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.
Highlights
In 1983 Gouras et al [1] reported an unusual type of retinal dystrophy, which was associated with characteristic alterations in the rod electroretinogram (ERG)
We observed compound heterozygous mutations in the two sib pairs (CHRO8.I and CHRO8.II, and BD27.I and BD27.II): both patients from family CHRO8 carried two compound heterozygous nonsense mutations p.Cys113stop and p.Glu148stop, while both patients of family BD27 were compound heterozygous for a complete deletion of the KCNV2 gene and a missense mutation p.Leu404Pro located in the linker between transmembrane domains S4 and S5
Previous clinical data have indicated that both the complete absence of Kv8.2 and its altered forms result in cone dystrophy with supernormal rod responses (CDSRR) [10], which suggests that the special constellation of Kv2.1/Kv8.2 heteromeric channels are essential for functionality in the photoreceptor cells
Summary
In 1983 Gouras et al [1] reported an unusual type of retinal dystrophy, which was associated with characteristic alterations in the rod electroretinogram (ERG). In contrast to other cone dystrophies, a disease-typical alteration of the rod system could be observed: while rod sensitivity to weak flashes was reduced, an augmented responsiveness to higher levels of flash stimuli could be detected, and implicit times were considerably prolonged [1,2,3,4,5,6,7,8,9]. These characteristics were unique for CDSRR, the underlying disease mechanism could not be elucidated at that time. To investigate rod and cone function and disease mechanisms in patients with KCNV2 retinopathy
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