Abstract
Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans.
Highlights
First reported in 1983 [1], Cone Dystrophy with Supernormal Rod Response (CDSRR, OMIM 610356) is an inherited autosomal recessive disease that causes lifelong visual loss.A previous study by our group [2] was the first to demonstrate that CDSRR is caused by homozygous or compound heterozygous mutations in the KCNV2 (Potassium VoltageGated Channel Modifier Subfamily V Member 2) gene encoding the voltage-gated K+channel protein subunit Kv8.2
The staining of retinal sections with Kv subunit antibodies showed that both Kv8.2 and Kv2.1 subunits were highly expressed in the wild type (WT) photoreceptor outer/inner segment (OS/IS) layers as reported previously [14] (Figure 1A)
Kv8.2 subunits were completely absent from Kv2.1 KO retinas (Figure 1C), suggesting that the presence of the Kv2.1 subunit is essential for channel assembly and subunit retention as previously suggested by us [18] and others [11]
Summary
First reported in 1983 [1], Cone Dystrophy with Supernormal Rod Response (CDSRR, OMIM 610356) is an inherited autosomal recessive disease that causes lifelong visual loss.A previous study by our group [2] was the first to demonstrate that CDSRR is caused by homozygous or compound heterozygous mutations in the KCNV2 (Potassium VoltageGated Channel Modifier Subfamily V Member 2) gene encoding the voltage-gated K+channel protein subunit Kv8.2. First reported in 1983 [1], Cone Dystrophy with Supernormal Rod Response (CDSRR, OMIM 610356) is an inherited autosomal recessive disease that causes lifelong visual loss. A previous study by our group [2] was the first to demonstrate that CDSRR is caused by homozygous or compound heterozygous mutations in the KCNV2 (Potassium VoltageGated Channel Modifier Subfamily V Member 2) gene encoding the voltage-gated K+. 40 disease-causing mutations in KCNV2 [3,4,5,6] This dystrophy affects the light-sensing rod and cone photoreceptors in the retina and is characterized by reduced visual acuity, photophobia and abnormal color vision that begins in early childhood and deteriorates rapidly by the second decade of life [1,2,7]. Unlike other cone-rod retinal dystrophies, CDSRR patients present with a supernormal rod ERG response to bright flashes; the rod a-wave response remains reduced and delayed, whereas the rod b-wave becomes supernormal in amplitude under high intensity light stimulus [8,9]
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