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Rong Wen, Byron L Lam, Ziqiang Guan, Zhengying Wang, Ning Wang, Yihui Chen, Yiwen Li; Abnormal synaptic transmission between photoreceptors and bipolar cells in DHDDSK42E/K42E mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):716.
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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.
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.
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.
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.
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