Background Truncation mutations in the elongation of very long chain fatty acids-4 (AF277094, MIM #605512) (ELOVL4) gene cause Stargardt-like macular dystrophy type 3 (STGD3). Mice expressing truncated ELOVL4 develop rapid retinal degeneration, but are poor STGD3 models since mice lack a macula. Photoreceptor topography in the pig retina is more similar to that in humans as it includes the cone rich, macula-like area centralis. The authors generated transgenic pigs expressing human disease-causing ELOVL4 mutations to better model the pathobiology of this macular disease.
Methods Pronuclear DNA microinjection and somatic cell nuclear transfer were used to produce transgenic pigs for two different ELOVL4 mutations: the 5 base pair deletion (5 bpdel) and the 270 stop mutation (Y270terEYFP). Retinal transgene expression, morphology and electrophysiology were examined.
Results The authors obtained four lines of Y270terEYFP and one line of 5 bpdel transgenic animals. Direct fluorescence microscopy indicated that the Y270terEYFP protein is expressed in photoreceptors and mislocalised within the cell. Immunohistochemical examination of transgenic pigs showed photoreceptor loss and disorganised inner and outer segments. Electroretinography demonstrated diminished responses in both transgenic models.
Conclusions These transgenic pigs provide unique animal models for examining macular degeneration and STGD3 pathogenesis.
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Funding The authors acknowledge funding support to KZ: National Basic Research Program of China (973 Program, No.2011CB510200), Chinese National 985 Project to Sichuan University and West China Hospital, NEI/NIH (RO1 EY014428, EY018660, EY019270), Research to Prevent Blindness, VA Merit Award, Macula Vision Research Foundation, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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