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9 pages, 864 KiB

Open AccessArticle

A Missense Variant in COMT Associated with Hearing Loss among Young Adults: The National Longitudinal Study of Adolescent to Adult Health (Add Health)

by Chuan-Ming Li, Le Chen, Guanjie Chen, Jianhua Zhang and Howard J. Hoffman

Biomedicines 2022, 10(11), 2756; https://doi.org/10.3390/biomedicines10112756 - 31 Oct 2022

Viewed by 1182

Abstract

Hearing loss is a major public problem with a heritability of up to 70%. Catechol-O-methyltransferase (COMT) encodes an enzyme that is highly expressed in sensory hair cells of the inner ear. The association between COMT and hearing loss has not been reported previously [...] Read more.

Hearing loss is a major public problem with a heritability of up to 70%. Catechol-O-methyltransferase (COMT) encodes an enzyme that is highly expressed in sensory hair cells of the inner ear. The association between COMT and hearing loss has not been reported previously in nationally representative population-based studies. A regression linear model was used to estimate associations between the allele/genotype of COMT and self-reported hearing loss based on 13,403 individuals from Wave IV of the Add Health study, a nationally representative sample of multiethnic U.S. young adults. The inverse variance-weighted effect magnitude was estimated using a genetic meta-analysis model. The “A” allele frequency of rs6480 (a missense variant in COMT) was 0.44. The prevalence of hearing loss was 7.9% for individuals with the “A” allele and 6.5% for those with the “G” allele. The “A” allele was significantly associated with increased hearing loss (p = 0.01). The prevalence of hearing loss was 6.0%, 7.2%, and 8.7% for individuals with GG, AG, and AA genotypes, respectively, which was consistent with a genetic additive model. The genotypic association model showed that rs4680 was significantly associated with increased hearing loss (p = 0.006). A missense variant of rs4680 in COMT was significantly associated with increased hearing loss among young adults in a multi-racial/ethnic U.S. population-based cohort. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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15 pages, 6044 KiB

Open AccessArticle

Depletion of CD4 and CD8 T Cells Reduces Acute Disease and Is Not Associated with Hearing Loss in ML29-Infected STAT1-/- Mice

by Rachel A. Reyna, Junki Maruyama, Emily K. Mantlo, John T. Manning, Satoshi Taniguchi, Tomoko Makishima, Igor S. Lukashevich and Slobodan Paessler

Biomedicines 2022, 10(10), 2433; https://doi.org/10.3390/biomedicines10102433 - 29 Sep 2022

Cited by 2 | Viewed by 1367

Abstract

Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. [...] Read more.

Lassa virus (LASV) is a zoonotic virus endemic to western Africa that can cause a potentially lethal and hemorrhagic disease, Lassa fever (LF). Survivors suffer a myriad of sequelae, most notably sudden onset sensorineural hearing loss (SNHL), the mechanism of which remains unclear. Unfortunately, studies aiming to identify the mechanism of these sequelae are limited due to the biosafety level 4 (BSL4) requirements of LASV itself. ML29, a reassortant virus proposed as an experimental vaccine candidate against LASV, is potentially an ideal surrogate model of LF in STAT1-/- mice due to similar phenotype in these animals. We intended to better characterize ML29 pathogenesis and potential sequelae in this animal model. Our results indicate that while both CD4 and CD8 T cells are responsible for acute disease in ML29 infection, ML29 induces significant hearing loss in a mechanism independent of either CD4 or CD8 T cells. We believe that this model could provide valuable information for viral-associated hearing loss in general. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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27 pages, 5632 KiB

Open AccessArticle

Two Loci Contribute to Age-Related Hearing Loss Resistance in the Japanese Wild-Derived Inbred MSM/Ms Mice

by Shumpei P. Yasuda, Yuki Miyasaka, Xuehan Hou, Yo Obara, Hiroshi Shitara, Yuta Seki, Kunie Matsuoka, Ai Takahashi, Eri Wakai, Hiroshi Hibino, Toyoyuki Takada, Toshihiko Shiroishi, Ryo Kominami and Yoshiaki Kikkawa

Biomedicines 2022, 10(9), 2221; https://doi.org/10.3390/biomedicines10092221 - 7 Sep 2022

Cited by 3 | Viewed by 1919

Abstract

An MSM/Ms strain was established using Japanese wild mice, which exhibit resistance to several phenotypes associated with aging, such as obesity, inflammation, and tumorigenesis, compared to common inbred mouse strains. MSM/Ms strain is resistant to age-related hearing loss, and their auditory abilities are [...] Read more.

