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

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.

Choroid plexus LAT2 and SNAT3 as partners in CSF amino acid homeostasis maintenance

“…These differences between the amino acid transporter mRNA expression levels measured in the present study and the previously published results are suggested to be due to different methodological approaches, in particular regarding the quantitation method. In support of our findings, another more recent study also suggested a significant expression of LAT2 mRNA in choroid plexus epithelial cells, but without localization by immunohistochemistry [33]. Protein expression of LAT2 had been detected previously by proteome analysis of whole CP but not in BAB [16].…”

“…We confirmed ablation of LAT2 transporter in CP on mRNA and protein levels (Additional file 1: Figure S2A, B) and measured amino acid levels in plasma and CSF samples. Previously Braun et al had reported elevated levels of 8 amino acids (Ala, Ser, Gly, Thr, Glu, Asp and Lys) for the serum of LAT2 knockout (KO) animals [37], however these alterations were not reproduced in our experiments using another LAT2 knock-out model (Additional file 2: Table S3) [32,33]. Therefore, we compared the CSF/ plasma ratio of each out of 19 detected amino acids [18 proteinogenic AA (all except Cys and Ile) and Tau] between wild type and LAT2 KO animals.…”

“…Considering the high level of LAT2 expression in CP, we examined the impact of LAT2 ablation on AA concentrations in CSF of Lat2 KO animals [33]. We confirmed ablation of LAT2 transporter in CP on mRNA and protein levels (Additional file 1: Figure S2A, B) and measured amino acid levels in plasma and CSF samples.…”

“…2d, m) and anti-SNAT1 (Fig. 2g, p) antibodies [30][31][32][33][34]. The fact that we localized only these three amino acid transporters may be considered as a limitation in view of the larger number of transporters detected at the mRNA level, but since protein localization studies are per se prone to artefacts (cross-reactivity etc.…”

Function and Regulation of Acid Resistance Antiporters

“…The latter controls intracellular trafficking and membrane topology of LAT in the covalent complex, while LAT functions as an amino acid antiporter, importing large neutral amino acid into the cells for the exchange of intracellular amino acid (Fotiadis et al 2013;Singh and Ecker 2018). LATs are involved in diseases as cystinuria (Feliubadaló et al 1999), lysinuric protein intolerance (Borsani et al 1999;Torrents et al 1999), autism (Tărlungeanu et al 2016), and age-related hearing loss (Espino Guarch et al 2018). They are a target in cancer therapy (Napolitano et al 2017), and have been exploited as a potential drug delivery system into the brain (Rautio et al 2013).…”