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Hum Mutat. 2015 Jul;36(7):720-7. doi: 10.1002/humu.22807. Epub 2015 May 20.

A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16).

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Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin.
McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin.
Center for Genetic Eye Diseases and Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
Casey Molecular Diagnostic Laboratory, Oregon Health & Science University, Portland, Oregon.


Mutations in the KCNJ13 gene that encodes the inwardly rectifying potassium channel Kir7.1 cause snowflake vitreoretinal degeneration (SVD) and leber congenital amaurosis (LCA). Kir7.1 controls the microenvironment between the photoreceptors and the retinal pigment epithelium (RPE) and also contributes to the function of other organs such as uterus and brain. Heterologous expressions of the mutant channel have suggested a dominant-negative loss of Kir7.1 function in SVD, but parallel studies in LCA16 have been lacking. Herein, we report the identification of a novel nonsense mutation in the second exon of the KCNJ13 gene that leads to a premature stop codon in association with LCA16. We have determined that the mutation results in a severe truncation of the Kir7.1 C-terminus, alters protein localization, and disrupts potassium currents. Coexpression of the mutant and wild-type channel has no negative influence on the wild-type channel function, consistent with the normal clinical phenotype of carrier individuals. By suppressing Kir7.1 function in mice, we were able to reproduce the severe LCA electroretinogram phenotype. Thus, we have extended the observation that Kir7.1 mutations are associated with vision disorders to include novel insights into the molecular mechanism of disease pathobiology in LCA16.


Kir7.1; LCA; RPE; electrophysiology; mouse model; nonsense mutation; shRNA

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