An MSM/Ms strain was established using Japanese wild mice, which exhibit resistance to several phenotypes associated with aging, such as obesity, inflammation, and tumorigenesis, compared to common inbred mouse strains. MSM/Ms strain is resistant to age-related hearing loss, and their auditory abilities are sustained for long durations. The age-related hearing loss 3 (ahl3) locus contributes to age-related hearing in MSM/Ms strain. We generated ahl3 congenic strains by transferring a genomic region on chromosome 17 from MSM/Ms mice into C57BL/6J mice. Although C57BL/6J mice develop age-related hearing loss because of the ahl allele of the cadherin 23 gene, the development of middle- to high-frequency hearing loss was significantly delayed in an ahl3 congenic strain. Moreover, the novel age-related hearing loss 10 (ahl10) locus associated with age-related hearing resistance in MSM/Ms strain was mapped to chromosome 12. Although the resistance effects in ahl10 congenic strain were slightly weaker than those in ahl3 congenic strain, slow progression of age-related hearing loss was confirmed in ahl10 congenic strain despite harboring the ahl allele of cadherin 23. These results suggest that causative genes and polymorphisms of the ahl3 and ahl10 loci are important targets for the prevention and treatment of age-related hearing loss. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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12 pages, 275 KiB

Open AccessArticle

Comprehensive Etiologic Analyses in Pediatric Cochlear Implantees and the Clinical Implications

by Chee-Yee Lee, Pei-Hsuan Lin, Cheng-Yu Tsai, Yu-Ting Chiang, Hong-Ping Chiou, Ko-Yin Chiang, Pei-Lung Chen, Jacob Shu-Jui Hsu, Tien-Chen Liu, Hung-Pin Wu, Chen-Chi Wu and Chuan-Jen Hsu

Biomedicines 2022, 10(8), 1846; https://doi.org/10.3390/biomedicines10081846 - 31 Jul 2022

Cited by 6 | Viewed by 1675

Abstract

Cochlear implantation is the treatment of choice for children with profound sensorineural hearing impairment (SNHI), yet the outcomes of cochlear implants (CI) vary significantly across individuals. To investigate the CI outcomes in pediatric patients with SNHI due to various etiologies, we prospectively recruited [...] Read more.

Cochlear implantation is the treatment of choice for children with profound sensorineural hearing impairment (SNHI), yet the outcomes of cochlear implants (CI) vary significantly across individuals. To investigate the CI outcomes in pediatric patients with SNHI due to various etiologies, we prospectively recruited children who underwent CI surgery at two tertiary referral CI centers from 2010 to 2021. All patients underwent comprehensive history taking, next generation sequencing (NGS)-based genetic examinations, and imaging studies. The CI outcomes were evaluated using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. Of the 160 pediatric cochlear implantees (76 females and 84 males) included in this study, comprehensive etiological work-up helped achieve clinical diagnoses in 83.1% (133/160) of the patients, with genetic factors being the leading cause (61.3%). Imaging studies identified certain findings in 31 additional patients (19.3%). Four patients (2.5%) were identified with congenital cytomegalovirus infection (cCMV), and 27 patients (16.9%) remained with unknown etiologies. Pathogenic variants in the four predominant non-syndromic SNHI genes (i.e., SLC26A4, GJB2, MYO15A, and OTOF) were associated with favorable CI outcomes (Chi-square test, p = 0.023), whereas cochlear nerve deficiency (CND) on imaging studies was associated with unfavorable CI outcomes (Chi-square test, p < 0.001). Our results demonstrated a clear correlation between the etiologies and CI outcomes, underscoring the importance of thorough etiological work-up preoperatively in pediatric CI candidates. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

10 pages, 1430 KiB

Open AccessArticle

Unexpected Motherhood-Triggered Hearing Loss in the Two-Pore Channel (TPC) Mutant Mouse

by Juliette Royer, José-Manuel Cancela and Jean-Marc Edeline

Biomedicines 2022, 10(7), 1708; https://doi.org/10.3390/biomedicines10071708 - 15 Jul 2022

Cited by 3 | Viewed by 1452

Abstract

Calcium signaling is crucial for many physiological processes and can mobilize intracellular calcium stores in response to environmental sensory stimuli. The endolysosomal two-pore channel (TPC), regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), is one of the key components in [...] Read more.

