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

PubMed ID: 25921210

Author(s): Pattnaik BR, Shahi PK, Marino MJ, Liu X, York N, Brar S, Chiang J, Pillers DA, Traboulsi EI. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes Leber congenital amaurosis (LCA16). Hum Mutat. 2015 Jul;36(7):720-7. doi: 10.1002/humu.22807. Epub 2015 May 20. PMID 25921210

Journal: Human Mutation, Volume 36, Issue 7, Jul 2015

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.