ABSTRACT
Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth ...most common cause of autosomal‐recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness‐causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long‐term maintenance of stereocilia, mechanosensory sound‐transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.
Pathogenic variants of MYO15A cause human deafness DFNB3 by two distinct molecular mechanisms. In the inner ear, MYO15A (green) localizes at the tips of v‐shaped stereocilia bundles (magenta) that act as mechanotransducers to detect sound waves. The shorter splice isoform is required for elongation of developing stereocilia, whilst a larger isoform (green) is necessary for their long‐term maintenance.
The basic-helix-loop-helix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been ...found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.
Hearing loss is the most widespread sensory disorder, with an incidence of congenital genetic deafness of 1 in 1600 children. For many ethnic populations, the most prevalent form of genetic deafness ...is caused by recessive mutations in the gene gap junction protein, beta 2, 26 kDa (GJB2), which is also known as connexin 26 (Cx26). Despite this knowledge, existing treatment strategies do not completely recover speech perception. Here we used a gene delivery system to rescue hearing in a mouse model of Gjb2 deletion. Mice lacking Cx26 are characterized by profound deafness from birth and improper development of cochlear cells. Cochlear delivery of Gjb2 using an adeno-associated virus significantly improved the auditory responses and development of the cochlear structure. Using gene replacement to restore hearing in a new mouse model of Gjb2-related deafness may lead to the development of therapies for human hereditary deafness.
Hearing loss can have a major impact on children's language development, academic success and hearing comprehension. The aim of the present study was to determinate risk factors for severe and ...profound hearing loss in child candidates for cochlear implantation in southeast of Iran during 2014-2020.
This case-control study consisted of 400 children referring to a cochlear implant center (in southeastern Iran) from Bandar Abbas, Zahedan and Kerman during the years 2014-2020 as cases. The subjects were selected using the random sampling method; 200 children hospitalized in Shafa and Afzalipour hospitals were selected as controls.
Based on the results of the multivariate logistic regression, weight less than 1500 g (OR = 4.40: p < 0.05), hospitalization in NICU (OR = 7.21: p < 0.05), family history of hearing loss (OR = 11.47: p < 0.05), Gestational age over 35 (OR = 9.63: p < 0.05), intracranial hemorrhage (OR = 5.18: p < 0.05), consanguineous marriage (OR = 12.48: p < 0.05) and high fever and seizures (OR = 3.02: p < 0.05) were recognized as risk factors for sensorineural deafness in children.
Most of the risk factors for deafness are preventable, and hereditary factors play an important role in congenital deafness in children. Therefore, genetic counseling before consanguineous marriage, early diagnosis, timely intervention can prevent many cases of hearing loss in children.
The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and ...their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.
Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing ...rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV
) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV
interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV
interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous γ oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.
Objectives/Hypothesis
To investigate cochlear implantation (CI) in patients with unilateral deafness with and without tinnitus.
Study Design
Prospective case series of patients undergoing cochlear ...implantation for unilateral deafness and tinnitus in a tertiary academic unit.
Methods
Nine postlingually deafened subjects with unilateral hearing loss, with and without tinnitus ipsilaterally, and functional hearing in the contralateral ear were implanted with a standard electrode. Speech perception in noise was tested using the Bamford‐Kowal‐Bench presented at 65 dB SPL. The Speech, Spatial, and Qualities (SSQ) of Hearing Scale was used to evaluate the subjective perception of hearing outcomes, and the Tinnitus Reaction Questionnaire assessed the effect on tinnitus.
Results
All patients were implanted with the Med‐El Flex soft electrode, Innsbruck, Austria. They are regularly wearing the speech processor and find it beneficial in improving their ability to hear, particularly in noise. Decrease of tinnitus perception and an improvement of sound localization sounds were also reported by these patients.
Conclusion
In our case series, CI was successful for all nine patients, with improvement of speech recognition in noise, self‐perceived improvement of hearing, and for tinnitus control. Several factors such as deafness duration, age of deafness onset, the presence of residual hearing, patient motivation, and the rehabilitation intensity need to be further investigated in order to understand their impact on performance after implantation.
Level of Evidence
4.
Canine Deafness Strain, George M
The Veterinary clinics of North America. Small animal practice,
11/2012, Letnik:
42, Številka:
6
Journal Article
Recenzirano
Conductive deafness, caused by outer or middle ear obstruction, may be corrected, whereas sensorineural deafness cannot. Most deafness in dogs is congenital sensorineural hereditary deafness, ...associated with the genes for white pigment: piebald or merle. The genetic cause has not yet been identified. Dogs with blue eyes have a greater likelihood of hereditary deafness than brown-eyed dogs. Other common forms of sensorineural deafness include presbycusis, ototoxicity, noise-induced hearing loss, otitis interna, and anesthesia. Definitive diagnosis of deafness requires brainstem auditory evoked response testing.
Estrogen is the major female hormone involved in reproductive functions, but it also exerts a variety of additional roles in non-reproductive organs. In this review, we highlight the preclinical and ...clinical studies that have pointed out sex differences and estrogenic influence on audition. We also describe the experimental evidences supporting a protective role of estrogen towards acquired forms of hearing loss. Although a high level of endogenous estrogen is associated with a better hearing function, hormonal treatments at menopause have provided contradictory outcomes. The various factors that are likely to explain these discrepancies include the treatment regimen as well as the hormonal status and responsiveness of the patients. The complexity of estrogen signaling is being untangled and many downstream effectors of its genomic and non-genomic actions have been identified in other systems. Based on these advances and on the common physio-pathological events that underlie age-related, drug or noise-induced hearing loss, we discuss potential mechanisms for their protective actions in the cochlea.
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