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Proc Natl Acad Sci U S A. 2019 May 28;116(22):11000-11009. doi: 10.1073/pnas.1817500116. Epub 2019 May 16.

Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.

Author information

1
Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH 44106.
2
Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106.
3
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106.
4
Department of Biology, Case Western Reserve University, Cleveland, OH 44106.
5
Department of Otolaryngology-Head and Neck Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH 44106; kna3@case.edu.

Abstract

The pathogenic variant c.144T>G (p.N48K) in the clarin1 gene (CLRN1) results in progressive loss of vision and hearing in Usher syndrome IIIA (USH3A) patients. CLRN1 is predicted to be an essential protein in hair bundles, the mechanosensory structure of hair cells critical for hearing and balance. When expressed in animal models, CLRN1 localizes to the hair bundle, whereas glycosylation-deficient CLRN1N48K aggregates in the endoplasmic reticulum, with only a fraction reaching the bundle. We hypothesized that the small amount of CLRN1N48K that reaches the hair bundle does so via an unconventional secretory pathway and that activation of this pathway could be therapeutic. Using genetic and pharmacological approaches, we find that clarin1 knockout (clrn1 KO/KO ) zebrafish that express the CLRN1 c.144T>G pathogenic variant display progressive hair cell dysfunction, and that CLRN1N48K is trafficked to the hair bundle via the GRASP55 cargo-dependent unconventional secretory pathway (GCUSP). On expression of GRASP55 mRNA, or on exposure to the drug artemisinin (which activates GCUSP), the localization of CLRN1N48K to the hair bundles was enhanced. Artemisinin treatment also effectively restored hair cell mechanotransduction and attenuated progressive hair cell dysfunction in clrn1 KO/KO larvae that express CLRN1 c.144T>G , highlighting the potential of artemisinin to prevent sensory loss in CLRN1 c.144T>G patients.

KEYWORDS:

USH3A; hearing loss; mitigation

PMID:
31097578
PMCID:
PMC6561152
[Available on 2019-11-16]
DOI:
10.1073/pnas.1817500116

Conflict of interest statement

Conflict of interest statement: S.R.G. and K.N.A. have filed a patent application (PCT/US17/55914) titled, “Methods of treating disorders associated with glycosylation defective proteins.”

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