Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration

Autor:	Michalis Georgiou, Michel Michaelides, Chrisostomos Prodromou, Isabelle Meunier, James W B Bainbridge, Hoang Mai Le, Anne-Françoise Roux, Almudena Sacristán-Reviriego, Béatrice Bocquet, Jacqueline van der Spuy
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Retinal degeneration Molecular biology Leber Congenital Amaurosis lcsh:Medicine Diseases Pathogenesis Epitopes chemistry.chemical_compound 0302 clinical medicine Gene Frequency Missense mutation lcsh:Science Genetics Microscopy Confocal Multidisciplinary Homozygote Retinal Degeneration Middle Aged Tetratricopeptide Phenotype Retinitis Pigmentosa Adult Heterozygote Cell biology Adolescent CHO Cells Biology Retina Article Young Adult 03 medical and health sciences Cricetulus Medical research Retinitis pigmentosa medicine Animals Humans HSP90 Heat-Shock Proteins Allele Allele frequency Alleles Adaptor Proteins Signal Transducing Aged Cyclic Nucleotide Phosphodiesterases Type 6 lcsh:R Genetic Variation Dystrophy Retinal DNA medicine.disease HEK293 Cells 030104 developmental biology chemistry 030221 ophthalmology & optometry lcsh:Q sense organs
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020) Scientific Reports
ISSN:	2045-2322
Popis:	Disease-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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b31303ccc11f49da50d0ff5bdafad714 http://link.springer.com/article/10.1038/s41598-020-74516-9 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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