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Bikash R Pattnaik, Meghan J Marino, John Chiang, De-Ann M Pillers, Elias I Traboulsi; A Novel Nonsense Mutation in KCNJ13 Causes Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3283.
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Leber Congenital Amaurosis (LCA) is a rare autosomal recessive disorder caused by the defects in the function of either photoreceptors or Retinal Pigment Epithelium (RPE). Recently, mutations in KCNJ13, an RPE inwardly rectifying potassium channel have been found to be associated with LCA. We describe a patient with a retinal dystrophy compatible with a moderately severe LCA phenotype due to homozygosity for a novel KCNJ13 nonsense mutation.
A nine year-old male presented with nyctalopia and decreased vision. Clinical studies including a complete eye examination, fundus photography, and OCT were performed. Genetic testing was obtained using PCR-based Next Generation Sequencing (NGS). To study the mutant protein, site-directed mutagenesis was performed on an N-terminal Green Fluorescence Protein (GFP) - fused human KCNJ13 open reading frame insert by Quick-Change Site-Directed Mutagenesis Kit from Stratagene (Agilient Technologies Inc., CA). Chinese Hamster Ovary (CHO) cells were transfected with either the wildtype or mutant plasmid, and cells were studied within 24 to 72 hours post transfection.
Best corrected visual acuity was 20/200 OD and 20/400 OS. Fundus photos showed a pale optic nerve head, attenuated blood vessels, and a pigmented, atrophic macula. Genetic testing detected a novel homozygous G→A transition (c.158G>A) in exon 1 of KCNJ13, which results in a stop codon at position 53 (p.W53X). This is predicted to result in a loss of the transmembrane domain and most of the C-terminal domain. Premature termination of translation was clearly demonstrated when the mutant protein was expressed in a heterologous expression system.
The present report confirms that mutations in KCNJ13 are strongly associated with LCA phenotype. The nature of the present truncating mutation sheds new light on the pathogenesis of the disease process. Kir7.1 is a critical player in vision and may be a candidate gene for other blindness.
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