Mutation of SLC7A14 Causes Auditory Neuropathy and Retinitis Pigmentosa Mediated by Lysosomal Dysfunction

ABSTRACT Lysosomes contribute to cellular homeostasis via processes including phagocytosis, macromolecule catabolism, secretion, and nutrient sensing mechanisms. Defective proteins related to lysosomal macromolecule catabolism are known to cause a broad range of lysosomal storage diseases. It is unclear, however, if mutations in genes in the autophagy-lysosomal pathway can cause syndromic disease. Here we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensitive 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 pre-synaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss of function mutation altered protein trafficking and disrupted lysosomal homeostasis, resulting in dysregulation of basal autophagy and progressive cell degeneration. This study is the first to implicate autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans.