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Cecinio Ronquillo, Jeanne Frederick, Wolfgang Baehr; Nephrocystin-5 knockout mice recapitulate retina and kidney pathologies of Senior-Løken Syndrome. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3149.
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Senior-Løken syndrome is an autosomal recessive disease characterized by retinal degeneration (RP/LCA) and nephronophthisis (kidney fibrosis and presence of cysts). Mutations in Nephrocystin-5 (NPHP5) have been shown to be the most common cause of Senior-Løken syndrome in humans; however, the function of NPHP5 is poorly understood. Here, we describe a novel mammalian model of Senior-Løken syndrome generated by deleting NPHP5 in the mouse.
A gene trap containing a reporter gene (β-gal) was inserted in intron 4 of the mouse Nphp5 gene causing premature termination of Nephrocystin-5 protein expression. Retina and renal tissue were characterized by immunocystochemistry using various antibodies at developmental time points. ERGs were recorded at different time points. Ultrastructure of the photoreceptor connecting cilium and basal body was examined on postnatal days P6 and P10.
Global knockout mice are viable and fertile. Retinal function in knockout animals was undetectable by ERG at P12 (eye opening). At P10, knockout animals already showed absence of outer segments and decreased number of cells in the outer nuclear layer. Rhodopsin transport is impaired as early as P6 and rhodopsin accumulates in rod perinuclear regions (Fig. 1). Apoptosis, fibrosis and presence of cysts are observed in the kidneys of knockout mice (Fig. 2). Knockdown of NPHP5 in a kidney cell line shows decreased numbers of primary cilia suggesting a role of NPHP5 in ciliogenesis or ciliary maintenance.
NPHP5 global knockout mouse is a novel model of Senior-Løken syndrome recapitulating the retina and renal pathologies observed in humans. This model will be an important tool to provide insight into detailed molecular mechanisms of NPHP5 function in ciliogenesis and primary cilium structure.
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