KCNJ13 – Leber congenital amaurosis

Leber congenital amaurosis (LCA) is an early-onset retinal dystrophy characterized by severe visual impairment and nystagmus. Biallelic mutations in KCNJ13, encoding the Kir7.1 inwardly rectifying potassium channel, have been causally linked to autosomal recessive LCA (PMID:21763485; PMID:27203561).

Inherited in an autosomal recessive manner, KCNJ13-associated LCA has been observed in at least five affected individuals across three unrelated families. The prototypical variant c.496C>T (p.Arg166Ter) exemplifies a loss-of-function allele leading to premature channel truncation. Compound heterozygosity for novel missense and nonsense mutations further expands the variant spectrum (PMID:27203561).

Segregation analysis in consanguineous pedigrees revealed two affected siblings harboring homozygous LoF variants and unaffected heterozygous carriers, consistent with recessive inheritance (PMID:21763485).

Functional studies confirm that Kir7.1 is abundantly expressed in human retinal pigment epithelium and that LCA-associated mutants abolish potassium currents. Xenopus oocyte assays demonstrate absent channel activity of truncating alleles, while zebrafish and mouse knockdown models recapitulate retinal degeneration observed in patients (PMID:18035352; PMID:25921210).

Therapeutic proof-of-concept is provided by readthrough and gene augmentation in patient-derived iPSC-RPE, which restore membrane potential and Kir7.1 currents, underscoring the feasibility of precision-medicine approaches for LCA16 (PMID:30686507).

Collectively, robust genetic and functional evidence affirms a strong gene-disease relationship between KCNJ13 and LCA, supporting molecular diagnosis and guiding future therapeutic development.

References

• American Journal of Human Genetics • 2011 • Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis PMID:21763485
• Retinal Cases & Brief Reports • 2017 • Leber congenital amaurosis with large retinal pigment clumps caused by compound heterozygous mutations in KCNJ13. PMID:27203561
• Experimental Eye Research • 2008 • Expression of Kir7.1 and a novel Kir7.1 splice variant in native human retinal pigment epithelium. PMID:18035352
• Human Mutation • 2015 • A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16). PMID:25921210
• American Journal of Human Genetics • 2019 • Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness. PMID:30686507

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