Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Meritxell Espino Guarch; Mariona Font-Llitjós; Silvia Murillo-Cuesta; Ekaitz Errasti-Murugarren; Adelaida M. Celaya; Giorgia Girotto; Dragana Vuckovic; Massimo Mezzavilla; Clara Vilches; Susanna Bodoy; Ignasi Sahún; Laura González; Esther Prat; Antonio Zorzano; Mara Dierssen; Isabel Varela-Nieto; Paolo Gasparini; Manuel Palacín; Virginia Nunes

doi:10.7554/eLife.31511

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

Meritxell Espino Guarch, Mariona Font-Llitjós, Silvia Murillo-Cuesta, Ekaitz Errasti-Murugarren, Adelaida M. Celaya, Giorgia Girotto, Dragana Vuckovic, Massimo Mezzavilla, Clara Vilches, Susanna Bodoy, Ignasi Sahún, Laura González, Esther Prat, Antonio Zorzano, Mara Dierssen, Isabel Varela-Nieto, Paolo Gasparini, Manuel Palacín, Virginia Nunes

IRCCS pediatrico Burlo Garofolo

Research output: Contribution to journal › Article

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.

Original language	English
Article number	e31511
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.31511
Publication status	Published - Jan 22 2018

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ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

Cite this

Guarch, M. E., Font-Llitjós, M., Murillo-Cuesta, S., Errasti-Murugarren, E., Celaya, A. M., Girotto, G., Vuckovic, D., Mezzavilla, M., Vilches, C., Bodoy, S., Sahún, I., González, L., Prat, E., Zorzano, A., Dierssen, M., Varela-Nieto, I., Gasparini, P., Palacín, M., & Nunes, V. (2018). 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

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. / Guarch, Meritxell Espino; Font-Llitjós, Mariona; Murillo-Cuesta, Silvia; Errasti-Murugarren, Ekaitz; Celaya, Adelaida M.; Girotto, Giorgia; Vuckovic, Dragana; Mezzavilla, Massimo; Vilches, Clara; Bodoy, Susanna; Sahún, Ignasi; González, Laura; Prat, Esther; Zorzano, Antonio; Dierssen, Mara; Varela-Nieto, Isabel; Gasparini, Paolo; Palacín, Manuel; Nunes, Virginia.

In: eLife, Vol. 7, e31511, 22.01.2018.

Research output: Contribution to journal › Article

Guarch, ME, Font-Llitjós, M, Murillo-Cuesta, S, Errasti-Murugarren, E, Celaya, AM, Girotto, G, Vuckovic, D, Mezzavilla, M, Vilches, C, Bodoy, S, Sahún, I, González, L, Prat, E, Zorzano, A, Dierssen, M, Varela-Nieto, I, Gasparini, P, Palacín, M & Nunes, V 2018, 'Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss', eLife, vol. 7, e31511. https://doi.org/10.7554/eLife.31511

Guarch, Meritxell Espino ; Font-Llitjós, Mariona ; Murillo-Cuesta, Silvia ; Errasti-Murugarren, Ekaitz ; Celaya, Adelaida M. ; Girotto, Giorgia ; Vuckovic, Dragana ; Mezzavilla, Massimo ; Vilches, Clara ; Bodoy, Susanna ; Sahún, Ignasi ; González, Laura ; Prat, Esther ; Zorzano, Antonio ; Dierssen, Mara ; Varela-Nieto, Isabel ; Gasparini, Paolo ; Palacín, Manuel ; Nunes, Virginia. / Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. In: eLife. 2018 ; Vol. 7.

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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{\textquoteright}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.",

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AU - Errasti-Murugarren, Ekaitz

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10.7554/eLife.31511