Rescue of ciliogenesis and hyperglutamylation mutant phenotype in AGBL5 -/- cell model of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) affects around 1 in 4000 individuals and represents approximately 25% of cases of vision loss in adults, through death of retinal rod and cone photoreceptor cells. It remains a largely untreatable disease, and research is needed to identify potential targets for therapy. Mutations in 94 different genes have been identified as causing RP, including AGBL5 which encodes the main deglutamylase that regulates and maintains functional levels of cilia tubulin glutamylation, which is essential to initiate ciliogenesis, maintain cilia stability and motility. In this study we use CRISPR-mutated AGBL5 clonal retinal pigmented epithelial cell lines to characterise the cilia defects and hyperglutamylation in these cells and identify potential targets for treatment. We demonstrate rescue of glutamylation to wild-type levels and restoration of ciliogenesis in AGBL5 mutant cells through exogenous expression of AGBL5, and independently through both stable genomic mutation and transient siRNA knockdown of TTLL5, which encodes a tubulin glutamylase. This identifies two potential routes to treatment for patients with RP associated with mutations in AGBL5 which will need to be explored further in retinal organoid models of this disease.

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Identifiers

ORCID for Suly Saray Villa Vasquez: orcid.org/0000-0002-6317-752X

ORCID for Reuben Pengelly: orcid.org/0000-0001-7022-645X

ORCID for Diana Baralle: orcid.org/0000-0003-3217-4833

ORCID for Gabrielle Wheway: orcid.org/0000-0002-0494-0783

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