Insights into the Pathobiology of TMPRSS3-Related Hearing Loss and Implications for Cochlear Implant Patients with TMPRSS3 Mutations.

Abstract OBJECTIVES To review the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated autosomal recessive non-syndromic hearing loss (ARNSHL) and evaluate the spatial expression pattern of TMPRSS3 within the human cochlea. METHODS Review all published cases of CI in patients with TMPRSS3-associated ARNSHL to compare postoperative consonant-nucleus-consonant (CNC) word performance to published adult CI cohorts. Protein structural modeling of TMPRSS3 variants associated with post-lingual hearing loss. Determine TMPRSS3 expression pattern in human inner ear organoids and human cochlea. RESULTS Nine articles detailed 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI. Of these, 6 cases reported prelingual onset (< 2yo) and 24 cases reported post-lingual onset (≥2yo) of hearing loss. Subjectively, 85% of cases had a favorable outcome. Objectively, the postoperative mean (SD) post-operative CNC word score was not significantly different than other adults [66.2% (25.8%) correct vs. 50.1% (12.5%); F(1,6) = 1.97, P = 0.21]. In the TMPRSS3 cohort, poor performers (CNC < 30% correct) were significantly older than good performers [49 (± 13.3) years vs. 17.4 (± 18.4) years; P < 0.01] and all harbored the A138E variant. TMPRSS3 immunostaining is restricted to the otic epithelial cells and is not expressed within auditory neurons of human cochlea and human inner ear organoids. CONCLUSIONS Patients with TMPRSS3-related hearing loss exhibit similar postoperative performance to other adult CI patients. TMPRSS3 is not expressed in human auditory neurons and the duration of hearing loss prior to CI likely contributes to poor performance.

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Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

International Journal of Molecular Sciences ◽

10.3390/ijms22126497 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6497

Author(s):

Anna Ghilardi ◽

Alberto Diana ◽

Renato Bacchetta ◽

Nadia Santo ◽

Miriam Ascagni ◽

...

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Hair Cells ◽

Muscle Fibers ◽

Underlying Mechanism ◽

Loss Of Function ◽

Zebrafish Model ◽

Developmental Defects ◽

Inner Ear Development ◽

Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

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A Human Inner Ear Model for assessment of Noise Induced Hearing Loss via energy methods

IFAC-PapersOnLine ◽

10.1016/j.ifacol.2020.12.727 ◽

2020 ◽

Vol 53 (2) ◽

pp. 16424-16429

Author(s):

Milka C.I. Madahana ◽

Otis T.C. Nyandoro ◽

John E.D. Ekoru

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Energy Methods ◽

Noise Induced Hearing Loss ◽

Human Inner Ear

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Cytomegalovirus Isolation from a Human Inner Ear

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348947908800322 ◽

1979 ◽

Vol 88 (3) ◽

pp. 424-426 ◽

Cited By ~ 17

Author(s):

Larry E. Davis ◽

Charles G. James ◽

Frederick Fiber ◽

Leroy C. McLaren

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Congenital Deafness ◽

Cmv Infection ◽

Human Inner Ear ◽

Congenital Cmv

Cytomegalovirus (CMV) infection of the fetus has been associated with congenital deafness or hearing loss. This association has previously been based on clinical or pathological studies. We report an infant who died with the congenital CMV syndrome in which CMV was isolated from the perilymph of the inner ear providing additional evidence that this virus can infect the labyrinth.

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High prevalence of theW24X mutation in the gene encoding connexin-26 (GJB2) in Spanish Romani (gypsies) with autosomal recessive non-syndromic hearing loss

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.30884 ◽

2005 ◽

Vol 137A (3) ◽

pp. 255-258 ◽

Cited By ~ 52

Author(s):

Araceli Álvarez ◽

Ignacio del Castillo ◽

Manuela Villamar ◽

Luis A. Aguirre ◽

Anna González-Neira ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Connexin 26 ◽

Gene Encoding ◽

High Prevalence ◽

Syndromic Hearing Loss

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Decreased disulphide/thiol ratio in patients with autosomal recessive non-syndromic hearing loss

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2018.07.014 ◽

2018 ◽

Vol 112 ◽

pp. 188-192

Author(s):

Burhan Balta ◽

Ramazan Gundogdu ◽

Murat Erdogan ◽

Murat Alisik ◽

Aslihan Kiraz ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Syndromic Hearing Loss

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An update of common autosomal recessive non-syndromic hearing loss genes in Iranian population

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2017.04.007 ◽

2017 ◽

Vol 97 ◽

pp. 113-126 ◽

Cited By ~ 13

Author(s):

Tohid Ghasemnejad ◽

Mahmoud Shekari Khaniani ◽

Fatemeh Zarei ◽

Mina Farbodnia ◽

Sima Mansoori Derakhshan

Keyword(s):

Hearing Loss ◽

Autosomal Recessive ◽

Iranian Population ◽

Syndromic Hearing Loss

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Whole Exome Sequencing of Six Chinese Families With Hereditary Non-Syndromic Hearing Loss: A Genetic Etiology Study

10.21203/rs.3.rs-132767/v1 ◽

2020 ◽

Author(s):

Pengfei Liang ◽

Fengping Chen ◽

Shujuan Wang ◽

Qiong Li ◽

Wei Li ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Large Scale ◽

Autosomal Recessive ◽

Autosomal Recessive Inheritance ◽

Chinese Families ◽

Whole Exome ◽

Syndromic Hearing Loss

Abstract Background: Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with >152 genes identified as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families.Methods: After excluding the mutations in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by whole-exome sequencing (WES). All the candidate variants were verified by Sanger sequencing in all patients and their parents.Results: Biallelic mutations were identified in all deaf patients. Among these six families, 10 potentially causative mutations, including 3 reported and 7 novel mutations, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identified. The mutations in MYO15A were frequent with 7/10 candidate variants. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family.Conclusions: Next-generation sequencing (NGS) approach becomes more cost-effective and efficient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current findings further extend the mutation spectrum of hearing loss in the Chinese population, which has a positive significance for genetic counseling.

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Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.599152 ◽

2020 ◽

Vol 14 ◽

Author(s):

Francis Rousset ◽

Vivianne B. C. Kokje ◽

Rebecca Sipione ◽

Dominik Schmidbauer ◽

German Nacher-Soler ◽

...

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Progenitor Cells ◽

Ganglion Cells ◽

Spiral Ganglion ◽

Specific Cell ◽

Auditory Neurons ◽

Self Renewal ◽

Starting Point ◽

Ganglion Neurons

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro. However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.

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