Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5EÀ08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive hearing impairment leads to social isolation and is also associated with comorbidities, such as frailty, falls, and late-onset depression. Moreover, there is a growing evidence linking it with cognitive decline and increased risk of dementia. Given the large social and welfare burden that results from ARHL, and because ARHL is potentially a modifiable risk factor for dementia, there is an urgent need for therapeutic interventions to ameliorate agerelated auditory decline. However, a prerequisite for design of therapies is knowledge of the underlying molecular mechanisms. Currently, our understanding of ARHL is very limited. Here, we review recent findings from research into ARHL from both human and animal studies and discuss future prospects for advances in our understanding of genetic susceptibility, pathology, and potential therapeutic approaches in ARHL.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2 , was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

During normal developmental tissue growth and in a number of diseases of the cardiopulmonary system, adventitial and interstitial fibroblasts are subjected to increased mechanical strain. This leads to fibroblast activation and enhanced collagen synthesis, but the underlying mechanisms involved remain poorly understood. In this study, we have begun to identify and characterize mechanical strain-responsive elements in the rat procollagen ␣1(I) (COL1A1) gene and show that the activity of COL1A1 promoter constructs, transiently transfected into cardiac fibroblasts, was increased between 2-and 4-fold by continuous cyclic mechanical strain. This was accompanied by a ϳ3-fold increase in the levels of total active transforming growth factor-␤ (TGF-␤) released into the medium. Inclusion of a panspecific TGF-␤ neutralizing antibody inhibited straininduced COL1A1 promoter activation. Deletion analysis revealed the presence of two potential strain response regions within the proximal promoter, one of which contains an inverted CCAAT-box overlapping a GC-rich element. Both mechanical strain and exogenously added TGF-␤1 enhanced the binding activity of CCAAT-binding factor, CBF/NF-Y, at this site. Moreover, this element was sufficient to confer strain-responsiveness to an otherwise unresponsive SV40 promoter. In summary, this study demonstrates that strain-induced COL1A1 promoter activation in cardiac fibroblasts is TGF-␤-dependent and involves increased binding of CCAAT-binding factor at the proximal promoter. Furthermore, these findings suggest a novel and potentially important TGF-␤ response element in the rat COL1A1 gene.

CF children who had received at least 10 courses of IV AG had a higher risk of ototoxicity. EHF audiometry identified 2 more children with ototoxicity than standard PTA and depending on facilities available, should be the test of choice for detecting ototoxicity in children with CF receiving IV AG.

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The Brn-3a POU family transcription factor is expressed only in postmitotic neurons in the central nervous system and identifies the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development. This factor is also induced when undifferentiated proliferating ND7 cells cease dividing and differentiate to a mature neuronal-like phenotype bearing numerous neurite processes. We show that overexpression of Brn-3a in undifferentiated ND7 cells induces a mature neuronal phenotype characterized by process outgrowth and the induction of genes encoding synaptic proteins, although the cells continue to proliferate. In contrast, the closely related factors Brn-3b and Brn-3c do not have this effect. Although the N-terminal activation domain of Brn-3a is required for maximum induction of neurite outgrowth and gene expression, these effects are primarily dependent on the DNA binding POU domain, which also acts as an activation domain. Overexpression of the isolated POU domain of Brn-3a is sufficient to induce neurite outgrowth, while the ability of full-length Brn-3a to do so is abolished by mutating a single amino acid in the Brn-3a POU homeodomain to its equivalent in Brn-3b. Thus, Brn-3a appears to play a critical role in the specification of the mature neuronal phenotype, acting by stimulating the expression of genes whose products are required for process outgrowth and synapse formation.During development and in the adult organism, the outgrowth of neurites is a tightly regulated process playing an essential role in axonal targeting, synapse formation, plasticity, and regeneration. This process involves the expression of a number of different growth-associated proteins (GAPs) in the neuronal cell body which are likely to be essential for neurite outgrowth (21). In agreement with this idea, the overexpression of one of these proteins, GAP-43, in transgenic mice has recently been shown to promote enhanced nerve sprouting (1). Similarly, the presynaptic nerve terminal protein has also been shown to be essential for neurite outgrowth both in vitro and in vivo (19). This finding suggests that exocytosis of synaptic vesicles which is required for synaptic transmission and the constitutive exocytosis which is required for axon outgrowth may have components such as SNAP-25 in common.Hence, neurite outgrowth is likely to require the activation of a number of genes encoding GAPs as well as others encoding synaptic proteins. In turn, such gene activation will require the enhanced activity and/or synthesis of one or more cellular transcription factors which regulate the expression of these genes. Clearly, the identification of such key regulatory factors would be of critical importance both for our understanding of neurite outgrowth itself and for successful attempts at enhancing it following nerve injury.To identify such transcription factors, we have focused initially on the ND7 cell line, which was obtained by fusing primary dorsal root ganglion neurons with C1300 neuroblastoma cells and w...

Objective To analyse the epidemiology of otosclerosis in a British cohort collected between 2011 and 2017. Design Retrospective cohort study. Setting Five UK ENT Departments. Patients Patients with surgically confirmed otosclerosis. Main Outcome Measures Questionnaire data documented family history of otosclerosis, age of onset, medical history and information on associated risk factors for 657 patients. Pre and post-surgical pure-tone audiometry was collected for 154 of these patients. Results The age of onset, incidence of bilateral disease, tinnitus and vertigo, a higher prevalence of women (65%) than men (35%) are similar to those reported previously for otosclerosis cohorts. No association with measles infection was detected. Patients with a family history (40%) have an earlier age of onset and a higher incidence of bilateral disease and vertigo than non-familial subjects. Pedigree analysis is consistent with an autosomal dominant inheritance with reduced penetrance being apparent in 44/91 pedigrees studied. Women who associate their hearing loss with pregnancy have an earlier age of onset than those that do not (p=6x10-6). Conclusions This study confirms that otosclerosis is an early adult onset disease that is more prevalent in women than men with a large minority of patients having a family history of otosclerosis. We report new evidence to support a relationship between pregnancy and otosclerosis progression in a proportion of women. In addition, this is the first study to identify differences in severity between familial and non-familial cases of otosclerosis, highlighting the possibility that more than one aetiology may be involved.