Mutations in the Gene KCNV2 Encoding a Voltage-Gated Potassium Channel Subunit Cause “Cone Dystrophy with Supernormal Rod Electroretinogram” in Humans

Abstract

"Cone dystrophy with supernormal rod electroretinogram (ERG)" is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. We have linked the disorder to a 0.98-cM (1.5-Mb) region on chromosome 9p24, flanked by rs1112534 and rs1074449, using homozygosity mapping in one large consanguineous pedigree. Analysis of one gene within this region, KCNV2, showed a homozygous nonsense mutation. Mutations were also found in 17 alleles of 10 other unrelated families with the same disorder. In situ hybridization demonstrated KCNV2 expression in human rod and cone photoreceptors. The precise function of KCNV2 in human photoreceptors remains to be determined, although this work suggests that mutations might perturb or abrogate I(KX), the potassium current within vertebrate photoreceptor inner segments, which has been shown to set their resting potential and voltage response.

Cytochrome P450 2C Epoxygenases Mediate Photochemical Stress-induced Death of Photoreceptors

“…Loss-of-function mutations in the PDE6 allele in rd1 mice induce apoptosis in rods starting at early postnatal days (P10) due to Ca 2ϩ overload via the cyclic nucleotide-gated channels (37,38). A homozygous nonsense mutation in the voltage-gated K ϩ channel subunit is genetically linked to human cone dystrophy (39). The mutually inclusive interaction between Ca 2ϩ and K ϩ is reiterated in isolated mouse retina in which a high K ϩ -induced depolarization of rods evokes Ca 2ϩ influx (40).…”

Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons

“…The heterotetramerization of K v 2 with silent subunits increases the functional diversity, which may reflect specific functions for these heterotetrameric channel complexes. For example, heterotetrameric K v 2.1 channels containing K v 9.3 subunits are involved in hypoxic pulmonary artery vasoconstriction (22), coassembly of K v 2.1 with K v 5.1 and K v 6 subunits shapes I K in smooth muscle of the mouse urinary bladder (34), and K v 8.2 subunits are involved in photoreception of the retina (41). In rat DRG neurons, both K v 2.1 and K v 2.2 have been shown to be well expressed (10,12).…”

The Retinal Clock Drives the Expression ofKcnv2, a Channel Essential for Visual Function and Cone Survival

“…1 These underlie the neuronal delayed rectifier potassium current, which is important for limiting membrane excitability. 2,3 Kv8.2 and Kv2.1 are coexpressed in the inner segment of rods and cones of the mouse 2 and human 4 retina, where they are involved in the exceptional electrical response system of photoreceptor cells 5 and, in this way, contribute to photoreception and visual function. In particular, Kv8.2/Kv2.1 channels appear to underlie the voltage-dependent potassium current 2 that is responsible for the transient over-hyperpolarization in response to rapid onset illumination.…”

“…39 Mutations in the Kcnv2 gene underlie the retinal disorder CDSRR, which is associated with altered ERG responses of cones and rods. 4,7,8,40 Although the mechanisms of dysfunction that link Kcnv2 mutations with the clinical picture of CDSRR are largely unknown, it is thought that mutations of the Kcnv2 gene may prohibit the formation of any voltage-gated potassium channels or result in pure homomeric Kv2.1 channels that lack the functional tuning of the Kv8.2 subunit for proper native function in photoreceptor cells. 4,9 However, the phenotype of CDSRR indicates an essential role of the Kcnv2 gene in photoreception and visual function.…”

“…4,7,8,40 Although the mechanisms of dysfunction that link Kcnv2 mutations with the clinical picture of CDSRR are largely unknown, it is thought that mutations of the Kcnv2 gene may prohibit the formation of any voltage-gated potassium channels or result in pure homomeric Kv2.1 channels that lack the functional tuning of the Kv8.2 subunit for proper native function in photoreceptor cells. 4,9 However, the phenotype of CDSRR indicates an essential role of the Kcnv2 gene in photoreception and visual function. Therefore, the presently seen daily regulation of the Kcnv2 gene appears to promote 24-hour variations in visual function and thus to contribute to the known daily changes of visual function seen in ERG.…”