and aid in our understanding of hearing and balance disorders.

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