Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

Hearing loss is a heterogeneous disorder. Identification of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants affecting 9 different non-GJB2 genes resulted novel: c.12829C > T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G > A, p.(Gly1167Glu) in COL4A3; c.1183C > T, p.(Pro395Ser) and c.1759C > T, p.(Pro587Ser) in COL4A5; c.580 + 2 T > C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939 T > C, p.(Phe647Leu), in MYO6; c.733C > T, p.(Gln245*) in MYO7A and c.242C > G, p.(Ser81*) in TMPRSS3 genes. To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.

Functional connectivity alteration of the deprived auditory regions with cognitive networks in deaf and inattentive adolescents

Adolescents with early profound deafness may present with distractibility and inattentiveness. The brain mechanisms underlying these attention impairments remain unclear. We performed resting-state functional magnetic resonance imaging to investigate the functional connectivity of the superior temporal and transverse temporal gyri in 25 inattentive adolescents with bilateral prelingual profound deafness, and compared the results with those of 27 age-matched normal controls. Pearson and Spearman’s rho correlation analyses were used to investigate the correlations of altered functional connectivity with the attention scores on the Montreal Cognitive Assessment, years of deafness, sign language, and hearing aid usage. Compared with normal controls, prelingual profound deafness demonstrated mainly decreased resting-state functional connectivity between the deprived auditory regions and several other brain functional networks, including the attention control, language comprehension, default-mode, and sensorimotor networks. Moreover, we also found enhanced resting-state functional connectivity between the deprived auditory cortex and salience network. These results indicate a negative impact of early hearing loss on the attentional and other high cognitive networks, and the use of sign language and hearing aids normalized the participants’ connectivity between the primary auditory cortex and attention networks, which is crucial for the early intervention and clinical care of deaf adolescents.

The Importance of Access to Bilateral Hearing through Cochlear Implants in Children

Children with hearing loss require early access to sound in both ears to support their development. In this article, we describe barriers to providing bilateral hearing and developmental consequences of delays during early sensitive periods. Barriers include late identification of hearing loss in one or both ears and delayed access to intervention with hearing devices such as cochlear implants. Effects of delayed bilateral input on the auditory pathways and brain are discussed as well as behavioral effects on speech perception and other developmental outcomes including language and academics. Evidence for these effects has supported an evolution in cochlear implant candidacy in children that was started with unilateral implantation in children with profound deafness bilaterally to bilateral implantation to implantation of children with asymmetric hearing loss including children with single-side deafness. Opportunities to enhance the developmental benefits of bilateral hearing in children with hearing loss are also discussed including efforts to improve binaural/spatial hearing and consideration of concurrent vestibular deficits which are common in children with hearing loss.

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and myosin-15 mutations cause profound deafness. In a companion study, we report that myosin-15 nucleates actin filament ("F-actin") assembly and identify a progressive hearing loss mutation (p.D1647G, "jordan") which disrupts stereocilia elongation by inhibiting actin polymerization. Here, we present cryo-EM structures of myosin-15 bound to F-actin, providing a framework for interpreting deafness mutations and their impacts on myosin-stimulated actin assembly. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin's D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. ADP-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin's structural plasticity in a myosin nucleotide-state dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

UNILATERAL PROFOUND DEAFNESS – A POSSIBLE MECHANISM

Purpose: To explain the clinical findings of patients with profound unilateral deafness who have recovered the hearing function after a combined treatment of hyperbaric oxygenation and dehydrant therapy. Material and method: 11 patients with profound sudden unilateral hearing loss above 90 dB SPL, intolerance to sounds similar to recruitment, at levels 10-20 dB above the hearing threshold (105-120 dB SPL), positive glycerol test and unexpected good recovery of hearing within 1-2 months are described. Results: All patients have perfect outcome results without the use of glucocorticoids. Conclusions: Based on articles about experiments with genetically modified animals and acquired deafness, we propose a possible mechanism of damage explaining the clinical findings and the favorable outcome of the disease – a disconnection between the tectorial membrane and stereocilia. Thus mechano-electrical transducer (MET) of hair cells cannot be activated. The combined use of hyperbaric oxygenation and dehydrant medications can lead to recovery of the hearing function.

