Next generation sequencing and animal models reveal SLC9A3R1 as a new gene involved in human age-related hearing loss

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Title: Next generation sequencing and animal models reveal SLC9A3R1 as a new gene involved in human age-related hearing loss
Authors: Girotto, G
Morgan, A
Krishnamoorthy, N
Cocca, M
Brumat, M
Bassani, S
La Bianca, M
Di Stazio, M
Gasparini, P
Item Type: Journal Article
Abstract: Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genome-wide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, SLC9A3R1 has been identified as a strong candidate and then validated by “in vitro” and “in vivo” studies. Briefly, a rare (MAF: 2.886e-5) missense variant c.539G > A, p.(R180Q) was detected in two unrelated male patients affected by ARHL characterized by a severe to profound high-frequency hearing loss. The variant, predicted as damaging, was not present in healthy matched controls. Protein modeling confirmed the pathogenic effect of p.(R180Q) variant on protein’s structure leading to a change in the total number of hydrogen bonds. In situ hybridization showed slc9a3r1 expression in zebrafish inner ear. A zebrafish knock-in model, generated by CRISPR-Cas9 technology, revealed a reduced auditory response at all frequencies in slc9a3r1R180Q/R180Q mutants compared to slc9a3r1+/+ and slc9a3r1+/R180Q animals. Moreover, a significant reduction (5.8%) in the total volume of the saccular otolith (which is responsible for sound detection) was observed in slc9a3r1R180Q/R180Q compared to slc9a3r1+/+ (P = 0.0014), while the utricular otolith, necessary for balance, was not affected in agreement with the human phenotype. Overall, these data strongly support the role of SLC9A3R1 gene in the pathogenesis of ARHL opening new perspectives in terms of diagnosis, prevention and treatment.
Issue Date: 26-Feb-2019
Date of Acceptance: 11-Feb-2019
ISSN: 1664-8021
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Genetics
Volume: 10
Copyright Statement: © 2019 Girotto, Morgan, Krishnamoorthy, Cocca, Brumat, Bassani, La Bianca, Di Stazio and Gasparini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) ( The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
hearing loss
new gene discovery
zebrafish model
next-generation sequencing
Publication Status: Published
Open Access location:
Article Number: 142
Online Publication Date: 2019-02-26
Appears in Collections:National Heart and Lung Institute

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