Calcium signaling is crucial for many physiological processes and can mobilize intracellular calcium stores in response to environmental sensory stimuli. The endolysosomal two-pore channel (TPC), regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), is one of the key components in calcium signaling. However, its role in neuronal physiology remains largely unknown. Here, we investigated to what extent the acoustic thresholds differed between the WT mice and the TPC KO mice. We determined the thresholds based on the auditory brainstem responses (ABRs) at five frequencies (between 4 and 32 kHz) and found no threshold difference between the WT and KO in virgin female mice. Surprisingly, in lactating mothers (at P9–P10), the thresholds were higher from 8 to 32 kHz in the TPC KO mice compared to the WT mice. This result indicates that in the TPC KO mice, physiological events occurring during parturition altered the detection of sounds already at the brainstem level, or even earlier. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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13 pages, 2001 KiB

Open AccessArticle

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study

by Pei-Hsuan Lin, Hung-Pin Wu, Che-Ming Wu, Yu-Ting Chiang, Jacob Shujui Hsu, Cheng-Yu Tsai, Han Wang, Li-Hui Tseng, Pey-Yu Chen, Ting-Hua Yang, Chuan-Jen Hsu, Pei-Lung Chen, Chen-Chi Wu and Tien-Chen Liu

Biomedicines 2022, 10(7), 1523; https://doi.org/10.3390/biomedicines10071523 - 28 Jun 2022

Cited by 11 | Viewed by 2975

Abstract

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six [...] Read more.

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients’ median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5–7/2–5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2–6/1–3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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9 pages, 1562 KiB

Open AccessArticle

Prevalence of Hearing Impairment by Age: 2nd to 10th Decades of Life

by Koichiro Wasano, Takashi Nakagawa and Kaoru Ogawa

Biomedicines 2022, 10(6), 1431; https://doi.org/10.3390/biomedicines10061431 - 17 Jun 2022

Cited by 3 | Viewed by 2397

Abstract

Background: Accurate data on the prevalence of hearing impairment and severity across age and gender are paramount to formulate hearing health policies. Here, we sought to analyze audiometric data from a large group of age-diverse people in Japan, which has not been previously [...] Read more.

Background: Accurate data on the prevalence of hearing impairment and severity across age and gender are paramount to formulate hearing health policies. Here, we sought to analyze audiometric data from a large group of age-diverse people in Japan, which has not been previously described in detail. Methods: We analyzed retrospective hearing threshold data of 23,860 participants (10–99 years; left-right hearing threshold difference <15 dB; air-bone gap ≤10 dB) at 500, 1000, 2000, and 4000 Hz, and then classified them for hearing impairment severity according to the WHO Classification. Findings: There was a significant gender difference in median hearing thresholds, starting in 20-year-olds up to early 80-year-olds. Twenty-five percent of men in their late 50s had some level of HI, ~50% in their late 60s, and ~75% in their late 70s. For women, 25% had some level of HI in their early 60s, ~50% in their early 70s, and ~75% in their late 70s. For participants in their early 80s, 50% of either gender had moderate or more severe HI. Interpretation: Our results, derived from a large number of participants, provide basic information about the prevalence of hearing loss by age decade. Since people can expect to live longer than those in previous generations, our detailed data can inform national social systems responsible for hearing screening in making decisions about hearing-aid qualification, which may reduce barriers to older people’s independence, productivity, and quality of life. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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15 pages, 3978 KiB

Open AccessArticle

Clinical Heterogeneity Associated with MYO7A Variants Relies on Affected Domains

by Sun Young Joo, Gina Na, Jung Ah Kim, Jee Eun Yoo, Da Hye Kim, Se Jin Kim, Seung Hyun Jang, Seyoung Yu, Hye-Youn Kim, Jae Young Choi, Heon Yung Gee and Jinsei Jung

Biomedicines 2022, 10(4), 798; https://doi.org/10.3390/biomedicines10040798 - 29 Mar 2022

Cited by 5 | Viewed by 2251

Abstract

Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype–phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural [...] Read more.

