ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy

Han, Kyu Hee; Oh, Doo Yi; Lee, Seungmin; Lee, Chung; Han, Jin Hee; Kim, Min Young; Park, Hye Rim; Park, Moo Kyun; Kim, Nayoung K.D.; Lee, Jaekwang; Yi, Eunyoung; Kim, Jong Min; Kim, Jeong Whun; Chae, Jong Hee; Oh, Seung Ha; Park, Woong-Yang; Choi, Byung Yoon

doi:10.1038/s41598-017-16676-9

Cited by 53 publications

(53 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Distortion product Otoacoustic Emissions (DPOAEs) responses are preserved, whereas ABRs are absent or abnormal. In accordance with the postsynaptic role of ATP1A3 encoded protein, CAPOS syndrome is listed among the auditory synaptopathies with a postsynaptic site of the lesion [99]. Overall good CI outcomes were reported [95] (Figure 2.…”

Section: Postsynaptic Synaptopathiesmentioning

confidence: 81%

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Siati

Rosenzweig

Gersdorff

et al. 2020

JCM

View full text Add to dashboard Cite

Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments characterized by deteriorated speech perception, despite relatively preserved pure-tone detection thresholds. Affected individuals usually present with abnormal auditory brainstem responses (ABRs), but normal otoacoustic emissions (OAEs). These electrophysiological characteristics have led to the hypothesis that ANSD may be caused by various dysfunctions at the cochlear inner hair cell (IHC) and spiral ganglion neuron (SGN) levels, while the activity of outer hair cells (OHCs) is preserved, resulting in discrepancies between pure-tone and speech comprehension thresholds. The exact prevalence of ANSD remains unknown; clinical findings show a large variability among subjects with hearing impairment ranging from mild to profound hearing loss. A wide range of prenatal and postnatal etiologies have been proposed. The study of genetics and of the implicated sites of lesion correlated with clinical findings have also led to a better understanding of the molecular mechanisms underlying the various forms of ANSD, and may guide clinicians in better screening, assessment and treatment of ANSD patients. Besides OAEs and ABRs, audiological assessment includes stapedial reflex measurements, supraliminal psychoacoustic tests, electrocochleography (ECochG), auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs). Hearing aids are indicated in the treatment of ANSD with mild to moderate hearing loss, whereas cochlear implantation is the first choice of treatment in case of profound hearing loss, especially in case of IHC presynaptic disorders, or in case of poor auditory outcomes with conventional hearing aids.

show abstract

Section: Postsynaptic Synaptopathiesmentioning

confidence: 81%

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Siati

Rosenzweig

Gersdorff

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…Mutations in ATP1A3 cause CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) as well as NSHL without any other neurologic features . Detailed audiometric analysis of two individuals with mutations in ATP1A3 showed auditory synaptopathy likely affecting the postsynaptic site .…”

Section: Genetic Lesions To the Synapsementioning

confidence: 99%

Auditory synaptopathy, auditory neuropathy, and cochlear implantation

Shearer

Hansen

2019

Laryngoscope Investig Oto

View full text Add to dashboard Cite

Cochlear implantation has become the standard‐of‐care for adults and children with severe to profound hearing loss. There is growing evidence that qualitative as well as quantitative deficits in the auditory nerve may affect cochlear implant (CI) outcomes. Auditory neuropathy spectrum disorder (ANSD) is characterized by dysfunctional transmission of sound from the cochlea to the brain due to defective synaptic function or neural conduction. In this review, we examine the precise mechanisms of genetic lesions causing ANSD and the effect of these lesions on CI outcomes. Reviewed data show that individuals with lesions that primarily affect the cochlear sensory system and the synapse, which are bypassed by the CI, have optimal CI outcomes. Individuals with lesions that affect the auditory nerve show poor performance with CIs, likely because neural transmission of the electrical signal from the CI is affected. We put forth a nuanced molecular classification of ANSD that has implications for preoperative counseling for patients with this disorder prior to cochlear implantation. We propose that description of ANSD patients should be based on the molecular site of lesion typically derived from genetic evaluation (synaptopathy vs. neuropathy) as this has implications for expected CI outcomes. Improvements in our understanding of genetic site of lesions and their effects on CI function should lead to better CI outcomes, not just for individuals with auditory neuropathy, but all individuals with hearing loss.

show abstract

“…The symptoms and signs characterizing the CAPOS syndrome are compatible with the abundant expression of the ␣3-isoform in the optic nerve, various parts of the cochlea, afferent and efferent nerve fibers innervating the muscle spindles, and cer-ebellar cortex. Hence, the defect leading to sensorineural hearing loss in CAPOS syndrome has been located to the synapses between the type I afferent terminals and the inner hair cells (20,42). Our results, moreover, exclude an increase of the proton leak current as contributing to the pathophysiology.…”

Section: Discussionmentioning

confidence: 50%

Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase

Roenn

Schack

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome is caused by the single mutation E818K of the ␣3-isoform of Na ؉ ,K ؉ -ATPase. Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K, as well as of E818Q and E818A mutants. We found that these amino acid substitutions reduce the apparent Na ؉ affinity at the cytoplasmic-facing sites of the pump protein and that this effect is more pronounced for the lysine and glutamine substitutions (3-4fold) than for the alanine substitution. The electrophysiological measurements indicated a more conspicuous, ϳ30-fold reduction of apparent Na ؉ affinity for the extracellular-facing sites in the CAPOS mutant, which was related to an accelerated transition between the phosphoenzyme intermediates E 1 P and E 2 P. The apparent affinity for K ؉ activation of the ATPase activity was unaffected by these substitutions, suggesting that primarily the Na ؉ -specific site III is affected. Furthermore, the apparent affinities for ATP and vanadate were WT-like in E818K, indicating a normal E 1 -E 2 equilibrium of the dephosphoenzyme. Proton-leak currents were not increased in E818K. However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K ؉ than the WT enzyme, which together with the reduced Na ؉ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions. The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen-bonding/salt-bridge network, connecting it to key residues involved in Na ؉ interaction at site III.

show abstract

ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy

Cited by 53 publications

References 108 publications

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Auditory synaptopathy, auditory neuropathy, and cochlear implantation

Functional consequences of the CAPOS mutation E818K of Na+,K+-ATPase

Contact Info

Product

Resources

About