Abstract
Purpose:
We recently identified a single-nucleotide mutation c.124A>G in the DHDDS gene encoding dehydrodolichol diphosphate synthase (DHDDS), which changes a highly conserved Lys42 to Glu and is responsible for 12% of autosomal recessive RP (arRP) cases in patients of Ashkenazi Jewish (AJ) origin. The present work characterizes electrophysiological changes in recently created DHDDSK42E/K42E mice.
Methods:
Transgenic mice with DHDDSK42E genotype were created by the knock-in (KI) technology and bred into homozygosity. Lipids were extracted from plasma and dolichols were measured by liquid chromatography-mass spectrometry (LC-MS). Scotopic full-field ERGs were recorded from 3 month old DHDDSK42E/K42E mice and compared to age-matched wild-type (wt) animals.
Results:
The DHDDSK42E/K42E genotype was confirmed by PCR. A characteristic shortening of dolichol length distribution was found in the plasma of DHDDSK42E/K42E mice, similar to what was found in patients. Dolichol 17 (D17) became the dominant species in the mutant mice instead of dolichol 18 (D18) in wt animals. As a result, the DHDDSK42E/K42E mice have much higher plasma D17/D18 ratio. The ERG a-wave in the DHDDSK42E/K42E mice was smaller than a-wave of the wt controls, and the b-wave was disproportionally smaller with the b- to a-wave amplitude ratio being close to 1. In contrast, the ratio was more than 2 in the wt controls.
Conclusions:
These results indicate that abnormal dolichol biosynthesis by the K42E DHDDS mutation leads to impaired synaptic transmission between photoreceptors and bipolar cells. Previous studies using artificial membrane suggest a potential role of dolichols in facilitating vesicle fusion. Our results provide the first in vivo evidence supporting a biological function of free dolichols in the activities of synaptic vesicles.
Keywords: 695 retinal degenerations: cell biology •
510 electroretinography: non-clinical •
696 retinal degenerations: hereditary