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Kruczek, Kamil; Qu, Zepeng; Welby, Emily; Shimada, Hiroko; Hiriyanna, Suja; English, Milton A.; Zein, Wadih M.; Brooks, Brian P.; Swaroop, Anand
Stem cell reports, 10/2022, Letnik: 17, Številka: 10Journal Article
Mutations in the IQ calmodulin-binding motif containing B1 (IQCB1)/NPHP5 gene encoding the ciliary protein nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction in Senior-Løken syndrome. For in vitro disease modeling, we obtained dermal fibroblasts from patients with NPHP5-LCA that were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into retinal pigment epithelium (RPE) and retinal organoids. Patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. Disease phenotype in NPHP5-LCA retinal organoids could be rescued by adeno-associated virus (AAV)-mediated IQCB1/NPHP5 gene augmentation therapy. Our studies thus establish a human disease model and a path for treatment of NPHP5-LCA. Display omitted •NPHP5-LCA patient-derived fibroblasts and RPE display abnormally elongated cilia•Outer segment protein localization is impaired in patient-derived photoreceptors•CEP290 protein reduction is observed across all NPHP5-LCA patient-derived cells•NPHP5 augmentation improves disease phenotypes in patient retinal organoids Swaroop and colleagues use in vitro disease modeling to characterize cilia abnormalities in human NPHP5-LCA patient-derived cells. Short photoreceptor outer segments with mislocalized opsin proteins and reduced CEP290 protein levels were observed in patient-derived retinal organoids. NPHP5-targeted gene therapy rescued the disease phenotypes in organoids, suggesting a key role of NPHP5 in stabilizing the CEP290-associated ciliary gate complex to ensure proper protein trafficking.
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in: SICRIS
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