Autosomal dominant hearing loss (ADHL) manifests as an adult-onset disease or a progressive disease. MYO7A variants are associated with DFNA11, a subtype of ADHL. Here, we examined the role and genotype–phenotype correlation of MYO7A in ADHL. Enrolled families suspected of having post-lingual sensorineural hearing loss were selected for exome sequencing. Mutational alleles in MYO7A were identified according to ACMG guidelines. Segregation analysis was performed to examine whether pathogenic variants segregated with affected status of families. All identified pathogenic variants were evaluated for a phenotype–genotype correlation. MYO7A variants were detected in 4.7% of post-lingual families, and 12 of 14 families were multiplex. Five potentially pathogenic missense variants were identified. Fourteen variants causing autosomal dominant deafness were clustered in motor and MyTH4 domains of MYO7A protein. Missense variants in the motor domain caused late onset of hearing loss with ascending tendency. A severe audiological phenotype was apparent in individuals carrying tail domain variants. We report two new pathogenic variants responsible for DFNA11 in the Korean ADHL population. Dominant pathogenic variants of MYO7A occur frequently in motor and MyTH4 domains. Audiological differences among individuals correspond to specific domains which contain the variants. Therefore, appropriate rehabilitation is needed, particularly for patients with late-onset familial hearing loss. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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12 pages, 1200 KiB

Open AccessArticle

There Is More Than Meets the Eye: Identification of Dual Molecular Diagnosis in Patients Affected by Hearing Loss

by Anna Morgan, Flavio Faletra, Giulia Severi, Martina La Bianca, Laura Licchetta, Paolo Gasparini, Claudio Graziano and Giorgia Girotto

Biomedicines 2022, 10(1), 12; https://doi.org/10.3390/biomedicines10010012 - 22 Dec 2021

Cited by 2 | Viewed by 2451

Abstract

Hearing loss (HL) is the most common sensory impairment, and it is characterized by a high clinical/genetic heterogeneity. Here we report the identification of dual molecular diagnoses (i.e., mutations at two loci that lead to the expression of two Mendelian conditions) in a [...] Read more.

Hearing loss (HL) is the most common sensory impairment, and it is characterized by a high clinical/genetic heterogeneity. Here we report the identification of dual molecular diagnoses (i.e., mutations at two loci that lead to the expression of two Mendelian conditions) in a series of families affected by non-syndromic and syndromic HL. Eighty-two patients who displayed HL as a major clinical feature have been recruited during the last year. After an accurate clinical evaluation, individuals have been analyzed through whole-exome sequencing (WES). This protocol led to the identification of seven families characterized by the presence of a dual diagnosis. In particular, based on the clinical and genetic findings, patients have been classified into two groups: (a) patients with HL and distinct phenotypes not fitting in a known syndrome due to mutations at two loci (e.g., HL in association with Marfan syndrome) and (b) patients with two genes involved in HL phenotype (e.g., TMPRSS3 and MYH14). These data highlight for the first time the high prevalence of dual molecular diagnoses in HL patients and suggest that they should be considered especially for those cases that depart from the expected clinical manifestation or those characterized by a significant intra-familiar variability. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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Review

Jump to: Research

14 pages, 804 KiB

Open AccessReview

The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

by Kazuaki Homma

Biomedicines 2022, 10(9), 2254; https://doi.org/10.3390/biomedicines10092254 - 12 Sep 2022

Cited by 2 | Viewed by 2211

Abstract

Deafness-associated genes KCNQ1 (also associated with heart diseases) and KCNQ4 (only associated with hearing loss) encode the homotetrameric voltage-gated potassium ion channels Kv7.1 and Kv7.4, respectively. To date, over 700 KCNQ1 and over 70 KCNQ4 variants have been identified in patients. The vast [...] Read more.

Deafness-associated genes KCNQ1 (also associated with heart diseases) and KCNQ4 (only associated with hearing loss) encode the homotetrameric voltage-gated potassium ion channels Kv7.1 and Kv7.4, respectively. To date, over 700 KCNQ1 and over 70 KCNQ4 variants have been identified in patients. The vast majority of these variants are inherited dominantly, and their pathogenicity is often explained by dominant-negative inhibition or haploinsufficiency. Our recent study unexpectedly identified cell-death-inducing cytotoxicity in several Kv7.1 and Kv7.4 variants. Elucidation of this cytotoxicity mechanism and identification of its modifiers (drugs) have great potential for aiding the development of a novel pharmacological strategy against many pathogenic KCNQ variants. The purpose of this review is to disseminate this emerging pathological role of Kv7 variants and to underscore the importance of experimentally characterizing disease-associated variants. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss)

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