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

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 prot...

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Published in:Science advances 2022-04, Vol.8 (14), p.eabk0942
Main Authors: Giffen, Kimberlee P, Li, Yi, Liu, Huizhan, Zhao, Xiao-Chang, Zhang, Chang-Jun, Shen, Ren-Juan, Wang, Tianying, Janesick, Amanda, Chen, Bo-Bei, Gong, Shu-Sheng, Kachar, Bechara, Jin, Zi-Bing, He, David Z
Format: Article
Language:English
Subjects:
Amino Acid Transport System y+ - genetics
Animals
Cellular Neuroscience
Hearing Loss, Central - metabolism
Humans
Lysosomes - metabolism
Lysosomes - pathology
Mammals
Mice
Mutation
Neuroscience
Retinitis Pigmentosa - genetics
Retinitis Pigmentosa - metabolism
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Summary: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 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abk0942