Photoreceptor degeneration in the DHDDS^K42E/K42E mouse

Abstract

Purpose: Transgenic DHDDS^K42E/K42E mice were created to reconstruct the genotype of a human mutation recently identified in the DHDDS mice gene encoding dehydrodolichol diphosphate synthase (DHDDS). This mutation 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 the retinal degeneration in the DHDDS^K42E/K42E mice.

Methods: Transgenic mice with DHDDS^K42E genotype were created by the knock-in (KI) technology and bred into homozygosity. Animals were kept in <50 lux 12:12 cyclic light. Eyes were collected from 3 month old animals, embedded in an Epon/Araldite mixture, and sectioned at 1 µm thickness to display the entire retina along the vertical meridian. Retinal sections were examined by light microscopy.

Results: The DHDDS^K42E/K42E genotype was confirmed by PCR. A characteristic shortening of dolichol length distribution, similar to the shortening in patients, was found in plasma dolichols by liquid chromatography-mass spectrometry. In the 3 months DHDDS^K42E/K42E mice, the outer segments (OS) of rod photoreceptors reduced to about half of the length seen in the age matched wild-type (wt) animals. In addition, the outer nuclear layer (ONL) thickness decreased to two-thirds compared to that of the wt controls.

Conclusions: The DHDDS^K42E/K42E mice recapitulate the phenotype of retinal degeneration in patients and are a viable model of arRP caused by the K42E DHDDS mutation.

Keywords: 695 retinal degenerations: cell biology • 696 retinal degenerations: hereditary • 648 photoreceptors