Perception Mechanism of Bone-Conducted Ultrasound and Its Clinical Use

It is generally believed that ultrasound cannot be heard. However, ultrasound is audible when it is presented through bone conduction. Bone-conducted ultrasound (BCU) has unique characteristics; the most interesting is its perception in patients with profound deafness. Some patients can perceive it and discriminate speech-modulated BCU. Previous reports have suggested that BCU can be used for a hearing aid or tinnitus sound therapy. In this review, the perception of BCU at both the peripheral and central levels was investigated based on previous studies, although some of them remain controversial. We also investigated the clinical use of BCU. To develop hearing aids utilizing BCU, the encoding of speech signals into BCU has to be established. The outcomes of the reported speech modulations were evaluated. Furthermore, the suppression of tinnitus by BCU was reviewed, and the feasibility of the application of BCU to tinnitus treatment was investigated.

Contralateral sensorineural deafness in the absence of temporal bone fractures: an ignored entity in traumatic brain injury

<p class="abstract">Traumatic brain injury (TBI) associated with temporal bone fractures causing ipsilateral hearing loss is not uncommon. But contralateral sensorineural hearing loss (SNHL) in the absence of temporal bone fractures is not frequently encountered or looked for in TBI patients. A simple bed side tuning fork test followed by a formal audiogram underscore the importance of pre-emptive assessment to prevent a permanent handicap. We report a case of a young man with no prior ear disease or comorbidities, who sustained traumatic brain injury with right parieto-temporal hemorrhagic contusion and cervical myelopathy following a two-wheeler fall. Although, there was no evidence of temporal bone fractures, he developed sudden profound deafness on the contralateral side of the brain injury. Evaluation and treatment for the same were initially delayed as the management solely focused on his neurological complaints and as the hearing loss was contralateral it was perceived to be unrelated to his brain injury. We want to highlight the importance of thorough evaluation and screening for bilateral hearing loss in patients with TBI irrespective of the presence or absence of temporal bone fractures to initiate appropriate management. We also want to add our patient to the very few such cases reported in the literature. We analyzed these cases and reviewed the possible pathophysiological mechanisms behind this entity.</p><p> </p>

Maximizing Cochlear Implant Outcomes with Short-Term Aural Rehabilitation

Background Increasing numbers of adults are receiving cochlear implants (CIs) and many achieve high levels of speech perception and improved quality of life. However, a proportion of implant recipients still struggle due to limited speech recognition and/or greater communication demands in their daily lives. For these individuals a program of aural rehabilitation (AR) has the potential to improve outcomes. Purpose The study investigated the effects of a short-term AR intervention on speech recognition, functional communication, and psychosocial outcomes in post lingually deafened adult CI users. Research Design The experimental design was a multisite clinical study with participants randomized to either an AR treatment or active control group. Each group completed 6 weekly 90-minute individual treatment sessions. Assessments were completed pretreatment, 1 week and 2 months post-treatment. Study Sample Twenty-five post lingually deafened adult CI recipients participated. AR group: mean age 66.2 (48–80); nine females, four males; months postactivation 7.7 (3–16); mean years severe to profound deafness 18.4 (2–40). Active control group: mean age 62.8 (47–85); eight females, four males; months postactivation 7.0 (3–13); mean years severe to profound deafness 18.8 (1–55). Intervention The AR protocol consisted of auditory training (words, sentences, speech tracking), and psychosocial counseling (informational and communication strategies). Active control group participants engaged in cognitive stimulation activities (e.g., crosswords, sudoku, etc.). Data Collection and Analysis Repeated measures ANOVA or analysis of variance, MANOVA or multivariate analysis of variance, and planned contrasts were used to compare group performance on the following measures: CasperSent; Hearing Handicap Inventory; Nijmegen Cochlear Implant Questionnaire; Client Oriented Scale of Improvement; Glasgow Benefit Inventory. Results The AR group showed statistically significant improvements on speech recognition performance, psychosocial function, and communication goals with no significant improvement seen in the control group. The two groups were statistically equivalent on all outcome measures at preassessment. The robust improvements for the AR group were maintained at 2 months post-treatment. Conclusion Results of this clinical study provide evidence that a short-term AR intervention protocol can maximize outcomes for adult post lingually deafened CI users. The impact of this brief multidimensional AR intervention to extend CI benefit is compelling, and may serve as a template for best practices with adult CI users.

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

Background. Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness. Results. Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs ∗ 20) in TECTA, c.3719 G>A (p. Arg1240Gln) in MYO7A, and c.482+1986_1988del in HGF were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked POU3F4 gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing. Conclusions. Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants.