41598_2020_Article_74516.pdf (3.6 MB)
Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration
journal contribution
posted on 2023-06-09, 22:32 authored by Almudena Sacristan-Reviriego, Hoang Mai Le, Michalis Georgiou, Isabelle Meunier, Beatrice Bocquet, Anne-Françoise Roux, Chrisostomos ProdromouChrisostomos Prodromou, James Bainbridge, Michel Michaelides, Jacqueline van der SpuyDisease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy.
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Publication status
- Published
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- Published version
Journal
Scientific ReportsISSN
2045-2322Publisher
Nature ResearchExternal DOI
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1Volume
10Page range
1-15Article number
a17520Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-12-18First Open Access (FOA) Date
2020-12-18First Compliant Deposit (FCD) Date
2020-12-18Usage metrics
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