TY - JOUR
T1 - The role of the voltage-gated potassium channel proteins Kv8.2 and Kv2.1 in vision and retinal disease
T2 - Insights from the study of mouse gene knock-out mutations
AU - Hart, Nathan S.
AU - Mountford, Jessica K.
AU - Voigt, Valentina
AU - Fuller-Carter, Paula
AU - Barth, Melanie
AU - Nerbonne, Jeanne M.
AU - Hunt, David M.
AU - Carvalho, Livia S.
N1 - Publisher Copyright:
© 2019 Hart et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Mutations in the KCNV2 gene, which encodes the voltage-gated K + channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K + channels in the generation of the a-, b-, and c-wave components of the ERG.
AB - Mutations in the KCNV2 gene, which encodes the voltage-gated K + channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K + channels in the generation of the a-, b-, and c-wave components of the ERG.
KW - Cone dystrophy
KW - Electroretinogram
KW - Photoreceptors
KW - Potassium channels
KW - Retina
KW - Retinal degeneration
UR - http://www.scopus.com/inward/record.url?scp=85064114373&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0032-19.2019
DO - 10.1523/ENEURO.0032-19.2019
M3 - Article
C2 - 30820446
AN - SCOPUS:85064114373
SN - 2373-2822
VL - 6
JO - eNeuro
JF - eNeuro
IS - 1
M1 - e0032-19.2019
ER -