Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration

Sommer, Jeffrey R.; Estrada, José L.; Collins, E. B.; Bedell, Matthew; Alexander, C.A.; Yang, Zhenglin; Hughes, Guy; Mir, Bashir Ahmed; Gilger, Brian C.; Grob, Seanna; Wei, Xingmei; Piedrahita, Jorge A.; Shaw, Peter X.; Petters, Robert M.; Zhang, Kang

doi:10.1136/bjophthalmol-2011-300417

Cited by 62 publications

(46 citation statements)

References 26 publications

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“…The current study as well as others (7,31,35) have shown that tagged-MUT is mislocalized in cultured cells. Mislocalization of the tagged-MUT to photoreceptor outer segments and inner retinal layers in transgenic pigs results in aberrations in photoreceptor structure and function (46). However, the effect of MUT on VLC-PUFA synthesis is undefined.…”

Section: Discussionmentioning

confidence: 99%

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.Stargardt disease | condensing enzyme | photoreceptor degeneration

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Section: Discussionmentioning

confidence: 99%

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Logan¹,

Agbaga

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Rodent eyes only remotely resemble human ocular anatomy, but the availability of genetic engineering tools such as transgenic and gene targeting in rodents has made it one of the most popular animal models in ocular research (Grossniklaus et al, 2010;Ou et al, 2010;Ramaesh et al, 2003;Zeiss, 2010). Transgenic rodents play a key role in dissecting the genetic cause of ocular diseases, even when they do not fully recapitulate human conditions, especially macular and fovea functions (Grossniklaus et al, 2010;Lassota, 2008;Sommer et al, 2011). On the other hand, canines with natural retinal degenerative diseases have been successfully used in the development of gene therapy, while transgenic pigs have also been developed because of the similarity in eye size to humans as well as their availability for preclinical trials.…”

Section: A Importance Of the Transgenic Nonhuman Primate Model Of Humentioning

confidence: 98%

Production of Transgenic Nonhuman Primates

Chan

Chong

Schatten

2014

Transgenic Animal Technology

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“…It is caused by truncated mutations in the elongation of very long chain fatty acids-4 (ELOVL4, MIM600110) gene. Two different transgenic pigs have been generated by MI, carrying a 5 base pair deletion or a 270 stop mutation in the ELOVL4 gene (Sommer et al 2011). Both types of ELOVL4 pigs developed similar symptoms (e.g.…”

Section: Eye Diseasesmentioning

confidence: 99%

Genetically modified pigs for biomedical research

Luo

Lin

Bolund

et al. 2012

J of Inher Metab Disea

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During the last two decades, pigs have been used to develop some of the most important large animal models for biomedical research. Advances in pig genome research, genetic modification (GM) of primary pig cells and pig cloning by nuclear transfer, have facilitated the generation of GM pigs for xenotransplantation and various human diseases. This review summarizes the key technologies used for generating GM pigs, including pronuclear microinjection, sperm‐mediated gene transfer, somatic cell nuclear transfer by traditional cloning, and somatic cell nuclear transfer by handmade cloning. Broadly used genetic engineering tools for porcine cells are also discussed. We also summarize the GM pig models that have been generated for xenotransplantation and human disease processes, including neurodegenerative diseases, cardiovascular diseases, eye diseases, bone diseases, cancers and epidermal skin diseases, diabetes mellitus, cystic fibrosis, and inherited metabolic diseases. Thus, this review provides an overview of the progress in GM pig research over the last two decades and perspectives for future development.

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Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration

Abstract: These transgenic pigs provide unique animal models for examining macular degeneration and STGD3 pathogenesis.

Cited by 62 publications

References 26 publications

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Production of Transgenic Nonhuman Primates

Genetically modified pigs for biomedical research

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