, 1:P83,
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Date: 16 Nov 2012

Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice

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Leber Congenital Amaurosis (LCA) is one of the most common forms of congenital blindness in young children. It is the most severe retinal dystrophy, characterized by strong visual impairment or blindness within the first months after birth. Despite its genetic heterogeneity, the clinical phenotype is highly overlapping, pointing towards a common disease mechanism. To gain insights into the mechanism, we compared the interactomes of wild type and LCA causing mutants of lebercilin by quantitative mass spectrometry using SILAC followed by MaxQuant based analysis. This revealed that the link of lebercilin to the IFT complex is disrupted due to LCA-associated mutations. The interaction of the IFT proteins with lebercilin was confirmed by GST pull-down from retina, the loss of IFT proteins from the complex of mutants by western blot. While the disruption of the lebercilin-IFT interaction does not lead to disturbed ciliogenesis in both, hTERT-RPE1 cell and in the generated lebercilin knockout ...