Abstract
USH2A variants are the most common cause of Usher syndrome type 2, characterized by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development; however, sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, we have performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalization from 6 to 12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalization with elevated autophagy levels at 6 days post fertilization, indicating a more severe genotype-phenotype correlation and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.
Highlights
Usher syndrome, characterised by combined sensorineural hearing loss and retinitis pigmentosa (RP), is the most common cause of deaf-blindness worldwide [1, 2]
We have explored the long-term USH2A pathophysiology in humans and examined the molecular defects underlying USH2A-associated retinal degeneration in a novel zebrafish mutant and the previously published ush2armc1 mutant, to further improve our understanding of the molecular pathology underlying the disease and to identify potential outcome measures for assaying a response to emerging therapeutics in both preclinical and clinical studies
Western blot analysis revealed increased levels of lipidated autophagosomal membrane protein LC3 (LC3 II), p62/SQSTM and beclin 1 in ush2armc1 larvae both before and after onset of light (Figure 10D). This is the first longitudinal study for Usher syndrome type II describing the retinal changes in a large USH2A patient cohort, and comparing it to ush2a zebrafish models to identify reliable therapeutic outcome measures for both preclinical and clinical studies
Summary
Usher syndrome, characterised by combined sensorineural hearing loss and retinitis pigmentosa (RP), is the most common cause of deaf-blindness worldwide [1, 2]. Three clinical types (Usher syndrome type 1, 2 and 3) can be distinguished based on the severity and progression of the hearing loss and presence or absence of vestibular dysfunction, with type 1 being the most severe and type 2 (USH2) being the most frequent [2]. Mutations in USH2A (MIM #608400) are the most frequent cause of Usher syndrome, accounting for up to 85% of USH2 cases, as well as causing up to 23% of nonsyndromic autosomal recessive RP [3]. USH2A encodes usherin, a 5202 amino acid (aa) transmembrane protein with domains common to extracellular matrix proteins and cell adhesion proteins, including several predicted laminin domains and fibronectin III repeats. A short secreted isoform of 1546 aa in size is expressed in various tissues, including intestine and testis, but the full-length protein is thought to be predominantly expressed in the retina and cochlea [7, 8]
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