Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients

Sengillo, Jesse D.; Cabral, Thiago; Schuerch, Kaspar; Duong, Jimmy; Lee, Winston; Boudreault, Katherine; Xu, Yu; Justus, Sally; Sparrow, Janet R.; Mahajan, Vinit B.; Tsang, Stephen H.

doi:10.1038/s41598-017-11679-y

Cited by 30 publications

(25 citation statements)

References 49 publications

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“…In both ush2a mutants, however, we observed impaired ERGs at 5 dpf, which is suggestive of early-onset cone dysfunction. Although ERG data of pre-symptomatic patients are typically not available, a recent study demonstrated markedly reduced ERG responses for both rods and cones in adolescent Usher syndrome type 2a patients (Sengillo et al, 2017), consistent with our observations of cone defects by the onset of vision in zebrafish ush2a mutants. Furthermore, USH2A -associated retinal degeneration in humans has a slow, progressive pathology.…”

Section: Discussionsupporting

confidence: 90%

Usherin defects lead to early-onset retinal dysfunction in zebrafish

Dona

Slijkerman

Lerner

et al. 2018

Experimental Eye Research

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Mutations in USH2A are the most frequent cause of Usher syndrome and autosomal recessive nonsyndromic retinitis pigmentosa. To unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration and to evaluate future therapeutic strategies that could potentially halt the progression of this devastating disorder, an animal model is needed. The available Ush2a knock-out mouse model does not mimic the human phenotype, because it presents with only a mild and late-onset retinal degeneration. Using CRISPR/Cas9-technology, we introduced protein-truncating germline lesions into the zebrafish ush2a gene (ush2a: c.2337_2342delinsAC; p.Cys780GlnfsTer32 and ush2a: c.15520_15523delinsTG; p.Ala5174fsTer). Homozygous mutants were viable and displayed no obvious morphological or developmental defects. Immunohistochemical analyses with antibodies recognizing the N- or C-terminal region of the ush2a-encoded protein, usherin, demonstrated complete absence of usherin in photoreceptors of ush2a, but presence of the ectodomain of usherin at the periciliary membrane of ush2a-derived photoreceptors. Furthermore, defects of usherin led to a reduction in localization of USH2 complex members, whirlin and Adgrv1, at the photoreceptor periciliary membrane of both mutants. Significantly elevated levels of apoptotic photoreceptors could be observed in both mutants when kept under constant bright illumination for three days. Electroretinogram (ERG) recordings revealed a significant and similar decrease in both a- and b-wave amplitudes in ush2a as well as ush2a larvae as compared to strain- and age-matched wild-type larvae. In conclusion, this study shows that mutant ush2a zebrafish models present with early-onset retinal dysfunction that is exacerbated by light exposure. These models provide a better understanding of the pathophysiology underlying USH2A-associated RP and a unique opportunity to evaluate future therapeutic strategies.

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Section: Discussionsupporting

confidence: 90%

Usherin defects lead to early-onset retinal dysfunction in zebrafish

Dona

Slijkerman

Lerner

et al. 2018

Experimental Eye Research

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“… 13 As anticipated in a rod-cone dystrophy, cone responses to LA 3.0 flicker ERG were less affected and remained measurable in the majority of participants at all ages. Similar to other studies, 16 the ARRP group had significantly larger LA 3.0 flicker ERG amplitudes than the USH2 group despite being older on average. In a multivariate analysis, no participant characteristic other than clinical diagnosis was associated with LA 3.0 flicker ERG amplitude.…”

Section: Discussionsupporting

confidence: 88%

The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline

Birch

Cheng

Duncan

et al. 2020

Trans. Vis. Sci. Tech.

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Purpose The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 ( USH2A )-related Retinal Degeneration (RUSH2A) multicenter study. Methods Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models. Results In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P = 0.001), and higher (white, blue, and red) FST thresholds (means [−26, −31, −23 dB] vs. [−39, −45, −28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated ( P = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders ( P = 0.04) and duration of visual loss ( P < 0.001) also were associated with FST white stimulus. Conclusions USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression. Translational Relevance Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.

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“…Of note, the USH2A patient cohort included patients with both arRP and Usher syndrome type 2. The findings of a previous study, which suggest that cone function as measured by 30 Hz ERG is higher in non-syndromic as compared to syndromic USH2A patients 19 , may account for Sandberg et al .’s observation that the loss of 30 Hz ERG function was faster in USH2A patients compared to RPGR .…”

Section: Discussionmentioning

confidence: 81%

Multimodal structural disease progression of retinitis pigmentosa according to mode of inheritance

Jauregui

Takahashi

Park

et al. 2019

Sci Rep

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We analyze disease progression in retinitis pigmentosa (RP) according to mode of inheritance by quantifying the progressive decrease of the ellipsoid zone (EZ) line width on spectral domain optical coherence tomography (SD-OCT) and of the dimensions of the hyperautofluorescent ring on short-wave fundus autofluorescence (SW-FAF). In this retrospective study of 96 patients, average follow-up time was 3.2 ± 1.9 years. EZ line width declined at a rate of −123 ± 8 µm per year, while the horizontal diameter and ring area declined at rates of −131 ± 9 µm and −0.5 ± 0.05 mm 2 per year, respectively. Disease progression was found to be slowest for autosomal dominant RP and fastest for X-linked RP, with autosomal recessive RP progression rates between those of adRP and XLRP. EZ line width and ring diameter rates of disease progression were significantly different between each mode of inheritance. By using EZ line width and horizontal diameter as parameters of disease progression, our results confirm that adRP is the slowest progressing form of RP while XLRP is the fastest. Furthermore, the reported rates can serve as benchmarks for investigators of future clinical trials for RP and its different modes of inheritance.

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Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients

Cited by 30 publications

References 49 publications

Usherin defects lead to early-onset retinal dysfunction in zebrafish

Usherin defects lead to early-onset retinal dysfunction in zebrafish

The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline

Multimodal structural disease progression of retinitis pigmentosa according to mode of inheritance

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