Rod and Cone Function in Patients with KCNV2 Retinopathy

Abstract

BackgroundTo investigate rod and cone function and disease mechanisms in patients with KCNV2 retinopathy.Methodology/Principal FindingsPsychophysical examinations as well as detailed electrophysiological examinations with Ganzfeld and multifocal electroretinogram (ERG) were performed to study response dynamics. Additionally, fundus photography, autofluorescence imaging and spectral domain OCTs were carried out for morphological characterization. Molecular genetic analysis revealed compound heterozygosity in five patients and homozygosity for the KCNV2 gene in one patient. The mutations resulted in complete absence of Kv8.2 subunits in three patients (no protein group, NOP), while the other three patients expressed mutant Kv8.2 subunits resulting in altered Kv2.1/Kv8.2 heteromeric or residual Kv2.1 homomeric potassium channel function (altered protein group, ALP). Although more advanced morphological changes were visible in the NOP group, a clear functional difference between the two groups could not be observed. All patients showed characteristic dynamics of the b-wave intensity-response function, however, scotopic b-wave response amplitudes were within normal limits. We also observed severely reduced oscillatory potentials.Conclusions/SignificanceA specific genotype-phenotype correlation in retinal function could not be demonstrated. KCNV2 mutations cause a unique form of retinal disorder illustrating the importance of K+-channels for the resting potential, activation and deactivation of photoreceptors, while phototransduction remains unchanged. The reduced oscillatory potentials further suggest an altered function of the inner retina. Besides the characteristically steep amplitude-versus-intensity relationship, flicker responses at intermediate frequencies (5–15 Hz) are significantly reduced and shifted in phase.

Achromatopsia: On the Doorstep of a Possible Therapy

“…Although the retinal structure seems to show great variability and a slow progressive cone loss has been suggested [12,13,14,33,35,36,37,38,39], no clear association between retinal structure and function could be described [12]. Therefore, ACHM can be best described as a functionally stationary disorder with slow degeneration of cone photoreceptors.…”

“…These differential diagnoses include blue-cone monochromatism, KCNV2 retinopathy, oligocone trichromacy, hereditary green-red color vision defects, and cone dystrophies [2,35,36]. …”

Heteromeric KV2/KV8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors

“…K V 8.2 is the only silent subunit that has thus far been implicated in human disease. Variants/mutations in the gene that encodes this protein, KCNV2, have been implicated in epilepsy susceptibility (Jorge et al, 2011), as well as in an inherited photoreceptor dystrophy known as "cone-dystrophy with supernormal rod response" (Wu et al, 2006;Wissinger et al, 2008Zelinger et al, 2013). The photoreceptor dystrophy causes re-duced visual acuity, photophobia, color vision deficits, and variable loss of night vision (Gouras et al, 1983).…”

“…Indeed, in expression systems, K V 2.1/K V 8.2 heteromers exhibit more hyperpolarized activation potentials, show less inactivation, and have lower current densities than homomeric K V 2.1 channels (Czirják et al, 2007;. Although K V 2.1 and K V 8.2 genes are expressed in human and rodent outer retina (Wu et al, 2006;Czirják et al, 2007), the localization of the proteins remains unclear (Pinto and Klumpp, 1998;Aslanidis et al, 2014). Moreover, to our knowledge, interactions between K V 2 and K V 8.2 subunits have not yet been demonstrated in any native tissue.…”

“…In darkness, photoreceptors are tonically depolarized by a "dark current" mediated by cGMP-gated cation channels in the outer segment. This inward dark current is balanced by a noninactivating delayed rectifier K V current in the inner segment, dubbed I Kx (Beech and Barnes, 1989;Yan and Matthews, 1992), which stabilizes the resting potential at ϳϪ40 mV (Schneeweis and Schnapf, 1995). Upon light stimulation, the photoreceptors hyperpolarize and the K V current shuts off with some delay, leading to a delayed depolarizing phase that renders the photoreceptor voltage response more transient and bandpass filtered.…”