Mutation of SLC7A14 causes auditory neuropathy and retinitis pigmentosa mediated by lysosomal dysfunction.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-

Amino Acid Transport System y+*/genetics ; Hearing Loss, Central*/metabolism ; Lysosomes*/metabolism ; Lysosomes*/pathology ; Retinitis Pigmentosa*/genetics ; Retinitis Pigmentosa*/metabolism; Animals ; Humans ; Mammals ; Mice ; Mutation

Lysosomes contribute to cellular homeostasis via processes including macromolecule degradation, nutrient sensing, and autophagy. Defective proteins related to lysosomal macromolecule catabolism are known to cause a range of lysosomal storage diseases; however, it is unclear whether mutations in proteins involved in homeostatic nutrient sensing mechanisms cause syndromic sensory disease. Here, we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensory hair cells and highly expressed in lysosomes of mammalian cochlear inner hair cells (IHCs) and retinal photoreceptors. Autosomal recessive mutation of SLC7A14 caused loss of IHCs and photoreceptors, leading to presynaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss-of-function mutation altered protein trafficking and increased basal autophagy, leading to progressive cell degeneration. This study implicates autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans.

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P20 GM139762 United States GM NIGMS NIH HHS; R01 DC016807 United States DC NIDCD NIH HHS; U24 DC015910 United States DC NIDCD NIH HHS

0 (Amino Acid Transport System y+)
0 (SLC7A14 protein, human)

Auditory neuropathy

Date Created: 20220408 Date Completed: 20220412 Latest Revision: 20240214

20240214

PMC8993119

10.1126/sciadv.abk0942

35394837