KCNV2 – Cone Dystrophy with Supernormal Rod Response

Autosomal recessive variants in KCNV2 underlie cone dystrophy with supernormal rod response (MONDO:0012475), a rare retinal disorder characterized by early-onset photophobia, impaired cone responses and a pathognomonic supernormal rod electroretinogram (PMID:16909397).

Initial linkage in a large consanguineous family and homozygosity mapping pinpointed a nonsense KCNV2 mutation segregating with disease, and subsequent analysis identified pathogenic alleles in 17 alleles across 10 unrelated pedigrees, confirming autosomal recessive inheritance (PMID:16909397).

The variant spectrum encompasses loss-of-function and missense alleles, including the recurrent LoF change c.153T>A (p.Tyr51Ter) (PMID:16909397), frameshifts, large genomic deletions and hypomorphic alleles. Biallelic mutations consistently abolish or alter Kv8.2 function, as evidenced by altered subunit interaction and channel assembly.

A cohort of 17 patients from 13 families demonstrated consistent ERG features, reduced visual acuity and variable macular atrophy; all KCNV2 variants segregated concordantly in available relatives under a recessive model (PMID:18235024). Large deletions account for ~15.5% of mutant alleles in a series of 367 patients, highlighting underdiagnosis and allele heterogeneity (PMID:21882291).

Functional studies reveal Kv8.2 expression in rod and cone inner segments by in situ hybridization and aberrant biophysical properties in heterologous systems. Kv8.2 knockout mice replicate the human ERG phenotype and display early photoreceptor loss, supporting a loss-of-function mechanism (PMID:34063002).

Recent identification of a hypomorphic allele, c.854T>G (p.Met285Arg), in trans with a frameshift variant, expands the mutational and phenotypic spectrum; patients exhibit preserved retinal sensitivity but progressive ellipsoid zone disruption (PMID:38454848).

Overall, extensive genetic and experimental data establish a Definitive association between KCNV2 and cone dystrophy with supernormal rod response. Clinical diagnosis is supported by characteristic ERG findings and genetic testing for KCNV2 variants. Early molecular confirmation enables accurate prognosis, carrier screening and consideration of future gene-targeted therapies.

References

• American Journal of Human Genetics • 2006 • Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause "cone dystrophy with supernormal rod electroretinogram" in humans PMID:16909397
• Investigative Ophthalmology & Visual Science • 2008 • Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2 PMID:18235024
• Human Mutation • 2011 • Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response PMID:21882291
• International Journal of Molecular Sciences • 2021 • Molecular, Cellular and Functional Changes in the Retinas of Young Adult Mice Lacking the Voltage-Gated K+ Channel Subunits Kv8.2 and K2.1 PMID:34063002
• Ophthalmic Genetics • 2024 • Structural and functional characterization of an individual with the M285R KCNV2 hypomorphic allele PMID:38454848

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