Functional Analysis of Missense Mutations in Kv8.2 Causing Cone Dystrophy with Supernormal Rod Electroretinogram

Smith, Katie E.; Wilkie, Susan E.; Tebbs-Warner, Joseph T.; Jarvis, Bradley J.; Gallasch, Linn; Stocker, Martin; Hunt, David M.

doi:10.1074/jbc.m112.388033

Cited by 19 publications

(29 citation statements)

References 57 publications

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“…CDSR-causing Kv8.2 mutations include (a) nucleotide changes that result in amino acid substitutions and protein truncations, (b) small in-frame insertions and deletions, (c) nucleotide insertions and deletions generating frameshifts that lead to protein truncations, and (d) whole gene loss ( Wu et al, 2006 ; Thiagalingam et al, 2007 ; Ben Salah et al, 2008 ; Wissinger et al, 2008 , 2011 ; Robson et al, 2010 ; Friedburg et al, 2011 ; Sergouniotis et al, 2012 ; Zobor et al, 2012 ; Fujinami et al, 2013 ; Vincent et al, 2013 ). Several of the N-terminal amino acid substitutions implicated in CDSR prevent the interaction of Kv8.2 with Kv2.1 in heterotetrameric channels ( Wissinger et al, 2011 ; Smith et al, 2012 ). Moreover, amino acid substitutions in the Kv8.2 pore region led to the generation of nonconducting Kv2.1/Kv8.2 heterotetramers ( Smith et al, 2012 ).…”

Section: Eyementioning

confidence: 99%

“…Several of the N-terminal amino acid substitutions implicated in CDSR prevent the interaction of Kv8.2 with Kv2.1 in heterotetrameric channels ( Wissinger et al, 2011 ; Smith et al, 2012 ). Moreover, amino acid substitutions in the Kv8.2 pore region led to the generation of nonconducting Kv2.1/Kv8.2 heterotetramers ( Smith et al, 2012 ). These findings suggest that the CDSR phenotype arises through the loss of functional Kv2.1/Kv8.2 heterotetramers reached by different mechanisms.…”

Section: Eyementioning

confidence: 99%

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Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders

Bocksteins

2016

Journal of General Physiology

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Members of the electrically silent voltage-gated K+ (Kv) subfamilies (Kv5, Kv6, Kv8, and Kv9, collectively identified as electrically silent voltage-gated K+ channel [KvS] subunits) do not form functional homotetrameric channels but assemble with Kv2 subunits into heterotetrameric Kv2/KvS channels with unique biophysical properties. Unlike the ubiquitously expressed Kv2 subunits, KvS subunits show a more restricted expression. This raises the possibility that Kv2/KvS heterotetramers have tissue-specific functions, making them potential targets for the development of novel therapeutic strategies. Here, I provide an overview of the expression of KvS subunits in different tissues and discuss their proposed role in various physiological and pathophysiological processes. This overview demonstrates the importance of KvS subunits and Kv2/KvS heterotetramers in vivo and the importance of considering KvS subunits and Kv2/KvS heterotetramers in the development of novel treatments.

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Section: Eyementioning

confidence: 99%

Section: Eyementioning

confidence: 99%

Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders

Bocksteins

2016

Journal of General Physiology

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“…More than 37 different KCNV2 mutations have now been identified (Gouras et al, 1983; Sandberg et al, 1990; Kato et al, 1993; Rosenberg and Simonsen, 1993; Hood et al, 1996; Michaelides et al, 2005; Wu et al, 2006; Thiagalingam et al, 2007; Ben Salah et al, 2008; Wissinger et al, 2008; Robson et al, 2010; Fujinami et al, 2013), which include missense, nonsense and deletion changes. In all cases, the disorder arises either from the absence of Kv8.2 subunits or, depending on the particular amino acid substitution, from mutant subunits that either fail to be transported to the cell membrane or form non-functional channels (Smith et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Voltage-Gated Potassium Channel Proteins Kv8.2 and Kv2.1 in Vision and Retinal Disease: Insights from the Study of Mouse Gene Knock-Out Mutations

Hart

Mountford

Voigt

et al. 2019

eNeuro

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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.

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“…Certain K v or K ir (e.g. K v 8.1 or K ir 5.1) subunits cannot form functional homomers on their own; however, via heteromerization they can also gain important physiological function (1); deletion or mutations of their genes have been associated with genetic diseases and pathophysiological conditions (2)(3)(4).…”

mentioning

confidence: 99%