Abstract
Mutations in the elongation of very long chain fatty acid 4 (ELOVL4) gene cause Stargardt macular dystrophy 3 (STGD3), a rare, juvenile-onset, autosomal dominant form of macular degeneration. Although several mouse models have already been generated to investigate the link between the three identified disease-causing mutations in the ELOVL4 gene, none of these models recapitulates the early-onset cone photoreceptor cell death observed in the macula of STGD3 patients. To address this specifically, we investigated the effect of mutant ELOVL4 in a mouse model with an all-cone retina. Hence, we bred mice carrying the heterozygously mutated Elovl4 gene on the R91W;Nrl-/- all-cone background and analyzed the retinal lipid composition, morphology, and function over the course of 1 year. We observed a reduction of total phosphatidylcholine-containing very long chain-polyunsaturated fatty acids (PC-VLC-PUFAs) by 39% in the R91W;Nrl-/-;Elovl4 mice already at 6 weeks of age with a pronounced decline of the longest forms of PC-VLC-PUFAs. Total levels of shorter-chain fatty acids (< C26) remained unaffected. However, this reduction in PC-VLC-PUFA content in the all-cone retina had no impact on morphology or function and did not accelerate retinal degeneration in the R91W;Nrl-/-;Elovl4 mice. Taken together, mutations in the ELOVL4 gene lead to cone degeneration in humans, whereas mouse models expressing the mutant Elovl4 show predominant rod degeneration. The lack of a phenotype in the all-cone retina expressing the mutant form of the protein supports the view that aberrant function of ELOVL4 is especially detrimental for rods in mice and suggests a more subtle role of VLC-PUFAs for cone maintenance and survival.
Highlights
Stargardt-3 (STGD3, OMIM #600110) is an early onset, autosomal dominant macular degenerative disease caused by mutations in the ELOVL4 that lead to C-terminal truncation of the ELOVL4 protein [1,2,3,4]
Several mouse models have been generated to investigate the link between disease causing mutations in the Elovl4 gene and macular degeneration that characterizes Stargardt macular dystrophy 3 (STGD3) pathophysiology [33,34,35,37]
None of these models showed the early onset cone PR degeneration observed in STGD3 patients but rather had rod PR cells affected
Summary
Stargardt-3 (STGD3, OMIM #600110) is an early onset, autosomal dominant macular degenerative disease caused by mutations in the ELOVL4 that lead to C-terminal truncation of the ELOVL4 protein [1,2,3,4]. STGD3 affects mostly cones, leads to loss of central vision, decreased visual acuity and extensive formation of fundus flecks [5,6] These clinical features are similar to other maculopathies like Stargardt-1 (STGD1) [7] and agerelated macular degeneration (AMD) [8]. Three independent mutations in the last exon (exon 6) of the ELOVL4 gene have been linked to STGD3 disease in humans [1,3,13,14] These mutations do not affect the catalytic domain but lead to loss of function due to mislocalization of the mutant protein lacking the C-terminal ER retention signal [1,15]. Mislocalized mutant ELOVL4 protein has a dominant-negative effect on the localization of wild-type (wt) ELOVL4 potentially by protein aggregation [15,16,17,18]
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