Faculty Collaboration Database

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

Date

04/30/2015

Pubmed ID

25921210

DOI

10.1002/humu.22807

Scopus ID

2-s2.0-84931568335 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

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.

Author List

Pattnaik BR, Shahi PK, Marino MJ, Liu X, York N, Brar S, Chiang J, Pillers DA, Traboulsi EI

Author

Simran Brar OD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Child
Codon, Nonsense
Eye Diseases
Humans
Leber Congenital Amaurosis
Male
Mice
Middle East
Phenotype
Potassium Channels, Inwardly Rectifying