Abstract
Purpose :
RP59 (OMIM# 613861) is caused by mutations in the dehydrodolichyl diphosphate synthase (DHDDS) gene. We previously reported that knock-in mice with K42E and T206A DHDDS mutations do not exhibit overt retinal degeneration, but exhibit a “negative ERG” [normal a-wave and reduced (scotopic and photopic) b-wave amplitudes]. Here, we describe further characterization of two RP59 mouse models.
Methods :
DhddsT206A/T206A and DhddsT206A/K42E knock-in mice (Nguyen et al., ARVO 2021) vs. age-matched WT (Dhdds+/+) mice were assessed by quantitative retinal morphometry (SD-OCT) and electroretinography (ERG; 500 nm LED stimulus). Visual acuity (VA; spatial frequency) was assessed by OKR under scotopic and photopic conditions. Statistical significance (Student’s t-test) threshold was p≤0.05 (N≥3 SD-OCT, N≥8 ERG, N≥3 OKR).
Results :
From PN 1- to PN 12-mo, neural retina full thickness declined <5% (p≤0.05), while INL thickness declined by 27% in DhddsT206A/T206A and 30% in DhddsT206A/K42E (p≤0.01), vs. WT mice. ERG b-to-a-wave amplitude (b/a) ratios declined (at 3-mo intervals) over the same time. At PN 12-mo: scotopic b/a ratios were reduced by ~25% in DhddsT206A/T206A and by ~35% in DhddsT206A/K42E mice, vs. WT values (p≤0.01). Photopic b/a ratios were also declined by ~33% in DhddsT206A/T206A and by ~41% in DhddsT206A/K42E mice, vs. WT values (p≤0.01). ERG c-wave amplitudes were like WT at PN 6-mo; however, at PN 12-mo, c-wave amplitudes were reduced by ~35% in both mutants, vs. WT mice (p≤0.01), and ERG d-wave amplitudes were reduced by ~35% in DhddsT206A/K42E mice, vs. WT values (p≤0.05). Scotopic VA was reduced by ~15% and ~10%, respectively, in DhddsT206A/T206A and DhddsT206A/K42E mice, and photopic VA was reduced by ~15% and ~20.5%, respectively, in DhddsT206A/T206A and DhddsT206A/K42E mice, vs. WT values.
Conclusions :
These results are consistent with defective rod- and cone-to-bipolar cell synaptic transmission (normal a-wave, reduced b- and d-waves) and compromised RPE and/or Müller cell responses (reduced c-wave) in these Dhdds mouse mutants.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.