Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in Age-Related Hearing Loss
- Sidra Medical and Research Center, Qatar
- Institut d'Investigació Biomédica de Bellvitge (IDIBELL), Spain
- Biomedical Research Networking Centre on Rare Diseases (CIBERER), Spain
- Institute for Research in Biomedicine (IRB Barcelona), Spain
- University of Trieste, Italy
Abstract
Age related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient's variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations.
Data availability
-
Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversityPublicly available at EBI BioStudies (accession no. S-EPMC3658181).
Article and author information
Author details
Funding
Spanish Health Institute Carlos III- FIS (PI13/00121-R-FEDER)
- Virginia Nunes
Spanish Ministry of Science and Innovation (SAF2014-53979-R-FEDER)
- Isabel Varela-Nieto
Spanish Health Institute Carlos III-FIS (PI16/00267-R-Feder)
- Virginia Nunes
CIBERER (ACCI 2017)
- Isabel Varela-Nieto
- Manuel Palacín
- Virginia Nunes
Spanish Ministry of Science and Innovation (SAF2015-64869-R-FEDER)
- Manuel Palacín
Generalitat de Catalunya (SGR2009-1490)
- Virginia Nunes
Qatar National Research Fund (JSREP07-013-3-006)
- Meritxell Espino Gaurch
CIBERER (ACCI 2016)
- Isabel Varela-Nieto
- Manuel Palacín
- Virginia Nunes
TARGEAR (FP7-PEOPLE-2013-IAPP)
- Isabel Varela-Nieto
Generalitat de Catalunya (SGR2009-1355)
- Manuel Palacín
Generalitat de Catalunya (SGR 2014/1125)
- Mara Dierssen
Spanish Ministry of Science and Innovation (SAF2016-79956-R)
- Mara Dierssen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation complied with the ARRIVE guidelines and was conducted in accordance with Spanish (RD 53/2013) and European (Directive 2010/63/EU) legislations. All protocols used in this study were reviewed and approved by the Institutional Animal Care and Use Committee at IDIBELL in a facility accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAELAC accredited facility, B900010). Mice procedures were done according with scientific, humane, and ethical principles. The studied mouse model did not show phenotype differences comparing male and female. Thus, to ensure that our research represents both genders, the studies describes in this work were performed using both sexes equitably. The number of biological and experimental replicates is detailed in the legend of each figure.
Human subjects: Ethical Consent Published in:Esko T, Mezzavilla M, Nelis M, Borel C, Debniak T, Jakkula E, et al. Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversity. Eur J Hum Genet. 2013;21(6):659-65.
Copyright
© 2018, Espino Gaurch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,263
- views
-
- 503
- downloads
-
- 40
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in Age-Related Hearing Loss
eLife 7:e31511.
https://doi.org/10.7554/eLife.31511
Further reading
-
- Chromosomes and Gene Expression
Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.
-
- Chromosomes and Gene Expression
The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.
