Haploinsufficiency Is Not the Key Mechanism of Pathogenesis in a Heterozygous Elovl4 Knockout Mouse Model of STGD3

Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: retinal degenerations: hereditary • transgenics/knock-outs