ZFIN ID: ZDB-PUB-200131-7
Clinical and preclinical therapeutic outcome metrics for USH2A-related disease
Toms, M., Dubis, A.M., de Vrieze, E., Tracey-White, D., Mitsios, A., Hayes, M., Broekman, S., Baxendale, S., Utoomprurkporn, N., Bamiou, D., Bitner-Glindzicz, M., Webster, A.R., Van Wijk, E., Moosajee, M.
Date: 2020
Source: Human molecular genetics   29(11): 1882-1899 (Journal)
Registered Authors: Baxendale, Sarah, de Vrieze, Erik, van Wijk, Erwin
Keywords: none
MeSH Terms:
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Autophagy/genetics
  • Disease Models, Animal
  • Electroretinography
  • Extracellular Matrix Proteins/genetics*
  • Female
  • Genetic Association Studies
  • Genotype
  • Hearing Loss, Sensorineural/genetics*
  • Hearing Loss, Sensorineural/physiopathology
  • Humans
  • Male
  • Middle Aged
  • Mutation/genetics
  • Opsins/genetics
  • Retina/diagnostic imaging
  • Retina/metabolism
  • Retina/physiopathology*
  • Retinal Cone Photoreceptor Cells/metabolism
  • Retinal Cone Photoreceptor Cells/pathology
  • Retinitis Pigmentosa/genetics*
  • Retinitis Pigmentosa/physiopathology
  • Rhodopsin/genetics
  • Rod Opsins/genetics
  • Usher Syndromes/diagnostic imaging
  • Usher Syndromes/genetics*
  • Usher Syndromes/pathology
  • Visual Acuity/genetics
  • Visual Acuity/physiology
  • Young Adult
  • Zebrafish/genetics
PubMed: 31998945 Full text @ Hum. Mol. Genet.
USH2A variants are the most common cause of Usher syndrome type 2, characterised 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 mislocalisation from 6-12 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 mislocalisation with elevated autophagy levels at 6 days post fertilisation indicating a more severe genotype-phenotype correlation, and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.