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D. Raz, R. Ayyagari, R.N. Fariss, M.A. Mandal, V. Vasireddy, A.L. Webber, R.A. Bush, N. Salem, Jr., K. Petrukhin, P.A. Sieving; Haploinsufficiency Is Not the Key Mechanism of Pathogenesis in a Heterozygous Elovl4 Knockout Mouse Model of STGD3 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5779.
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© ARVO (1962-2015); The Authors (2016-present)
Autosomal dominant Stargardt disease (STGD) results from deletion mutations in the ELOVL4 gene (ELOngation of Very Long chain fatty acids). We characterized a mouse model with a targeted deletion of Elovl4 to explore the role of this gene in retinal/macular degeneration.
Sixteen month old heterozygous knockout Elovl4 (Elovl4+/–) and littermate wild type (WT) control mice were characterized by examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition.
Elovl4 RNA was reduced to 25% of control levels (p= 0.009) and ELOVL4 protein was also markedly reduced in Elovl4+/– retinas. However, these changes were disproportionate to the minimal abnormalities in Elovl4+/– retinas compared to WT controls. Rod outer segment length was 20±18% lower (p<0.01) in Elovl4+/– retinas, but morphology was otherwise mostly unremarkable and retinal (ERG) function was essentially normal. Systemic fatty acid profiles of Elovl4+/– mice were unremarkable although several fatty acids had a significantly lower concentration in Elovl4+/– retinas, particularly the monounsaturated fatty acids.
The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models which will help elucidate the disease mechanism.
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